KEYNOTE-040 evaluates pembrolizumab in head and neck cancer

Immunotherapy with the checkpoint inhibitor pembrolizumab may be a better option than standard treatments for patients whose head and neck cancer has spread, or recurred after an initial round of chemotherapy, according to results of the Keynote-040 trial presented at the ESMO 2017 Congress in Madrid. (1)

Although the 19% improvement in overall survival among patients treated with pembrolizumab did not meet the prespecified difference for statistical significance, it was nevertheless a clinically meaningful difference for this population who only lived seven to eight months, on average, after initiating treatment, said lead investigator Dr. Ezra Cohen, from the University of California, San Diego Moores Cancer Center, in La Jolla, California.

“Even though the study did not meet its primary endpoint, I still think it is a positive trial,” he said. “It reinforces that pembrolizumab should continue to be offered as an important option for all patients with this devastating disease.”

The KEYNOTE-040 trial was a global, open-label, phase 3 study which included patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) after a platinum-based chemotherapy.

Patients were randomised to receive either pembrolizumab (n=247) or standard of care (SOC) treatment (n=248), which was the investigator’s choice of either methotrexate, docetaxel, or cetuximab.

Median overall survival (OS) was only marginally higher in the pembrolizumab compared to standard treatment arm (8.4 versus 7.1 months, hazard ratio [HR] 0.81 95% CI 0.66-0.99, P= .0204), however for a subset of patients who had PD-L1-expressing tumours, pembrolizumab was associated with dramatic and significantly improved outcomes.

Specifically, among patients with combined tumour and immune cell PD-L1-expression (CPS) of at least 1%, median OS was 8.7 months with pembrolizumab versus 7.1 months with standard treatments (HR 0.75; 95% CI 0.59-0.95, P=.0078), and among patients with PD-L1-expression in more than 50% of their cancer cells, median OS was 11.6 versus 7.9 months respectively (HR 0.54; 95% CI 0.35-0.82, P=.0017).

Compared to the other treatments, pembrolizumab measured up well in terms of side-effects.

“In almost every category it had a better side-effect profile, meaning a lower incidence of toxicity, versus standard treatments,” said Cohen. “The exception is hypothrodism, which occurred in 13% of those treated with pembro versus only 1% of those given other treatments.”

Overall, Cohen said the KEYNOTE-040 trial reinforces what is already known about anti-PD therapy in head and neck cancer. “From a clinician’s perspective I would feel the same in any country. This is a meaningful therapy that improves survival.”

Asked to comment for ESMO, Dr. Amanda Psyrri, from the University of Athens Medical School, and Attikon University Hospital in Athens said: “Keynote-040 did not reach its primary endpoint of overall survival; however, pembrolizumab was superior to investigator’s choice in terms of toxicity, an important consideration in treatment decisions for these poor-prognosis patients with recurrent/metastatic platinum-refractory HNSCC. As the authors point out, subsequent immunotherapy in the SOC arm may have confounded OS analysis. The magnitude of treatment effect was greater in patients with PD-L1 combined positive score (CPS) ? 1%, especially those with CPS ?50%,suggesting that pembrolizumab may represent the preferable treatment option for this subset of patients.”

Study Unlocks How Changes in Gene Activity Early During Therapy Can Establish the Roots of Drug-Resistant Melanoma

FINDINGS
A UCLA-led study of changes in gene activity in BRAF-mutated melanoma suggests these epigenomic alterations are not random but can explain how tumors are already developing resistance as they shrink in response to treatment with a powerful class of drugs called MAP kinase (MAPK)-targeted inhibitors. The discovery marks a potential milestone in the understanding of treatment-resistant melanoma and provides scientists with powerful targets for drug development and new clinical studies.

BACKGROUND
Approximately 50 percent of advanced melanoma tumors are driven to grow by the presence of BRAF mutations. The use of BRAF inhibitors, both alone and in combination with another MAPK pathway inhibitor called MEK, have shown unprecedented responses as a treatment for these types of tumors, rapidly shrinking them. However, BRAF-mutated tumors frequently show early resistance to treatment and respond only partially to BRAF inhibitors, leaving behind cancer cells that may evolve to cause eventual tumor regrowth.

The findings build upon research by Dr. Roger Lo, professor of medicine (dermatology) and molecular and medical pharmacology at the David Geffen School of Medicine, and lead author of the new study. Previously, he discovered that epigenomic alterations (via a regulatory mechanism called CpG methylation) accounted for a wide range of altered gene activities and behaviors in BRAF-mutant therapy-resistant melanoma tumor cells. The loss of tumor-fighting immune or T-cells in drug-resistant tumors may lead to resistance to subsequent salvage immunotherapy, Lo said, and drug resistance can grow at the same time that anti-tumor immune cells diminish and weaken.

This means that in some patients the melanoma might develop resistance to both MAP kinase-targeted therapy and anti-PD-L1 antibodies, which capitalize on the abundance of immune cells inside the tumor to unleash their anti-cancer activities. Lo concluded that non-genomic, epigenomic, and immunologic evolution of melanoma explain why patients relapse on MAPK-targeted therapies.

Along with co-first authors, Drs. Chunying Song, Marco Piva and Lu Sun, Lo hypothesized that epigenomic and immunologic resistance evident during clinical relapse may be developing already during the first few weeks of therapy as the tumors shrink and clinical responses are viewed as successes. If this proves to be true, then scientists could potentially identify combination treatments that suppress the earliest resistance-promoting activities.

METHOD
Lo’s team utilized state-of-the-art technologies to comprehensively profile recurrent patterns of gene activity changes. They analyzed 46 samples of patients’ melanoma tumors, both before and early during MAPK therapy. They also replicated the process outside of the human body, modeling both non-genomic drug resistance by growing melanoma cell lines from patients’ tumors and immunologic resistance in mouse melanoma. Patient-derived cell lines and mouse melanoma tumors were treated with drugs that block the MAP kinase pathway and sampled at various times over the course of the study to track gene activity changes.

The researchers found that MAPK therapies fostered CpG methylation and gene activity reprogramming of tumors. This reduced the tumor cells’ dependence on the mutated BRAF protein, and switched their growth and survival strategies to rely on proteins called receptor-tyrosine kinases and PD-L2. In addition, PD-L2 gene activity was found to be turned on in immune cells surrounding the tumor cells. They also demonstrated that blocking PD-L2 with an antibody could prevent the loss of T-cells in the tumor’s immune microenvironment and suppressing therapy resistance.

Lo’s team continues to identify other adaptations during this early phase of therapy that could be targets of future combination treatment regiments.

IMPACT
More than 87,000 new cases of melanoma will be diagnosed this year in the United States alone, and more than 9,500 people are expected to die of the disease.

The findings can prompt drug development and new clinical studies based on epigenetic or gene expression and immune targets in combination with mutation-targeted therapies. As scientists learn what these mechanisms of tumor resistance are, they can combine inhibitor drugs that block multiple resistance routes and eventually make the tumors shrink for much longer or go away completely, Lo said.

JOURNAL
The research is published online in Cancer Discovery, the peer-reviewed journal of the American Association of Cancer Research.

AUTHORS
UCLA’s Dr. Roger Lo is senior author. The co-first authors are Drs. Chunying Song, Marco Piva and Lu Sun at the David Geffen School of Medicine at UCLA. Other authors are Drs. Aayoung Hong, Gatien Moriceau, Xiangju Kong, Hong Zhang, Shirley Lomeli, Jin Qian, Clarissa Yu, Robert Damoiseaux, Philip Scumpia, Antoni Ribas and Willy Hugo at UCLA; and Mark Kelley, Kimberly Dahlman, Jeffrey Sosman, Douglas Johnson at Vanderbilt University. Lo, Damoiseaux, Scumpia and Ribas are members of UCLA’s Jonsson Comprehensive Cancer Center.

FUNDING
The research was supported by the National Institutes of Health, the American Cancer Society, the Melanoma Research Alliance, the American Skin Association, the American Association for Cancer Research, the National Cancer Center, the Burroughs Wellcome Fund, the Ressler Family Foundation, the Ian Copeland Melanoma Fund, the SWOG/Hope Foundation, the Steven C. Gordon Family Foundation, the Department of Defense Horizon Award, the Dermatology Foundation, and the ASCO Conquer Cancer Career Development Award.

Penn’s Glowing Cancer Tool Illuminates Benign, but Dangerous, Brain Tumors during Pituitary Surgery

Fluorescent, targeted dye illuminates molecular signature of tumor tissue in personalized surgery.

An experimental imaging tool that uses a targeted fluorescent dye successfully lit up the benign brain tumors of patients during removal surgery, allowing surgeons to identify tumor tissue, a new study from researchers at the Perelman School of Medicine at the University of Pennsylvania shows. The tumors, known as pituitary adenomas, are the third most common brain tumor, and very rarely turn cancerous, but can cause blindness, hormonal disorders, and in some cases, gigantism.

Findings from the pilot study of 15 patients, published this week in the Journal of Neurosurgery, build upon previous clinical studies showing intraoperative molecular imaging developed by researchers at Penn’s Center for Precision Surgery can improve tumor surgeries. According to first author John Y.K. Lee, MD, MSCE, an associate professor of Neurosurgery in the Perelman School of Medicine at the University of Pennsylvania and co-director of the Center for Precision Surgery, this study describes the first targeted, near infrared dye to be employed in brain tumor surgery. Other dyes are limited either by their fluorescent range being in the busy visible spectrum or by lack of specificity.

“This study heralds a new era in personalized tumor surgery. Surgeons are now able to see molecular characteristics of patient’s tumors; not just light absorption or reflectance,” Lee said. “In real time in the operating room, we are seeing the unique cell surface properties of the tumor and not just color. This is the start of a revolution.”

