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

MD Anderson study also finds reduced toxicities with use of more advanced radiation therapy.

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

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.

Radiation Therapy Prior to Surgery Reduces the Risk of Secondary Tumors in Early-Stage Breast Cancer Patients

Breast cancer patients receiving neoadjuvant radiation therapy have improved cancer-free survival over adjuvant radiation

Moffitt Cancer Center researchers launched a first of its kind study comparing the long-term benefits of radiation therapy in women with breast cancer either before surgery (neoadjuvant) or after surgery (adjuvant). Their study, published in the June 30 issue of Breast Cancer Research, found that patients who have neoadjuvant radiation therapy have a significantly lower risk of developing a second primary tumor at any site.

The majority of patients who have early stage breast cancer have surgery to remove their tumor or a complete mastectomy. Surgery is commonly followed by radiation therapy, which has been shown to increase relapse-free survival. However, in some cases, patients may require neoadjuvant radiation therapy to decrease the size of the tumor before surgery.  Currently, there are no studies that have analyzed the long-term effects of neoadjuvant radiation therapy on breast cancer patients.

Moffitt researchers compared the overall survival and the time to diagnosis of a second tumor, if any, of 250,195 breast cancer patients who received either neoadjuvant or adjuvant radiation therapy. They analyzed patient outcomes from a National Cancer Institute (NCI) registry database of cancer incidence and survival rates in the United States.  They included female patients in the analysis who were diagnosed between 1973 and 2011 with early-stage breast cancer. The analysis included 2,554 women who received localized neoadjuvant breast radiation therapy before surgery and 247,641 women who received localized adjuvant breast radiation therapy after surgery.

The researchers discovered that among the breast cancer patients who tested positive for the estrogen receptor (ER) biomarker, patients who had neoadjuvant radiation therapy had a significantly lower risk of developing a second primary tumor than patients who had adjuvant radiation therapy. This was true for patients who underwent both partial and complete mastectomies.  The researchers found that delaying surgery due to neoadjuvant radiation therapy was not a detriment to survival.

A number of recent studies have suggested that radiation therapy may re-educate and stimulate the immune system to target cancer cells. “The observed benefit of neoadjuvant radiation therapy aligns with the growing body of literature of the immune activation effects of radiation, including shrinking of untreated metastases outside the radiation field,” explained Heiko Enderling, Ph.D., associate member of Moffitt’s Integrated Mathematical Oncology Department.

T-cells lacking HDAC11 enzyme perform more effectively in destroying cancer cells

Researchers at the George Washington University (GW) Cancer Center have discovered a new role for the enzyme, histone deacetylase 11 (HDAC11), in the regulation of T-cell function.

T-cells can infiltrate tumors with the purpose of attacking the cancer cells. However, prior studies have found that the T-cells group around the tumor, but do not perform the job that they are meant to.

“The goal of the T-cell is to destroy the cancer tumor cells,” Eduardo M. Sotomayor, MD, director of the GW Cancer Center and senior author of the study, explained. “We wanted to look at and understand the mechanisms that allowed crosstalk between the tumor and the T-cells that stopped the T-cells from doing their job.”

The recent research, published in the journal Blood, centered on the discovery of “epigenetic checkpoints” in T-cell function in an effort to explain how and why these cells are modified to behave differently. The study found that when HDAC11 was removed the T-cells, they were more primed to attack the tumor.

More importantly, this research highlights that HDAC11, which was the last of 11 HDAC to be discovered, should be treated as an immunotherapeutic target.

While the study focused on the T-cells around a lymphoma tumor, this research is pertinent to all types of cancer. The goal for the team was to find a way to activate the T-cells so that they could destroy the tumor. However, the process of cell activation does need to be refined and handled carefully.

“We don’t want T-cells to be easily activated, as they can cause harm to the host — the patient. So we want to look at possible methods and therapies to activate the T-cells when they need to work,” said Sotomayor.

“The next step is to perform preclinical studies with specific inhibitors of HDAC11 alone and in tandem with other existing immunotherapies, such as anti-PD1/anti-PDL1 antibodies, in order to find the most potent combination. Our goal is to make the T-cells better at destroying cancer tumors.”

This study represents a step forward in understanding the underlying mechanisms of T-cell function and epigenetic regulation of the HDAC11 enzyme.

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.

Pioneering cancer gene therapy by Novartis backed by U.S. panel

(Reuters) – Novartis AG’s (NOVN.S) pioneering cancer drug won the backing of a federal advisory panel on Wednesday, paving the way for the first gene therapy to be approved in the United States.