Non-specific dyes have been used to visualize and precisely cut out brain tumors during resection surgery, but this dye is believed to be the first targeted, near infrared dye to be used in neurosurgery. The fluorescent dye, known as OTL38, consists of two parts: vitamin B9 (a necessary ingredient for cell growth), and a near infrared glowing dye. As tumors try to grow and proliferate, they overexpress folate receptors. Pituitary tumors can overexpress folate receptors more than 20 times above the level of the normal pituitary gland in some cases. This dye binds to these receptors and thus allows us to identify tumors.

“Pituitary adenomas are rarely cancerous, but they can cause other serious problems for patients by pushing up against parts of their brain, which can lead to Cushing’s disease, gigantism, blindness and death,” Lee explained. “The study shows that this novel, targeted, near infrared fluorescent dye technique is a safe, and we believe this technique will improve surgery.”

Lee says larger studies are warranted to further demonstrate its clinical effectiveness, especially in nonfunctioning pituitary adenomas.

A big challenge with this type of brain surgery is ensuring the entire tumor is removed. Parts of the tumor issue are often missed by conventional endoscopy approaches during removal, leading to a recurrence in 20 percent of patients. The researchers showed that the technique was safe and effective at illuminating the molecular features of the tumors in the subset of patients with nonfunctioning pituitary adenomas.

The technique uses near-infrared, or NIR, imaging and OTL38 fluoresces brightly when excited by NIR light. The VisionSense IridiumTM 4mm endoscope is a unique camera system which can be employed in the narrow confines of the nasal cavity to illuminate the pituitary adenoma. Both the dye and the camera system are needed in order to perform the surgery successfully.

The rate of gross-total resection (GTR) for the 15 patients, based on postoperative MRI, was 73 percent. The GTR with conventional approaches ranges from 50 to 70 percent. Residual tumor was identified on MRI only in patients with more severe tumors, including cavernous sinus invasion or a significant extrasellar tumor.

In addition, for the three patients with the highest overexpression of folate, the technique predicted post-operative MRI results with perfect concordance.

Some centers have resorted to implementing MRI in the operating room to maximize the extent of resection. However, bringing a massive MRI into the operating room theater remains expensive and has been shown to produce a high number of false-positives in pituitary adenoma surgery. The fluorescent dye imaging tool, Lee said, may serve as a replacement for MRIs in the operating room.

Co-authors on the study include M. Sean Grady, MD, chair of Neurosurgery at Penn, and Sunil Singhal, MD, an associate professor of Surgery, and co-director the Center for Precision Surgery.

Over the past four years, Singhal, Lee, and their colleagues have performed more than 400 surgeries using both nonspecific and targeted near infrared dyes. The breadth of tumor types include lung, brain, bladder and breast.

Most recently, in July, Penn researchers reported results from a lung cancer trial using the OTL38 dye. Surgeons were able to identify and remove a greater number of cancerous nodules from lung cancer patients with the dye using preoperative positron emission tomography, or PET, scans. Penn’s imaging tool identified 60 of the 66 previously known lung nodules, or 91 percent. In addition, doctors used the tool to identify nine additional nodules that were undetected by the PET scan or by traditional intraoperative monitoring.

Researchers at Penn are also exploring the effectiveness of additional contrast agents, some of which they expect to be available in the clinic within a few months.

“This is the beginning of a whole wave of new dyes coming out that may improve surgeries using the fluorescent dye technique,” Lee said. “And we’re leading the charge here at Penn.”

Exploring Immunotherapy for Carcinoid and Pancreatic Neuroendocrine Tumors

A clinical trial testing the immunotherapy drug pembrolizumab shows the drug to be well tolerated among patients who have carcinoid or pancreatic neuroendocrine tumors.  Janice M. Mehnert, MD, director of the Phase 1 and Developmental Therapeutics Program at Rutgers Cancer Institute of New Jersey, is the lead author of research that is part of an oral presentation at the European Society for Medical Oncology 2017 Congress taking place this week in Madrid, Spain. Dr. Mehnert, who is also a medical oncologist in the Melanoma and Soft Tissue Oncology Program at Rutgers Cancer Institute, shares more about the work, conducted by a collective of international investigators.

Q: Why explore immunotherapy in these particular patient populations?

A: Immunotherapy drugs put the body’s natural defenses back to work by targeting the PD-L1 protein and PD-1 receptor and blocking their ability to prevent T cells from destroying cancer cells. Pembrolizumab has shown anti-tumor activity in advanced malignancies including melanoma and non-small cell lung cancer. With treatment options being limited for patients with carcinoid and pancreatic neuroendocrine tumors, it is imperative to explore new therapy options for these populations.

Q:  How was the study structured?

A: At the time our abstract was submitted, 25 participants who presented with advanced carcinoid tumors and 16 patients with pancreatic neuroendocrine tumors were accrued from multiple international sites.  Participants received 10 mg of pembrolizumab for up to 24 months or until confirmed progression or intolerable toxicity.  Safety, tolerability and response were assessed every eight weeks for the first six months and every 12 weeks thereafter.

Q:  What did you find?

A: At the time our results were reported we discovered findings similar to other trials of immunotherapy agents, with the majority of patients actually not responding to therapy. 12 percent of patients with carcinoid tumors and six percent of patients with pancreatic neuroendocrine tumors experienced a response to therapy. However, patients who achieved response were likely to have durable control of their disease, with all responses greater than or equal to six months in duration. Therapy was overall well tolerated and safe, with some side effects related to autoimmune processes caused by the medication.

Q: What is the implication of these findings?

A: These findings are interesting but need further validation in larger studies of patients with carcinoid and pancreatic neuroendocrine tumors. As well, investigative work focusing on identifying valuable biomarkers that could help predict which patients would respond to treatment with these agents is critical. Discoveries in this realm would improve the selection of patients for this particular therapeutic approach.

CRI Scientists Discover Vitamin C Regulates Stem Cell Function and Suppresses Leukemia Development

Not much is known about stem cell metabolism, but a new study from the Children’s Medical Center Research Institute at UT Southwestern (CRI) has found that stem cells take up unusually high levels of vitamin C, which then regulates their function and suppresses the development of leukemia.

“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why. Our research provides part of the explanation, at least for the blood-forming system,” said Dr. Sean Morrison, the Director of CRI.

The metabolism of stem cells has historically been difficult to study because a large number of cells are required for metabolic analysis, while stem cells in each tissue of the body are rare. Techniques developed during the study, which was published in Nature, have allowed researchers to routinely measure metabolite levels in rare cell populations such as stem cells.

The techniques led researchers to discover that every type of blood-forming cell in the bone marrow had distinct metabolic signatures – taking up and using nutrients in their own individual way. One of the main metabolic features of stem cells is that they soak up unusually high levels of ascorbate. To determine if ascorbate is important for stem cell function, researchers used mice that lacked gulonolactone oxidase (Gulo) – a key enzyme that most mammals, including mice but not humans, use to synthesize their own ascorbate.

Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do. This gave CRI scientists strict control over ascorbate intake by the mice and allowed them to mimic ascorbate levels seen in approximately 5 percent of healthy humans. At these levels, researchers expected depletion of ascorbate might lead to loss of stem cell function but were surprised to find the opposite was true – stem cells actually gained function. However, this gain came at the cost of increased instances of leukemia.

“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said Dr. Michalis Agathocleous, lead author of the study, an Assistant Instructor at CRI, and a Royal Commission for the Exhibition of 1851 Research Fellow. “The epigenome is a set of mechanisms inside a cell that regulates which genes turn on and turn off.  So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”

This increased risk is partly tied to how ascorbate affects an enzyme known as Tet2, the study showed. Mutations that inactivate Tet2 are an early step in the formation of leukemia. CRI scientists showed that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of leukemia.

These findings have implications for older patients with a common precancerous condition known as clonal hematopoiesis. This condition puts patients at a higher risk of developing leukemia and other diseases, but it is not well understood why certain patients with the condition develop leukemia and others do not. The findings in this study might offer an explanation.

“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of Tet2. Our results suggest patients with clonal hematopoiesis and a Tet2 mutation should be particularly careful to get 100 percent of their daily vitamin C requirement,” Dr. Morrison said. “Because these patients only have one good copy of Tet2 left, they need to maximize the residual Tet2 tumor-suppressor activity to protect themselves from cancer.”

Researchers in the Hamon Laboratory for Stem Cell and Cancer Biology, in which Dr. Morrison is also appointed, intend to use the techniques developed as part of this study to find other metabolic pathways that control stem cell function and cancer development. They also plan to further explore the role of vitamin C in stem cell function and tissue regeneration.

Dr. Morrison is a Professor of Pediatrics at UT Southwestern, a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research, and a Howard Hughes Medical Institute (HHMI) Investigator. He also holds the Mary McDermott Cook Chair in Pediatric Genetics at UT Southwestern and the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research at Children’s Research Institute at UT Southwestern.

CRI and UTSW co-authors include Dr. Zhiyu Zhao, Assistant Professor at CRI and of Pediatrics at UT Southwestern; Dr. Weina Chen, Associate Professor of Pathology at UT Southwestern; Dr. Corbin Meacham, Dr. Rebecca Burgess, and Dr. Malea Murphy, postdoctoral researchers; and Dr. Ralph DeBerardinis, Associate Professor at CRI, of Pediatrics, and in the Eugene McDermott Center for Human Growth & Development. Dr. DeBerardinis, who holds the Joel B. Steinberg, M.D. Chair in Pediatrics and is a Sowell Family Scholar in Medical Research at UTSW, also is the Director of CRI’s Genetic and Metabolic Disease Program and Chief of the Division of Pediatric Genetics and Metabolism at UTSW.

The National Institutes of Health, HHMI, CPRIT, and donors to the Children’s Medical Center Foundation supported this work.

Research opens possibility of reducing risk of gut bacterial infections with next-generation probiotic

A team of researchers is exploring the possibility that next-generation probiotics – live bacteria that are good for your health – would reduce the risk of infection with the bacterium Clostridium difficile. In laboratory-grown bacterial communities, the researchers determined that, when supplied with glycerol, the probiotic Lactobacillus reuteri produced reuterin, an antibacterial compound that selectively killed C. difficile. The study appears in Infection and Immunity.

C. difficile causes thousands of deaths and billions of dollars in healthcare expenses in the U.S. each year. Although most patients respond to antibiotic treatment, up to 35 percent will relapse and require extended antibiotic treatments,” said first and corresponding author Dr. Jennifer K. Spinler, instructor of pathology & immunology at Baylor College of Medicine, who oversees microbial genetics and genomics efforts at the Texas Children’s Microbiome Center at Texas Children’s Hospital.

C. difficile infections are the most common cause of diarrhea associated with the use of antibiotics. If these bacteria attempt to invade the human gut, the ‘good bacteria,’ which outnumber C. difficile, usually prevent them from growing. However, when a person takes antibiotics, for example to treat pneumonia, the antibiotic also can kill the good bacteria in the gut, opening an opportunity for C. difficile to thrive into a potentially life-threatening infection.

“When repeated antibiotic treatments fail to eliminate C. difficile infections, some patients are resorting to fecal microbiome transplant – the transfer of fecal matter from a healthy donor – which treats the disease but also could have negative side effects,” Spinler said. “We wanted to find an alternative treatment, a prophylactic strategy based on probiotics that could help prevent C. difficile from thriving in the first place.”

“Probiotics are commonly used to treat a range of human diseases, yet clinical studies are generally fraught by variable clinical outcomes and protective mechanisms are poorly understood in patients. This study provides important clues on why clinical efficacy may be seen in some patients treated with one probiotic bacterium but not with others,” said senior author Dr. Tor Savidge, associate professor of pathology & immunology and of pediatrics at Baylor and the Texas Children’s Microbiome Center.

Working in the Texas Children’s Microbiome Center, Spinler and her colleagues tested the possibility that probiotic L. reuteri, which is known to produce antibacterial compounds, could help prevent C. difficile from establishing a microbial community in lab cultures.

An unexpected result with major implications for a preventative strategy

Spinler and Savidge established a collaboration with co-author Dr. Robert A. Britton, professor of molecular virology and microbiology at Baylor and member of the Dan L Duncan Comprehensive Cancer Center.

The Britton lab uses mini-bioreactor arrays – multiple small culture chambers – that provide a platform in which researchers could recreate the invasion of an antibiotic-treated human intestinal community by C. difficile.

“Using the mini-bioreactors model we showed that L. reuteri reduced the burden of C. difficile infection in a complex gut community,” Britton said. “To achieve its beneficial effect, L. reuteri requires glycerol and converts it into the antimicrobial reuterin.”

The literature reports reuterin as a broad-spectrum antibiotic; it affects the growth of a wide variety of bacteria when they are tested individually in the lab. What was intriguing in this study is that reuterin didn’t have a broad-spectrum effect in the mini-bioreactor bacterial community setting.

“I expected reuterin to have an antibacterial effect on several different types of bacteria in the community, but it only affected C. difficile and not the good bacteria, which was exciting because it has major implications for a preventative strategy,” Spinler said.

“Although these results are too preliminary to be translated directly into human therapy, they provide a foundation upon which to further develop treatments based on co-administration of L. reuteri and glycerol to prevent C. difficile infection,” said co-author Dr. Jennifer Auchtung, director of the Cultivation Core at Baylor’s Alkek Center for Metagenomics and Microbiome Research and assistant professor of molecular virology and microbiology at Baylor.

In the future, this potential treatment could be administered prophylactically to patients before they take antibiotics known to disrupt normal gut microbes. The L. reuteri/glycerol formulation would help maintain the healthy gut microbial community and also help prevent the growth of C. difficile, which would result in decreased hospital stay and costs and reduced long-term health consequences of C. difficile recurrent infections.

Fat Rats Show Why Breast Cancer May Be More Aggressive in Patients with Obesity

Women with obesity are more likely to get breast cancer, and a number of studies have provided a reasonable explanation why: after menopause, fat tissue manufactures estrogen, and the estrogen then promotes tumor growth. But why, then, do women with obesity continue to have more aggressive tumors even after anti-estrogen treatment? Once the tumor’s source of estrogen is removed, obesity should have no effect on prognosis, but it does.

A University of Colorado Cancer Center study published in the journal Hormones & Cancer offers a possible explanation: In an animal model of obesity and breast cancer (affectionately referred to as the “fat rat”), tumor cells in obese animals, but not lean animals, had especially sensitive androgen receptors, allowing these cells to magnify growth signals from the hormone testosterone. Similar to the way in which many breast cancers drive their growth with estrogen receptors, these tumors in obese rats drove their growth with androgen receptors.

“Our original goal was to make a model of obesity and breast cancer that would reflect the condition in women.  At first, we were disappointed to discover that rats don’t make much estrogen in fat tissue like humans do. But we then realized that this aspect of the model gave us an excellent opportunity to study cancer progression after anti-estrogen treatment. Because fat cells in these rats don’t make estrogen, they are like human breast cancer patients treated to remove estrogen.  This allowed us to ask what is responsible for obesity-associated tumor progression in conditions of low estrogen availability,” says Elizabeth Wellberg, PhD, the paper’s first author, who works with Steven Anderson, PhD and Paul MacLean, PhD. Dr. Anderson is the vice chair for research at CU Cancer Center and James C. Todd Professor of Experimental Pathology in the CU School of Medicine. Dr. MacLean is a professor in the Division of Endocrinology, Metabolism, & Diabetes, also in the CU SOM.  Together, these investigators and their team have identified an important role for obesity in changing how breast tumors respond to hormones.

About 40 percent of American women have obesity; about 75 percent of breast cancers are estrogen-receptor positive, most of which will go on to be treated with anti-estrogen therapies. This combination means that thousands of women every year could benefit from treatments aimed at the aspects of obesity that promote breast cancer in low- or non-estrogen environments.

Androgen receptors and their hormone partner, testosterone, have long been known as drivers of prostate cancer and work at CU Cancer Center and elsewhere is implicating androgen as a driver in many breast cancers. When Wellberg and colleagues treated their obese rats with the anti-androgen drug enzalutamide, existing tumors shrank and new tumors failed to form. But this brought up another question: If overactive androgen receptors create poor prognosis in obese breast cancer patients, what is creating these overactive androgen receptors? It wasn’t that they were simply responding to more testosterone – it was that these receptors had been somehow tuned to be more sensitive to existing levels of testosterone.

“When you talk about what’s different between lean and obese individuals there are a lot of things – resistance to insulin, high sugar, and an elevated inflammatory response, what we call chronic low-grade inflammation, to name a few. In a lot of ways, you can walk through these differences looking for what may be causing this androgen receptor sensitivity,” says Anderson.

The group had previously shown that a component of inflammation, namely levels of a cytokine known as interleukin 6 (IL-6), is higher in the circulation of obese compared to lean rats. In the current paper, the group shows that administering IL-6 to breast cancer cells amplifies the activity of androgen receptors. In all, the storyline of this paper suggests the following:

  • Obesity leads to inflammation
  • Inflammation is associated with higher levels of IL-6
  • IL-6 sensitizes androgen receptors
  • Sensitized androgen receptors amplify growth signals that drive breast cancer even in an environment of low estrogen availability.

The current paper and others in this line of study lay the groundwork for considering obesity as a variable in the clinic.

“Down the line, we can imagine a day in which the BMI or metabolic state of breast cancer patients would be considered when choosing a treatment. These patients may benefit significantly from a more personalized therapeutic strategy, based on what obesity is doing to the tumor environment,” Wellberg says.

Study identifies molecules that could help to prevent the development of brain tumors

Researchers from the University of Portsmouth’s Brain Tumour Research Centre of Excellence have identified molecules which are responsible for metastatic lung cancer cells binding to blood vessels in the brain.

In order for a cancer cell to enter the brain, it must first bind to the cells which line the structure separating the blood from the brain which is called the blood-brain barrier (BBB). Such information about the factors associated with this process may provide a way of preventing the cancer cells binding to the BBB and crossing over into the brain.

Twenty to 40 percent of patients with non-small cell lung cancer (NSCLC) develop brain metastasis.

The study, funded by the charity Brain Tumour Research and conducted by researchers at their UK Centre of Excellence at the University of Portsmouth, examined the factors present on the surface of NSCLC cells. These cells have different factors on their surfaces which determines how “sticky” the cells are and whether they are responsible for mediating the cancer cells binding to the blood vessel walls.

One of these factors is a molecule called CD15s. While it is present on a number of different types of cells in the body, it is expressed at higher levels on metastatic tumour cells, including those which have spread from the lung. It is only present at low levels in lung cancer cells which are not metastatic and remain within the lung.

The scientists examined what CD15s binds to on the blood vessel wall and identified another factor called CD62E. The researchers then used a specific tool to block the CD15s on the surface of the tumour cells, and this prevented the NSCLC cells from attaching to the blood vessels. They also used a model which simulated the cancer cells flowing through the blood vessels, and got the same result. So, blocking the adhesive properties of CD15s may provide a tool to prevent the establishment of secondary cancers.

Professor Geoff Pilkington, study co-author and Head of the Brain Tumour Research Centre, said: “Although this work is still at an early stage, we have demonstrated key elements that are associated with tumour cell binding to blood vessels and this may provide a target for future drug development to prevent the development of secondary tumours in the brain. Increasing our understanding of the adhesive properties of tumours may also help to develop new treatments to halt the development and spread of primary brain tumours.”

The adhesive properties of cancer cells play a key role in the formation and development of a tumour. While cells in a low-grade tumour bind very tightly together, the cells become less adhesive as the tumour becomes malignant. This is very important for the tumour cells which then spread into the surrounding nervous tissue.

Understanding more about the factors which mediate cell adhesion is key for the potential identification of new therapies.