An advisory panel to the Food and Drug Administration voted 10-0 that the drug, tisagenlecleucel, should be approved to treat patients with relapsed B-cell acute lymphoblastic leukemia (ALL), the most common form of U.S. childhood cancer.

The FDA is not obliged to follow the recommendations of its advisers but typically does so. The agency is expected to rule on the drug by the end of September.

Approval of tisagenlecleucel would have significant implications not only for Novartis but for companies developing similar treatments, including Kite Pharma Inc (KITE.O), Juno Therapeutics Inc (JUNO.O) and bluebird bio Inc (BLUE.O).

All four are developing chimeric antigen receptor T-cell therapies (CAR-T), which harness the body’s own immune cells to recognize and attack malignant cells.

If approved, the drugs, which are infused just once, are expected to cost up to $500,000 and generate billions of dollars for their developers. Success would also help advance a cancer-fighting technique that scientists have been trying to perfect for decades and lift the broader field of cell therapy.

“In the last five years there have been a significant number of cell therapy companies that have gone public or gotten investment in hopes of moving this type of therapy forward,” said Reni Benjamin, an analyst at Raymond James. “This is our first glimpse from a commercial and regulatory perspective about how the FDA is thinking about this space.”

A clinical trial of Novartis’s drug showed that 83 percent of patients who had relapsed or failed chemotherapy, achieved complete or partial remission three months post infusion. Patients with ALL who fail chemotherapy typically have only a 16 to 30 percent chance of survival.

Novartis is also testing the drug in diffuse large b-cell Lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, as is Kite. Part of the competitive landscape will include which company is best able to manufacture its product most efficiently and reliably.

The products are made by extracting and isolating a patient’s T cells, genetically engineering them to recognize and target specific cancer cells, and then infusing them back into the patient. Novartis said the entire process will take 22 days by the time it is launched.

More than half of patients experienced a serious complication known as cytokine release syndrome (CRS) which occurs when the body’s immune system goes into overdrive. Doctors were able to manage the condition and the syndrome caused no deaths.

The FDA expressed concern that the drug could cause new malignancies over the long term, but panelists generally felt that risk was low.

Reporting by Toni Clarke in Washington; Editing by Lisa Shumaker

Personal neoantigen vaccine prompts strong anti-tumor response in patients, study shows

A personal cancer treatment vaccine that targets distinctive “neoantigens” on tumor cells has been shown to stimulate a potent, safe, and highly specific immune anti-tumor response in melanoma patients, report scientists from Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard.

The study, published online by Nature “provides proof-of-principle that a personal vaccine tailored to a patient’s tumor can be produced and generates highly specific responses to that patient’s tumor after vaccination,” said the researchers, led by Catherine J. Wu, MD, senior author of the report. She is a researcher at Dana-Farber, the Broad Institute, and Harvard Medical School.

The scientists said that while most therapies are based on the on-size-fits-all model of medicine, “we’ve long recognized in cancer that every patient’s tumor is different. With recent advances in technology, it’s now becoming possible to create a therapy that’s suited to target an individual’s tumor.”

The researchers say the results warrant further development of neoantigen vaccines, both alone and in combination with other immunotherapy weapons such as checkpoint inhibitors. The vaccine, known as NeoVax, prompted strong activity by the patients’ immune systems while causing negligible side effects.

First authors of the report are Patrick A. Ott, MD, PhD, and Zhuting Hu, PhD, of Dana-Farber. Other senior authors include Nir Hacohen, PhD, of the Broad Institute and Massachusetts General Hospital, Edward Fritsch, PhD, formerly of Dana-Farber and now at Neon Therapeutics in Cambridge, Mass, and Eric Lander, PhD, of the Broad Institute.

Antigens are molecules that are displayed on the surface of cells and stimulate the immune system. Neoantigens are molecules on cell’s surfaces that are produced by DNA mutations that are present in cancer cells but not in normal cells, making neoantigens ideal targets for immune therapy against cancer, say the scientists. The vaccines used in the phase I trial contained up to 20 neoantigens, derived from an individual patient’s tumor. The vaccines were administered to patients to train their immune system to recognize these neoantigens, with the goal of stimulating the immune system to destroy the cancer cells that display them.

While other immunotherapies, such as checkpoint inhibitor drugs, also trigger immune responses against cancer neoantigens, they are not designed to be specific. They can also induce responses against normal tissue antigens, leading the immune system to attack normal tissues and cause toxicity in a subset of patients. The researchers found that the personal vaccine induced a focused T cell response against several tumor neoantigens, beyond what is normally seen in response to existing immunotherapies.