Dr Kieran Breen, Director of Research at Brain Tumour Research, said: “Brain tumours kill more children and adults under the age of 40 than any other cancer, yet just 1 per cent of the national spend on cancer research has been allocated to this devastating disease. We are funding vital research in the UK to address this situation and are encouraged by Professor Pilkington’s findings.”

In addition to primary tumours which start in the brain, the secondary or ‘metastatic’ tumours which originate elsewhere and which migrate to the brain have been the focus of this new study. Secondary brain tumours are most likely to originate in the breast, lung or skin (melanoma). When they enter the brain, they generally form multiple tumours and can be extremely difficult to treat. Usually, treatment would require whole-brain radiation which is extremely toxic and the average survival time is just 3-6 months from diagnosis, with fewer than 20 per cent of patients surviving more than one year. If the people whose tumours are more likely to spread to the brain could be identified, researchers may be able to prevent this from happening.

A new HER2 mutation, a clinical trial and a promising diagnostic tool for metastatic breast cancer

There is a group of metastatic breast cancers that has the HER2 gene amplified – the cells have many copies of it – which leads to enhanced activity of the product enzyme, a tyrosine kinase. HER2 has been established as a therapeutic target in breast cancer, and breast cancers in which the HER2 gene is not amplified do not, in general, respond to HER2-directed therapeutic approaches.

A few years ago, when the research teams of Dr. Matthew Ellis and others carried out a molecular characterization of breast cancer tumors, they found a new mutation in HER2 that was different from gene amplification but also resulted in tyrosine kinase being constantly activated.

“In this particular activation mechanism, the cells develop a subtle mutation within the functional part of the HER2 gene that activates the enzyme,” said Ellis, professor and director of the Lester and Sue Smith Breast Center, part of the National Cancer Institute-designated Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine. “The mutation locks the enzyme into an ‘on’ position.”

Ellis and his colleagues developed a preclinical model to study this new HER2 mutation and discovered that the enhanced enzymatic activity could trigger tumor formation. Furthermore, these tumor cells were sensitive to an experimental drug, neratinib. With this information in hand, the researchers took the next step.

“We launched a phase II clinical trial of neratinib in patients with metastatic breast cancer carrying a HER2 mutation,” Ellis said. “Finding patients that are positive for a HER2 mutation required a national collaboration because we had to screen hundreds of patients to identify the 2 to 3 percent that have a tumor driven by a HER2 mutation. The results of the clinical trial were encouraging in that about 30 percent of the 16 patients treated with neratinib had a meaningful clinical response showing significant disease stabilization or regression. Neratinib was well tolerated by most patients.”

“This is the first time we had a reasonable number of patients treated for HER2 mutations in whom we could estimate the response rate.”

The number of patients who could potentially benefit from this new treatment approach is estimated to be in the thousands. The researchers estimate that as many as 200,000 patients are likely to be living with metastatic breast cancer today in the United States. Based on the estimate that the new mutation is present in 2 to 3 percent of cases, the researchers calculated that approximately 4,000 to 6,000 patients with metastatic breast cancer carry a HER2 mutation and are therefore potential candidates for neratinib treatment.

Circulating tumor DNA analysis, a promising diagnostic tool

To identify the patients in this study who carried the new HER2 mutation, the researchers required tissue from the tumor, a biopsy, from which they could extract and sequence the genetic material to determine the presence of the HER2 mutation. This task turned out to be a major challenge because for 20 to 30 percent of the patients the researchers did not have sufficient material to make the diagnosis.

“To assist in our ability to identify patients with HER2 mutation-positive tumors, we conducted circulating tumor DNA analysis,” Ellis said. “The tumor’s DNA is released into the human bloodstream, and we were able to determine the presence of the mutation in blood samples from the patients. Importantly the circulating tumor DNA results were highly concordant with the tumor sequencing results, and they were much easier to determine. Notably, the blood test was sensitive enough that we could use it as a tool to determine eligibility for the clinical trial.”

In addition to bringing to the table a novel treatment for metastatic breast cancer carrying a HER2 mutation, the researchers have tested the value of the circulating tumor DNA as a disease-monitoring marker.

“A circulating tumor DNA-based blood test also could therefore be potentially used to monitor tumor progression and to determine whether patients are responding or not to treatment after just one month of therapy,” Ellis said.

Ellis also is a McNair Scholar at Baylor.

HemAcure and Sernova, A Big Deal

Richard (Rick) Mills
Ahead of the Herd

As a general rule, the most successful man in life is the man who has the best information

When most of us suffer a cut cells in the blood, called platelets, go to where the cut is, plug the hole and stop the bleeding. While the platelets are plugging the hole they release chemicals that attract more of the ‘sticky’ platelets and twelve (numbered using Roman numerals I through XII) proteins in the blood known as clotting factors are activated. These proteins mix with the platelets to form fibers which make the clot stronger and stop the bleeding.

Having too little of factors VIII (8) or IX (9) is what causes hemophilia. A person with hemophilia will lack only one factor, either factor VIII or factor IX, but not both. There are two major kinds of hemophilia: hemophilia A, which is a factor VIII deficiency; and hemophilia B, which is a factor IX deficiency.

Hemophilia is a genetic disorder which means it’s the result of a change in genes that was either inherited (passed on from parent to child) or occurred during development in the womb. Although it is mostly passed down from parents to children, about 1/3 of cases are caused by a spontaneous mutation, a change in a gene. All races and ethnic groups are equally affected by hemophilia A. The disease almost always affects males but can also affect females.

Many people believe that hemophiliacs bleed a lot from minor cuts but external wounds are usually not that serious. Much more serious is internal hemorrhaging that can take place in joints (especially knees, ankles and elbows) and into tissues and muscles. Bleeding can also occur in vital organs putting a hemophiliac’s life in danger.

Although effective treatment of the symptoms is available, there is no cure for hemophilia A at present and therapy has to be individualized to specific patients. Patients have to get lifelong infusions with recombinant factor VIII (rFVIII) several times a week to compensate for the missing clotting factor.

The global total hemophilia market was valued at US$ 9.3 billion in 2015. Approximately 20,000 people in the United States, 10,000 in Europe and approximately 2,500 in Canada have a moderate or severe form of hemophilia A. Annual costs for the treatment of the disease for each patient may range from US$60,000 to US$260,000 for a total cost of between $2-5B per year just in North America and Europe.

Grand View Research

The Horizon 2020 program

Horizon 2020 is the largest European Union (EU) research and innovation program ever undertaken with nearly €80 billion of funding available over the seven years between 2014 to 2020. Horizon 2020 promises breakthroughs, discoveries and world firsts by taking great ideas from the lab to the market, for example in the field of personalized medicine providing novel therapies such as gene or cell therapy.

HemAcure project, a novel personalized medicine curative therapy

An international research consortium, under the name HemAcure unites scientific academic institutions from Germany, Italy, the UK and Sernova Corp from Canada.

The following institutions are involved in HemAcure:

  • ARTTIC, a Munich-based enterprise that specializes in the management of EU-funded collaborative research projects, is in charge of project management.
  • The Department of Tissue Engineering and Regenerative Medicine of the Wuerzburg University Hospital is responsible for isolating the cells.
  • The Università del Piemonte Orientale (Italy) is developing, optimizing and performing the gene correction of the patient cells for expression of the Factor VIII therapy.
  • Scientists from Loughborough University (UK) are focussing on the manufacturing process and safety testing.
  • Sernova a Canadian public company, is responsible for conducting the preclinical safety and efficacy studies with the Factor VIII producing cells in its proprietary Cell Pouch™ using a model of hemophilia developed by consortium partner Universita del Piemonte Orientale (Italy) in preparation for clinical trials.
  • The quality management (GMP processes) is being monitored by IMS – Integrierte Management Systeme in Heppenheim, Germany. The company acts as a point of contact for international projects in the pharmaceutical and medical engineering sector.

The overall objective of the HemAcure project is to develop and refine the tools and technologies for a novel, curative ex vivo (outside the body) prepared cell based therapy to treat hemophilia A that should ultimately lead to improved quality of life for patients. The EU’s Horizon 2020 programme has stage funded the HemAcure project with €5.5 million (Cdn$8.06M, US$6.3). The most recent tranche of funding has just been approved based on the encouraging results to date.

The consortium’s idea: A personalized medicine solution using the patients’ own cells (remember each patient has to have individualized therapy) which are genetically modified outside the body to produce the missing clotting factor using precursor cells of endothelial cells flowing in the bloodstream. After modification these cells are transplanted back into the patient’s body in Sernova Corp’s Cell Pouch™.

After Sernova’s Cell Pouch™ is implanted in the body and forms its unique vascularized tissue chambers, the genetically modified cells are then transplanted into the vascularized chambers and are expected to continuously produce the clotting factor and release it into the bloodstream for a long period of time. This should mitigate the disease’s impact noticeably, increase the patients’ quality of life and reduce the overall cost of therapy.

Sernova

Sernova Corp. (TSX-V: SVA) (OTCQB: SEOVF) (FSE: PSH), is a Canadian publically traded, clinical stage, regenerative medicine company developing an implantable, scalable device, the Cell Pouch System™ and therapeutic cells for the treatment of diseases such as diabetes, and hemophilia.

Sernova’s Cell Pouch™ forms a natural vascularized environment for long-term survival and function of the therapeutic cells which release into the bloodstream required but missing proteins or hormones.

Sernova’s Cell Pouch™ technology would be beneficial if it provided a simple reduction in the number of therapeutic injections a patient must take; however, there is the possibility that it could even essentially ‘cure’ the disease through natural release and regulation of the therapeutic proteins or hormones.

“Sernova has developed its proprietary highly innovative Cell Pouch technologies for the placement and long-term survival and function of immune protected therapeutic cells. It has proven to be safe and efficacious in multiple small and large animal preclinical models and has demonstrated safety alone and with therapeutic cells in a clinical trial in humans for another therapeutic indication (diabetes – editor). We believe the Cell Pouch platform is the first such patented technology proven to become incorporated with blood vessel enriched tissue-forming tissue chambers without fibrosis for the placement and long-term survival and function of immune protected therapeutic cells.” Sernova News Release, Marketwire – July 24, 2017

Sernova is today a relatively unknown pure regenerative medicine play that has partnered their Cell Pouch™ with a network of academic cell therapy research and development partners. Below is a HemAcure consortium approved news release issued by Sernova Corp. on Monday July 24, 2017.

It’s your authors opinion ‘relatively unknown’ is a term that will shortly no longer apply to Sernova Corp.

Sernova-HemAcure Consortium Announce Significant Progress in Development of ‘First in World’ Regenerative Medicine Therapy for Treatment of Hemophilia A Patients

Breakthrough scientific progress is made in development of a disruptive personalized regenerative medicine therapy within Sernova’s Cell Pouch(TM) for treatment of Hemophilia A validated by European Commission’s confirmation of next stage of funding of the €5.6Million EU Horizon 2020 Grant Award to the HemAcure Consortium

LONDON, ONTARIO – (Marketwire – July 24, 2017) – Sernova Corp. (TSX-V: SVA) (OTCQB: SEOVF) (FSE: PSH), a clinical stage regenerative medicine company, announced today significant scientific progress achieved in the development of a ‘first in world’ personalized regenerative medicine therapy for the treatment of Hemophilia A patients by the HemAcure Consortium and confirmation of the second phase of funding of the Consortium by the European Commission.

The therapy being developed by international scientific Consortium members consisting of three European academic institutions, an enterprise for quality management and Sernova Corp is to treat severe Hemophilia A, a serious genetic bleeding disorder caused by missing or defective clotting factor VIII in the blood stream. This therapy consists of Sernova’s implanted Cell Pouch(TM) device transplanted with therapeutic cells, corrected to produce Factor VIII at a level sufficient to significantly reduce the side effects of the disease and improve patient quality of life.

“The international HemAcure Consortium team members are pleased with the ground breaking scientific advances achieved at this point and are on track for this regenerative medicine solution to advance into human clinical evaluation,” remarked Dr. Philip Toleikis, Sernova President and CEO.

Toleikis added, “Sernova’s Cell Pouch platform technologies are achieving important world first milestones in both diabetes and now hemophilia, two significant clinical indications which are being disrupted by its regenerative medicine approach aimed at significantly improving patient quality of life.”

“We are thrilled with the approval by the European Union of the next stage of funding for the HemAcure program based on our quality interim report. This is a strong validation of the Consortium’s dedication and teamwork and the importance of this regenerative medicine approach,” said Dr. Joris Braspenning, HemAcure Program Coordinator.

In summary, the following ground-breaking developments have been achieved by the Consortium:

  • A reliable procedure has been implemented to isolate and maintain required endothelial cells from a sample of the patient’s blood.
  • Using a novel gene correction process, the cells have been corrected and tuned to reliably produce the required Factor VIII to treat Hemophilia A.
  • The cells have been successfully scaled up to achieve the required therapeutic number, and cryopreserved for shipping and future transplant into the implanted Cell Pouch.
  • A preliminary study confirmed survival of the Factor VIII corrected human cells injected into the hemophilia model, achieving sustained therapeutic Factor VIII levels. This preliminary work is being used to aid in dosing of these cells in the Cell Pouch.
  • Safe Cell Pouch surgical implant and cell transplant procedures have been developed in the hemophilia A model in preparation for use in hemophilia patients.
  • Development of Cell Pouch vascularized tissue chambers suitable for Factor VIII producing cell transplant has been demonstrated in the hemophilia A model, expected to mimic the predicted findings in human patients.
  • In combination, this work is in preparation for safety and efficacy studies of the human hemophilia corrected Factor VIII producing cells in the Cell Pouch in a preclinical model of hemophilia.

This combination of advances by the HemAcure team represents a ‘first in world’ achievement towards developing a regenerative medicine therapy for the treatment of severe hemophilia A patients.

“In this regard, these fundamental advancements have set the stage for further optimization and implementation of cell production processes under controlled GMP conditions,” stated Martin Zierau, IMS member consortium team leader responsible for coordination of GMP processes.

With Factor VIII corrected cells, studies are ongoing to optimize cell dosing within the Cell Pouch and for study of safety and efficacy of hemophilia corrected Factor VIII cells in the hemophilia model. These studies are in support of the current extensive regulatory package already assembled for the Cell Pouch in anticipation of human clinical evaluation of the Cell Pouch with hemophilia corrected Factor VIII producing cells.

A big deal

Any discussions regarding advancing HemAcure’s plan, and more funding from Horizon 2020, had to be centered around success in these three areas:

  • CELLS ARE PRODUCING FACTOR VIII: The Consortium has successfully developed the process for isolating and maintaining the required cells from a sample of patient’s blood. Using a special technique these cells have been corrected and tuned to produce Factor VIII on a constant basis.
  • CORRECTED CELLS HAVE BEEN SCALED UP: The corrected cells have then been multiplied to demonstrate that the required number of cells can be produced. After testing, batches of corrected cells have been frozen, stored for later transplantation and successfully shipped, thawed and recovered. With further optimization and GMP production, this being the process anticipated to be used for future treatment of patients with hemophilia A.
  • CELLS PRODUCING THERAPEUTIC BLOOD LEVELS OF FACTOR VIII: In further preclinical tests, in a preliminary study, Factor VIII producing cells have been shown to produce therapeutic blood levels of Factor VIII. Studies have already shown that the Cell Pouch can produce vascularized tissue chambers in the hemophilia model and further studies will optimize dosing of hemophilic patient corrected cells that will then be transplanted into the Cell Pouch™ for evaluation of safety and efficacy in the preclinical model of hemophilia.

Conclusion

Being that all the companies in the HemAcure consortium are private, except SVA, and that they plan on ‘bringing breakthroughs, discoveries and world firsts from the lab to the market’ might not Sernova be a great way to leverage this in your portfolio?

And SVA is no one trick pony, the company is a leader in the regenerative space with their Cell Pouch™ and upon FDA clearance plan to initiate clinical trials in the United States for diabetes – expected to start patient enrollment this fall.

Add in developing local immune protection technology within the Cell Pouch™ and the company’s very own glucose responsive stem cell technology, you can see why your author thinks Sernova Corp might just be the best regenerative medicine pure play out there.

All of these reasons are why Sernova Corp. is on my radar screen. Is SVA on yours?

If not, maybe it should be.

Richard (Rick) Mills

aheadoftheherd.com

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New Therapeutic Approach for Difficult-to-Treat Subtype of Ovarian Cancer Identified

Scientists from The Wistar Institute demonstrate how a mutation in ovarian clear cell carcinoma can be exploited to design a targeted treatment.

A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Ovarian clear cell carcinoma accounts for approximately 5 to 10 percent of American ovarian cancer cases and about 20 percent of cases in Asia, ranking second as the cause of death from ovarian cancer. People with the clear cell subtype typically do not respond well to platinum-based chemotherapy, leaving limited therapeutic options for these patients.

Previous studies, including those conducted at The Wistar Institute, have revealed the role of ARID1A, a chromatin remodeling protein, in this ovarian cancer subtype. When functioning normally, ARID1A regulates expression of certain genes by altering the structure of chromatin – the complex of DNA and proteins in which DNA is packaged in our cells. This process dictates some of our cells’ behaviors and prevents them from becoming cancerous.

“Conventional chemotherapy treatments have proven an ineffective means of treating this group of ovarian cancer patients, meaning that alternative strategies based on a person’s genetic makeup must be explored,” said Rugang Zhang, Ph.D., professor and co-program leader in Wistar’s Gene Expression and Regulation Program and corresponding author of the study. “Therapeutic approaches based on the ARID1A mutation have the potential to revolutionize the way we treat these patients.”

Recent studies have shown that ARID1A is mutated in more than 50 percent of cases of ovarian clear cell carcinoma. Mutations of ARID1A and the tumor suppressor gene TP53 are mutually exclusive, meaning that patients with a mutation of ARID1A do not also carry a mutation of TP53. Despite this, the function of TP53, which protects the integrity of our genome and promotes programmed cell death, is clearly impaired as patients with the disease still have a poor prognosis.

In this study, Zhang and colleagues studied the connection between ARID1A and histone deacetylases (HDACs), a group of enzymes involved in key biological functions. They found that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. They were able to show that HDAC6 is typically inhibited by ARID1A, whereas in the presence of mutated ARID1A, HDAC6 levels increase. Because HDAC6 suppresses the activity of TP53, therefore inhibiting its tumor suppressive functions, higher level of HDAC6 allow the tumor to grow and spread.

Using a small molecule drug called rocilinostat that selectively inhibits HDAC6, the Zhang lab found that by blocking the activity of the enzyme in ARID1A-mutated cancers, they were able to increase apoptosis, or programmed cell death, in only those tumor cells containing the ARID1A mutation. This correlated with a significant reduction in tumor growth, suppression of peritoneal dissemination and extension of survival of animal models carrying ARID1A-mutated ovarian tumors.

“We demonstrated that targeting HDAC6 activity using a selective inhibitor like rocilinostat represents a possible therapeutic strategy for treating ovarian clear cell carcinoma and other tumors impacted by mutated ARID1A,” said Shuai Wu, Ph.D., a postdoctoral fellow in the Zhang lab and co-first author of the study. “Inhibitors like the one we used in this study have been well-tolerated in clinical trials, so our findings may have far-reaching applications.”

Concurrent Chemotherapy, Proton Therapy Improves Survival in Patients with Advanced Lung Cancer

For patients with advanced, inoperable stage 3 lung cancer, concurrent chemotherapy and the specialized radiation treatment, proton therapy, offers improved survival compared to historical data for standard of care, according to a new study from The University of Texas MD Anderson Cancer Center.