The vaccine was administered to six patients with melanoma whose tumors had been removed by surgery and who were considered at high risk for recurrence. The vaccinations were started at a median of 18 weeks after surgery. At a median of 25 months after vaccination, four of the six patients showed no evidence of cancer recurrence. In the other two patients, whose cancer had spread to their lungs, the disease recurred after vaccination. At that point, they began treatment with the drug pembrolizumab, which inhibits the PD-1 immune checkpoint. Both patients had complete resolution of their tumors and remain free of disease according to imaging scans.

The study results suggest, that a personalized neoantigen vaccine can potentially overcome two major hurdles in cancer therapy.

One is the heterogeneity of tumors – the fact that they are made up of cells with a variety of different traits, which often allows cancers to evade drugs targeted to malignant cells having a single genetic abnormality. The vaccine, because it contains many different neoantigens from the tumor, targets multiple genetic types of tumor cells. Wu added that in this respect, the response generated by a neoantigen vaccine is similar to the new wave of combination therapies, which are showing more promise in treating cancers that typically develop resistance to single drugs. “We are leveraging the immune system’s natural ability to detect and attack many target antigens, as it does every time we get an infection,” she said.

A second hurdle in cancer is to generate an immune response sharply focused on cancer cells while avoiding normal cells and tissues. This aim was achieved by the vaccine, which appeared to have few “off-target” effects, causing only flu-like symptoms, fatigue, rashes, and irritation at the site of the vaccine injection, according to the report.

Despite decades of attempts to develop effective cancer treatment vaccines, they have mostly failed at producing potent antitumor immune responses. The study authors say that is because these vaccines have generally been made with tumor antigens that are too similar to antigens on normal cells: as a result, the body generates a weaker immune response to avoid harming normal cells, a process called immune tolerance. By contrast, the neoantigen vaccine is custom-made for each patient using antigens produced by mutations unique to the patient’s cancer and only present on cancer cells, thus bypassing the nature immune tolerance process.

To create the vaccine, samples of a patient’s tumor and normal DNA from the patient’s blood underwent whole-exome sequencing to reveal mutations present only in the tumor’s genetic program. Because some mutations are present in the DNA but the gene is not made into RNA and protein, the researchers used RNA sequencing to identify mutations that caused the production of a mutated RNA, which is then normally translated into a protein.

Since T cells can only recognize neoantigens that are “presented” to them by HLA molecules of the immune system, a key step in making the vaccine is using computer algorithms to predict which neoantigen peptides will bind strongly to the HLA molecules for recognition by T cells. Algorithms, such as NetMHC, have been developed in recent years, making it feasible to select HLA-binding neoantigen peptides for the vaccine. Applying this tool to the six patients’ tumor samples yielded dozens of unique neoantigens for each patient’s personal vaccine.

Finally, the selected neoantigen peptides were synthesized and mixed with an adjuvant – a biochemical substance that helps to jump-start the immune response. The vaccine was then injected under the skin of the patient, with five priming doses followed by two booster doses of the vaccine.

The vaccine was aimed at generating responses to the neoantigens from T cells of two kinds – CD8+ killer cells and CD4+ helper cells. When the team monitored the vaccine’s effects on the immune system in each patient, they found that both T cell types had indeed been activated by the vaccine and could recognize the neoantigens bound to HLA molecules. Most importantly, many of the T cells were able to recognize the tumor cells directly, demonstrating that the vaccine had triggered a tumor-specific immune response that could target the patient’s tumor.

“Future neoantigen vaccine trials will recruit more patients with advanced disease to test the efficacy of the vaccine, take advantage of improved methods for predicting antigen presentation to boost the number of effective neoantigens and test for synergy with checkpoint blockade and other immunotherapeutics,” the scientists said. “If successful in subsequent trials, a personal vaccine has the potential to be applied to any cancer that harbors a sufficient numbers of neoantigens for vaccination.”

FDA Halts Three Multiple Myeloma Studies Evaluating Merck’s KEYTRUDA®

Merck known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has placed a clinical hold on KEYNOTE-183, KEYNOTE-185 and KEYNOTE-023, three combination studies of KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy, in the blood cancer multiple myeloma.

This decision follows a review of data by the Data Monitoring Committee in which more deaths were observed in the KEYTRUDA arms of KEYNOTE-183 and KEYNOTE-185 and which led to the pause in new patient enrollment, as announced on June 12, 2017. The FDA has determined that the data available at the present time indicate that the risks of KEYTRUDA plus pomalidomide or lenalidomide outweigh any potential benefit for patients with multiple myeloma. All patients enrolled in KEYNOTE-183 and KEYNOTE-185 and those in the KEYTRUDA/lenalidomide/dexamethasone cohort in KEYNOTE-023 will discontinue investigational treatment with KEYTRUDA.