The research, published in JAMA Oncology, reported an overall survival (OS) of 26.5 months. In contrast, the historical OS rate with standard of care concurrent chemotherapy and traditional radiation was 16 months at the time when the study was designed.

The findings are the final results of the single institution, Phase II study and represent the longest follow-up to date of stage 3 lung cancer patients who have received proton therapy, said Joe Y. Chang, M.D., professor, Radiation Oncology and the study’s corresponding author.

Lung cancer is the leading cause of cancer death in both men and women in the U.S. According to the American Cancer Society, more than 222,500 people will be diagnosed and 155,870 will die from the disease in 2017, with the majority of patients still being diagnosed when the disease is in an advanced stage.

“Advanced lung cancer patients with inoperable disease traditionally have been treated with concurrent chemotherapy and conventional photon radiation therapy. However, the therapy can be very difficult for patients due to associated toxicities and because many patients are also dealing with comorbidities,” explained Chang.

Proton therapy is an advanced type of radiation treatment that uses a beam of protons to deliver radiation directly to the tumor, destroying cancer cells while sparing healthy tissues. Protons enter the body with a low radiation dose and stop at the tumor, matching its shape and volume or depth. They deposit the bulk of their cancer-fighting energy right at the tumor, thereby reducing the dose to cardiopulmonary structures, which impacts the toxicity, functional status, quality of life and even survival for patients, explained Chang.

“With our study, we hypothesized that proton therapy would offer a survival benefit to patients and reduce treatment-associated toxicities, which can be very serious,” he said.

The study opened at MD Anderson in 2006; in this research, Chang and his colleague report on the study’s five-year results.

For the prospective Phase II trial, 64 patients with inoperable, Stage III non-small-cell lung cancer were enrolled. The study’s primary endpoint was OS. The researchers hypothesized that the median OS would increase from historical data of 16 months on standard therapy to 24 months. Secondary endpoints included distant metastasis and local and regional recurrence rates. Toxic effects of treatment in both the acute and late settings also were analyzed.

Median follow up was 27.3 months for all patients, and 79.6 months for alive patients. At five years, the median OS was 26.5 months, and the corresponding five-year OS was 29 percent. Median progression-free survival was 12.9 months, with a five-year progression-free survival of 22 percent.

In sum, 39 patients experienced a relapse, with distant sites representing 62 percent of all recurrences. Local and regional recurrence rates were low, 16 percent and 14 percent, respectively.

Among the acute and late toxic effects diagnosed in patients were: esophagitis, pneumonitis and cardiac arrhythmia. Of note, said Chang, no patients developed the most severe, or grade five, toxicities, as seen in patients who receive standard of care.

Chang noted his study is not without limitations. Of greatest significance: the study was designed more than a decade ago. While the study’s survival, recurrence rates and toxic effects are still favorable when compared to rates associated with the most advanced traditional photon radiation therapy, intensity modulated radiation therapy (IMRT), technology to diagnose and stage the disease, as well all treatment modalities have significantly improved.

“When the study opened, PET imaging had just been approved for lung cancer staging. The image quality was poor and didn’t include a CT component in most facilities across the country,” said Chang. “Obviously, the technology has improved dramatically over the last decade and has made a significant impact on diagnosis and staging. Also, delivery of both the conventional intensity-modulated radiation therapy (IMRT) and proton therapy (IMPT), have improved, thereby reducing side effects for both treatment modalities.”

For example, MD Anderson proton therapy patients with advanced lung cancer now can receive IMPT. The technique uses an intricate network of magnets to aim a narrow proton beam at a tumor and “paint” the radiation dose onto it layer by layer. Healthy tissue surrounding the tumor is spared, and side effects are even more reduced than earlier proton delivery, said Chang. A Phase II trial studying IMPT and concurrent chemotherapy is underway. Chang also noted the advancements in cancer biology and immunotherapy and that both are important areas of research focus in combination with proton therapy.

Immune-cell numbers predict response to combination immunotherapy in melanoma

Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco researchers joined by physicians from UCSF Health. The findings provide a novel predictive biomarker to identify patients who are most likely to respond well to a combination of immunotherapy drugs known as checkpoint inhibitors — and to protect those who won’t respond from potentially adverse side effects of combination treatment.

“Combination immunotherapy is super-expensive and very toxic,” said Adil Daud, MD, director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center and senior author of the new study. “You’re putting patients at a lot of extra risk if they don’t need it, and you can adjust for that risk by knowing in advance who can benefit.”

The study, published online July 20, 2017 in Journal of Clinical Investigation Insight, describes an assay that measures the abundance of immune cells that infiltrate melanoma tumors. The findings revealed that patients who had lower levels of immune cells called T cells within their tumors benefitted most from two immunotherapy drugs in tandem. The measurements could provide clinicians with a means to predict patients who would most benefit from combination immunotherapy, the authors said.

“This is clinical research at its best,” said UCSF’s Katy Tsai, MD, a medical oncologist and lead author of the new report. “We have identified something as a predictive biomarker in melanoma, and we’re hoping to validate it in other tumor types as well.”

T cells are immune cells that patrol our body for signs of infection or other diseases, recognizing culprit cells via telltale proteins on their membranes. Our body’s normal cells carry certain proteins on their coats that act as “checkpoints,” making them invisible to T cells. But it turns out many cancer cells adopt the same trick — they cloak themselves with one of those same proteins, called PD-L1, causing T cells, which carry a complementary protein called PD-1, to mistake them as harmless. PD-L1 thus acts like a fake identification card, allowing cancer cells to live and multiply without being detected by the immune system.

Immunotherapy drugs called checkpoint inhibitors work to uncloak cancer cells by throwing a wrench in their disappearing act: these drugs block PD-L1 or PD-1, allowing T cells to recognize cancer cells as detrimental and kill them.

There are four FDA-approved checkpoint inhibitors: ipilimumab, nivolumab, pembrolizumab and atezolizumab. These drugs have been very successful in some cases, but they help only about 20 to 40 percent of patients. One of the ways doctors have improved their efficacy is by using multiple drugs at the same time. But the toxic side effects of these drugs can add up, and clinicians need to be able to correctly predict those who are most likely to respond to single drugs or combinations.

In a previous study, Daud and colleagues homed in on what makes some individuals respond well to checkpoint inhibitors that block PD-1, finding that patients whose tumors harbored high populations of T cells known as partially exhausted CD8+ cells responded well to treatment with nivolumab, an anti-PD-1 drug. Intriguingly, these cells had high levels of both PD-1 and CTLA-4, another well-known immune checkpoint protein, which is targeted by immunotherapy drugs such as ipilimumab.

In the new report, the researchers studied tumor samples from 102 melanoma patients, extracted T cells from the samples, and used cell sorting equipment to estimate the relative proportion of immune cells in the samples. The patients then underwent treatment either with only nivolumab, or with both nivolumab and ipilimumab. Finally, the researchers ran statistical tests to discover correlations among patient demographics, immune cell populations, and drug responses.

The team found that patients with high levels of exhausted T cells benefitted significantly from treatment with only a single drug. On the other hand, women and those who had liver metastases had lower number of immune cells patrolling their tumors, and responded well to the combination treatment.

“You’re pushing on two different gas pedals – PD-1 and CTLA-4,” said Daud, a member of UCSF’s Parker Institute for Cancer Immunotherapy center. “If you’re one of those patients with a low number of exhausted T cells, you have a better likelihood of benefitting from both drugs.”

The team will next explore why women have fewer T cells — and in turn, a diminished response to single immunotherapy drugs — and whether these factors could be related to age, estrogen levels, or are related to pregnancy.

The cell-counting assay developed by the researchers is time- and resource-intensive, especially because it requires fresh tumor samples and elaborate cell-sorting machines, and it is only available at UCSF. To get around these limitations, the team is now working on a more broadly applicable test that would measure the levels of PD-1 and CTLA-4 proteins — both present on T cells — in tumors and use that as a surrogate marker for immune cell count.

“In six months to a year, we should have an assay that works using fairly common, less expensive techniques,” said Daud. “And it could work on fresh, frozen or paraffin-embedded tumor blocks.” With this easier test, the researchers hope to expand their study of immune cell infiltration to other cancer types and to bigger groups of patients, both from different areas of the U.S. and internationally

New combination of anti-obesity drugs may have beneficial effects

Research conducted in the Perelman School of Medicine at the University of Pennsylvania has revealed that a unique combination of hormone-based drugs can produce enhanced weight loss in laboratory tests with obese animals. The research is to be presented this week at the Annual Meeting of the Society for the Study of Ingestive Behavior (SSIB), the foremost society for research into all aspects of eating and drinking behavior.

“Imagine a drug regimen where an obese person would cycle between different drug therapies over the course of a month to achieve a greater degree of body weight loss compared to the effects achieved with either a single drug or the continuous combination of drugs,” said senior author Dr. Matthew Hayes. His team studied the combination of two different drug classes that target different hormones: amylin and glucagon-like peptide-1 (GLP-1). They found that combined treatments acted synergistically to suppress feeding and body weight. They also discovered that the weight loss effects of chronic amylin- and GLP-1-based combination therapies could be enhanced when obese lab animals are cycled through their drug treatments. “The idea of drug-cycling is nothing new,” says lead author Kieran Koch-Laskowski. “Millions of women on birth control pills, for example, already take daily pills that cycle between drug and placebo throughout the month,” she goes on to say.

Perhaps the most exciting finding of the current data coming out of Penn is the fact that the research finds these enhanced weight loss effects with a combination of drugs that are either already FDA approved or in clinical trials for metabolic diseases, “making the translational impact of our work extremely timely and highly clinically relevant!” says Hayes. The authors are now finalizing their research to demonstrate mechanically how these two hormonal systems interact to achieve greater weight loss in the hopes of fast-tracking their findings to new clinical treatments for obesity.

Identification of PTPRZ as a drug target for cancer stem cells in glioblastoma

Glioblastoma is the most malignant brain tumor with high mortality. Cancer stem cells are thought to be crucial for tumor initiation and its recurrence after standard therapy with radiation and temozolomide (TMZ) chemotherapy. Protein tyrosine phosphatase receptor type Z (PTPRZ) is an enzyme that is highly expressed in glioblastoma, especially in cancer stem cells.

The research group of Professor Masaharu Noda and Researcher Akihiro Fujikawa of the National Institute for Basic Biology (NIBB) showed that the enzymatic activity of PTPRZ is requisite for the maintenance of stem cell properties and tumorigenicity in glioblastoma cells. PTPRZ knockdown strongly inhibited tumor growth of C6 glioblastoma cells in a mouse xenograft model. In addition, the research team discovered NAZ2329, an allosteric inhibitor of PTPRZ, in collaboration with ASUBIO Pharma Co. Ltd.. NAZ2329 efficiently suppressed stem cell-like properties of glioblastoma cells in culture, and tumor growth in C6 glioblastoma xenografts. These results indicate that pharmacological inhibition of PTPRZ is a promising strategy for the treatment of malignant gliomas.

CAR T-Cell Therapy for Leukemia Leads to Remissions in Clinical Trial

In an early-phase clinical trial of an experimental immunotherapy, researchers achieved durable molecular remissions in patients with chronic lymphocytic leukemia who had failed other treatments

Researchers at Fred Hutchinson Cancer Research Center showed about 70 percent of patients with the most common adult leukemia had their tumors shrink or disappear following an experimental chimeric antigen receptor (CAR) T-cell immunotherapy.

The researchers also found that measuring genetic traces of cancer cells taken from bone marrow biopsies might be a better indicator of prognosis than the standard lymph node scan.

The Journal of Clinical Oncology published the results online July 17 of the Phase 1/2 clinical trial, which included 24 patients with chronic lymphocytic leukemia (CLL) who had failed other treatments. Most of the patients had seen their cancer progress despite treatment with ibrutinib, a targeted cancer drug approved in 2014 for CLL by the U.S. Food and Drug Administration.

This history placed them in a high-risk group that was found in previous studies to have short survival with standard therapies.

“It was not known whether CAR T-cells could be used to treat these high risk CLL patients,” said lead author Dr. Cameron Turtle, an immunotherapy researcher at Fred Hutch. “Our study shows that CD19 CAR T-cells are a highly promising treatment for CLL patients who have failed ibrutinib.”

CD19 CAR T-cells are a type of immunotherapy in which a patient’s T cells are extracted from their blood and modified in a lab to recognize CD19, a target on the surface of leukemia cells. The engineered T cells are then infused back into the patient where they multiply and hunt down and kill cancer cells.

In CLL, bone marrow makes too many abnormal lymphocytes, which are a type of white blood cell. The American Cancer Society estimates that in the U.S., there will be about 20,000 new cases and 4,600 deaths from CLL in 2017. Tests of blood, bone marrow and lymph nodes—where lymphocytes congregate to fight infection—reveal the disease.

The 24 patients participating in the study ranged in age from 40 to 73 years, with a median age of 61. They had received a median of five other therapies with as few as three and as many as nine.

Researchers found that 17 out of 24 (71 percent) of patients saw their tumors shrink or disappear following CAR T-cell therapy using the standard measure of lymph node size by CT scans four weeks after treatment.

Of side effects of CAR-T cell therapy, 20 of the 24 patients—83 percent—experienced cytokine release syndrome (grade 1-2, 18 patients; grade 4, one patient; grade 5, one patient) and 8 patients (33 percent) developed neurotoxicity (grade 3, five patients; grade 5, one patient). For the most part the side effects were reversible, but two patients had side effects severe enough to require being admitted to the intensive care unit and one of those patients died.

 (An earlier report on trial results was presented by Turtle in December at the American Society of Hematology annual meeting.)

The new paper expands on the measures used to indicate whether the CAR T-cell treatment is working.

To take a closer look to see if any cancer cells remained after treatment, the research team analyzed samples taken from some of the patients’ bone marrow four weeks after the CAR T-cell infusion. The team used a genetic test called IGH deep sequencing, which is akin to a bar code and enables researchers to track cancer cells in the body.

Turtle and his collaborators did the sequencing analysis in 12 of the patients. Seven of the 12 patients had no malignant copies. All patients without malignant copies were alive and free of disease at a median follow-up of 6.6 months after CAR T-cell infusion.

Compared with the CT scans, having no malignant gene sequences in bone marrow following CAR T-cell therapy was a better predictor of the cancer staying at bay—known as “progression-free survival,” the researchers found.

The study is the first to suggest that deep sequencing might be a superior measure for predicting outcomes four weeks after CAR T-cell therapy for CLL.

The immunotherapy team at Fred Hutch is still enrolling eligible patients with CLL, acute lymphoblastic leukemia and non-Hodgkin lymphoma for treatment on CD19 CAR T-cell trials. The patients are seen at Seattle Cancer Care Alliance, the clinical care partner for Fred Hutch.

Fred Hutch co-authors of the paper are Kevin Hay, Laila-Aicha Hanafi, Shelly Heimfeld, Stanley R. Riddell and David G. Maloney. Other co-authors are Daniel Li, Juno Therapeutics; Sindhu Cherian, Xueyan Chen and Brent Wood, University of Washington; and Arletta Lozanski and John C. Byrd, The Ohio State University.

Funding for the project came from Juno Therapeutics, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Life Science Discovery Fund, the Bezos family, and the University of British Columbia.

Turtle, Maloney and Riddell receive research funding from Juno Therapeutics and are named as inventors on one or more patents or patent applications related to this work. Riddell is a co-founder of Juno Therapeutics and has equity interest in Juno Therapeutics. Li is an employee of and has equity interests in Juno Therapeutics. Fred Hutch receives research funding from Juno Therapeutics.

Largest study of malaria gene function reveals many potential drug targets

The malaria parasite’s success is owed to the stripping down of its genome to the bare essential genes, scientists at the Wellcome Trust Sanger Institute and their collaborators have found. In the first ever large-scale study of malaria gene function, scientists analysed more than half of the genes in the parasite’s genome and found that two thirds of these genes were essential for survival — the largest proportion of essential genes found in any organism studied to date.

The results, published today (13 July) in Cell, identify many potential targets for new antimalarial drug development, which is an important finding for this poorly understood parasite where drug resistance is a significant problem.

Nearly half of the world’s population is at risk of malaria and more than 200 million people are infected each year. The disease caused the deaths of almost half a million people globally in 2015*.

The genetics of the parasite that causes malaria, Plasmodium, have been tricky to decipher. Plasmodium parasites are ancient organisms and around half their genes have no similar genes — homologs — in any other organism, making it difficult for scientists to find clues to their function. This study provides the first ever experimental evidence of function for most of the genes.

Scientists studied the genes in one species of malaria, Plasmodium berghei, which were expressed in a single blood stage of its complicated, multi-stage life cycle. In the study, scientists designed a new method to decipher the function of the malaria parasite’s genes. The team switched off, or knocked out, 2,578 genes — more than half of the genome — and gave each knockout a unique DNA barcode**.

The team then used next generation genome sequencing technology to count those barcodes, and hence measure the growth of each genetically modified malaria parasite. If the switched-off gene was not essential, the parasite numbers shot up, but if the knocked out gene was essential, the parasite disappeared.

Dr Oliver Billker, joint lead author from the Wellcome Trust Sanger Institute, said: “This work was made possible by a new method that enabled us to investigate more than 2,500 genes in a single study — more than the entire research community has studied over the past two decades. We believe that this method can be used to build a deep understanding of many unknown aspects of malaria biology, and radically speed up our understanding of gene function and prioritisation of drug targets.”

The team systematically showed that the malaria parasite can easily dispose of the genes which produce proteins that give away its presence to the host’s immune system. This poses problems for the development of malaria vaccines as the parasite can quickly alter its appearance to the human immune system, and as a result the parasite can build resistance to the vaccine.

Dr Julian Rayner, joint lead author from the Wellcome Trust Sanger Institute, said: “We knew from previous work that on its surface the malaria parasite has many dispensable parts. Our study found that below the surface the parasite is more of a Formula 1 race car than a clunky people carrier. The parasite is fine-tuned and retains the absolute essential genes needed for growth. This is both good and bad: the bad news is it can easily get rid of the genes behind the targets we are trying to design vaccines for, but the flip side is there are many more essential gene targets for new drugs than we previously thought.”

Dr Francisco Javier Gamo, Director of the Malaria Unit at GlaxoSmithKline, said: “This study of unprecedented scale has resulted in many more, unique drug targets for malaria. The Holy Grail would be to discover genes that are essential across all of the parasite lifecycle stages, and if we could target those with drugs it would leave malaria with nowhere to hide. The technology that the Sanger Institute has developed gives us the potential to ask those questions systematically for the first time.”

Genetically enhanced, cord-blood derived immune cells strike B-cell cancers

Immune cells with a general knack for recognizing and killing many types of infected or abnormal cells also can be engineered to hunt down cells with specific targets on them to treat cancer, researchers at The University of Texas MD Anderson Cancer Center report in the journal Leukemia.

The team’s preclinical research shows that natural killer cells derived from donated umbilical cords can be modified to seek and destroy some types of leukemia and lymphoma. Genetic engineering also boosts their persistence and embeds a suicide gene that allows the modified cells to be shut down if they cause a severe inflammatory response.

A first-in-human phase I/II clinical trial of these cord-blood-derived, chimeric antigen receptor-equipped natural killer cells opened at MD Anderson in June for patients with relapsed or resistant chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), or non-Hodgkin lymphoma. All are cancers of the B cells, another white blood cell involved in immune response.

“Natural killer cells are the immune system’s most potent killers, but they are short-lived and cancers manage to evade a patient’s own NK cells to progress,” said Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation and Cellular Therapy.

“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer — potentially for months instead of two or three weeks — are designed to address these challenges,” Rezvani said.

Moon Shots Program funds project

The clinical trial is funded by MD Anderson’s Moon Shots Program™, designed to more rapidly develop life-saving advances based on scientific discoveries.

The chimeric antigen receptor (CAR), so-called because it’s added to the cells, targets CD19, a surface protein found on B cells.

In cell lines and mouse models of lymphoma and CLL, CD19-targeted NK cells killed cancer cells and extended survival of animals compared to simply giving NK cells alone. Addition of IL-15 to the CD19 receptor was crucial for the longer persistence and enhanced activity of the NK cells against tumor cells.

NK cells are a different breed of killer from their more famous immune system cousins, the T cells. Both are white blood cells, but T cells are highly specialized hunters that look for invaders or abnormal cells that bear a specific antigen target, kill them and then remember the antigen target forever.

Natural killers have an array of inhibitory and activating receptors that work together to allow them to detect a wider variety of infected, stressed or abnormal cells.

“By adding the CD19 CAR, we’re also turning them into guided missiles,” said Elizabeth Shpall, M.D., professor of Stem Cell Transplantation and Cell Therapy.

Using a viral vector, the researchers transduce NK cells taken from cord blood with the CD19 CAR, the IL-15 gene, and an inducible caspase-9-based suicide gene.

Cell line tests found the engineered NK cells to be more efficient killers of lymphoma and CLL cells, compared to unmodified NK cells, indicating the engineered cells’ killing was not related to non-specific natural killer cell cytotoxicity.

Another experiment showed the engineered cord blood NK cells killed CLL cells much more efficiently than NK cells taken from CLL patients and engineered, highlighting the need to transplant CAR-engineered NK cells from healthy cord blood rather than use a patient’s own cells.

Suicide gene to counter cytokine release syndrome

Mouse model lymphoma experiments using a single infusion of low dose NK cells resulted in prolongation of survival. At a higher, double dose, none of the mice treated with the CD19/IL-15 NK cells died of lymphoma, with half surviving for 100 days and beyond. All mice treated with other types of NK cells died by day 41.

A proportion of mice treated with the higher dose of engineered NK cells died of cytokine release syndrome, a severe inflammatory response that also occurs in people treated with CAR T cells.

To counteract this toxicity, the researchers incorporated a suicide gene (iC9) that can be activated to kill the NK cells by treatment with a small-molecule dimerizer. This combination worked to swiftly reduce the engineered NK cells in the mouse model.

Subsequent safety experiments were conducted in preparation for the clinical trial. Rezvani, the principal investigator of the clinical trial, says the protocol calls for vigilance for signs of cytokine release syndrome, treatment with steroids and tocilizumab for low-grade CRS with AP1903 added to activate the suicide gene for grade 3 or 4 CRS.

NK CARs available off the shelf

T cells modified with chimeric antigen receptors against CD19 have shown efficacy in clinical trials. In these therapies, a patient’s own T cells are modified, expanded, and given back to the patient, a process that takes weeks. Finding a matched donor for T cells would be a challenge, but would be necessary because unmatched T cells could attack the recipient’s normal tissue – graft vs. host disease.

Rezvani and Shpall have given patients cord-blood derived NK cells in a variety of clinical trials and found that they do not cause graft vs. host disease, therefore don’t have to be matched. NK cells can be an off-the-shelf product, prepared in advance with the necessary receptor and given promptly to patients.

“CAR NK cells are scalable in a way that CAR T cells are not,” Rezvani noted.

A strength of T cells is the development of memory cells that persist and repeatedly attack cells bearing the specific antigen that return. NK cells do not seem to have a memory function, but Rezvani says the experience of the longer-lived mice, which are now more than a year old, raises the possibility that a prolonged NK cell attack will suffice.

Shpall, Rezvani and colleagues are developing cord blood NK CARs for other targets in a variety of blood cancers and solid tumors.

MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.

Shpall founded and directs MD Anderson’s Cord Blood Bank, originally established to provide umbilical cord blood stem cells for patients who need them but cannot get a precise donor match. Donated by mothers who deliver babies at seven Houston hospitals and two others from California and Michigan, the bank now has 26,000 cords stored. MD Anderson researchers pioneered the extraction and expansion of NK cells from umbilical cords.

Tumor-Targeting Drug Shows Potential for Treating Bone Cancer Patients

Preclinical study shows BMTP-11 targets high-risk osteosarcoma

The treatment of osteosarcoma, the most common tumor of bone, is challenging. A study led by The University of Texas MD Anderson Cancer Center found a drug known as bone metastasis-targeting peptidomimetic (BMTP-11) has potential as a new therapeutic strategy for this devastating illness.

Results from the preclinical study, which looked at BMTP-11 alone and in combination with the chemotherapy agent gemcitabine, were published in the July 11, 2017, online issue of Proceedings of the National Academy of Sciences.

Although osteosarcoma is a relatively rare cancer, it is a leading disease-related cause of death in children and young adults ages 10 to 20. However, over the last 25 years, the five-year survival rate has remained unchanged, and the treatment options for these patients are few. In addition, the side effects of available treatment options often are significant and cumulative, and may cause other health problems and damage to major organs.

“What’s novel about this treatment is that BMTP -11 targets the tumor and spares other organs,” said Valerae O. Lewis, M.D., chair of Orthopaedic Oncology at MD Anderson. “We believe this study lays the groundwork for a clinical trial for the treatment of osteosarcoma without the cumulative and mortal side effects seen with the current treatment options.”

The study results identified IL-11Rα as an osteosarcoma cell surface receptor that correlated with tumor progression and poor prognosis in osteosarcoma patients. The team, which included co-authors Renata Pasqualini, Ph.D., and Wadih Arap, M.D., Ph.D., both of whom worked on the study while at MD Anderson and are now professors at the University of New Mexico Health Sciences Center (UNMSC) School of Medicine, also illustrated that IL-11Rα and IL-11 are up-regulated in human metastatic osteosarcoma cell lines, and this correlated with the development of lung metastases in mouse models of the disease. The metastatic potential of the osteosarcoma cell lines could be modulated by targeting IL-11Rα expression. Death from respiratory failure linked to metastasis to the lungs remains a significant problem among osteosarcoma patients.

“We were able to document anti-tumor activity against osteosarcoma models,” said Pasqualini. “Given that a first-in-human trial of BMTP-11 has recently been reported, one would hope that this proof-of-concept study might lead to early translational clinical trials in human osteosarcoma as a logical next step in the context of an unmet medical oncology need.”

Arap added that “this work provides a preclinical foundation for the potential design and development of a second line combination therapy regimen composed of conventional chemotherapeutics plus the targeted candidate drug BMTP-11 for application in unfortunate patients with recalcitrant osteosarcoma.”

Blood Test for Early Detection of Pancreatic Cancer Headed to Clinic

A newly identified biomarker panel could pave the way to earlier detection and better treatment for pancreatic cancer, according to new research from the Perelman School of Medicine at University of Pennsylvania. Currently over 53,000 people in the United States are diagnosed with pancreatic cancer — the fourth leading cause of cancer death — every year. The blood biomarkers, detailed today in Science Translational Medicine, correctly detected pancreatic cancer in blood samples from patients at different stages of their disease.

The majority of pancreatic cancer patients are not diagnosed until an advanced stage, beyond the point at which their tumors can be surgically removed.

A team led by Ken Zaret, PhD, director of the Penn Institute for Regenerative Medicine and the Joseph Leidy Professor of Cell and Developmental Biology, and Gloria Petersen, PhD, from the Mayo Clinic, identified a pair of biomarkers that physicians could soon use to discover the disease earlier.

“Starting with our cell model that mimics human pancreatic cancer progression, we identified released proteins, then tested and validated a subset of these proteins as potential plasma biomarkers of this cancer,” Zaret said. The authors anticipate that health care providers will use the early-detection biomarkers to test for their presence and levels in blood from pancreatic cancer patients and blood drawn from individuals with a high risk of developing pancreatic cancer, including those who have a first-degree relative with pancreatic cancer, are genetically predisposed to the disease, or who had a sudden onset of diabetes after the age of 50.

“Early detection of cancer has had a critical influence on lessening the impact of many types of cancer, including breast, colon, and cervical cancer. A long standing concern has been that patients with pancreatic cancer are often not diagnosed until it is too late for the best chance at effective treatment,” said Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center (ACC) at the University of Pennsylvania. “Having a biomarker test for this disease could dramatically alter the outlook for these patients.”

The biomarker panel, enabled by discovery work of first author Jungsun Kim, PhD, a postdoctoral fellow in Zaret’s lab, builds on a first-of-its-kind human-cell model of pancreatic cancer progression the lab described in 2013. They used stem-cell technology to create a cell line from a patient with advanced pancreatic ductal adenocarcinoma. Genetically reprogramming late-stage human cancer cells to a stem-cell state enabled them to force the reprogrammed cells to progress to an early cancerous state, revealing secreted blood biomarkers of early-stage disease along the way.

The best candidate biomarker, plasma thrombospondin-2 (THBS2), was screened against 746 cancer and control plasma samples using an inexpensive, commercially available protein-detection assay. The team found that blood levels of THBS2, combined with levels of a known later-stage biomarker called CA19-9, was reliable at detecting the presence of pancreatic cancer in patients.

The team refined the assay with independent investigations of plasma samples from patients with different stages of cancer, from individuals with benign pancreatic disease, and from healthy controls, all obtained from Petersen, who directs the biospecimen resource program for pancreas research at the Mayo Clinic.

“Positive results for THBS2 or CA19-9 concentrations in the blood consistently and correctly identified all stages of the cancer,” Zaret said. “Notably, THBS2 concentrations combined with CA19-9 identified early stages better than any other known method.” The combination panel also improved the ability to distinguish cases of cancer from pancreatitis. The panel will next be validated in a set of samples from pancreatic cancer patients who provided a research blood sample prior to their diagnosis.