This clinical hold does not apply to other studies with KEYTRUDA.

The following studies have been placed on full clinical hold:

  • KEYNOTE-183: “A Phase III study of Pomalidomide and low-dose Dexamethasone with or without Pembrolizumab (MK3475) in refractory or relapsed and refractory Multiple Myeloma (KEYNOTE-183).”
  • KEYNOTE-185: “A Phase III study of Lenalidomide and low-dose Dexamethasone with or without Pembrolizumab (MK3475) in newly diagnosed and treatment naïve Multiple Myeloma (KEYNOTE-185).”

The following study has been placed on partial clinical hold:

  • KEYNOTE-023 Cohort 1: “A Phase I Multi-Cohort Trial of Pembrolizumab (MK-3475) in Combination with Backbone Treatments for Subjects with Multiple Myeloma (KEYNOTE 023).” Cohort 1 of KEYNOTE-023 evaluated KEYTRUDA (pembrolizumab) in combination with lenalidomide and dexamethasone in patients who received prior anti-multiple myeloma treatment with an immunomodulatory (IMiD) treatment (lenalidomide, pomalidomide or thalidomide).

“Patient safety is Merck’s primary concern, and we are grateful to the study investigators and patients involved in these studies for their commitment to this important research,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “Merck’s development program for KEYTRUDA, spanning more than 30 different tumor types, has one priority: helping patients suffering from cancer.”

For more information about Merck’s oncology clinical trials, visit www.merck.com/clinicaltrials.

Combo immunotherapy may herald new standard of care for kidney cancer

Combination therapy with two immunotherapy drugs produces an unprecedented doubling of response rates from 20 percent to 40 percent, a new study shows.

The multicenter trial involving 100 patients showed that the addition of ipilimumab to nivolumab, which is currently FDA-approved for treatment of kidney cancer, leads to responses that can last beyond two years. Half of the patients in the study, which appears in the Journal of Clinical Oncology, had metastases that had grown while they were on previous therapy.

“For this group of patients, these are very significant results,” said lead author Dr. Hans Hammers, Associate Professor of Internal Medicine and co-leader of the Kidney Cancer Program at the Harold C. Simmons Comprehensive Cancer Center of UT Southwestern Medical Center.

The results set the stage for a pivotal Phase III trial, which has completed enrollment of patients. Should the results of this study be repeated in the larger Phase III trial, it would lead to a new standard of care for kidney cancer patients, said Dr. Hammers, formerly of Johns Hopkins medical system, who holds the Eugene P. Frenkel, M.D. Scholar in Clinical Medicine at UT Southwestern.

While significant advances in the treatment for kidney cancer over the last decade have led to the approval of a dozen drugs, these drugs are mostly palliative, lacking the potential for cure. “By contrast, durable responses lasting many years can be achieved with immunotherapy,” said Dr. Hammers.

Activation of the immune system, however, can lead to serious complications, requiring potent anti-inflammatory drugs. “While side effects of immunotherapy can be significant, they are typically reversible, and unlike current therapies, don’t significantly dampen patients’ daily quality of life,” said Dr. Hammers.

“Given the potential severity of the adverse effects, patients benefit from expert management available at centers of excellence,” said Dr. James Brugarolas, Associate Professor of Internal Medicine and Leader of the Kidney Cancer Program at UT Southwestern.

Ongoing efforts in the Kidney Cancer Program focus on leveraging Nobel Prize-winning discoveries from UT Southwestern’s Dr. Bruce Beutler leading to a new family of proteins that activate the immune system, the toll-like receptors. “Another avenue we are exploring, is the combination of immunotherapy and radiation,” said Dr. Brugarolas.

Nobel Laureate Dr. Beutler, Regental Professor and Director of the Center for the Genetics of Host Disease, discovered an important family of receptors that allow mammals to sense infections when they occur, triggering a powerful inflammatory response. For this work, he received the 2011 Nobel Prize in Physiology or Medicine. Dr. Beutler, also Professor of Immunology, holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr.

Kidney cancer is the sixth most common cancer type affecting both men and women. Classic chemotherapy has never worked well for kidney cancer. Targeted therapies have prolonged life expectancy, but are associated with daily side effects. Single-agent immunotherapies improve patients’ survival, but only benefit a subset of patients. Combination immunotherapy with nivolumab and ipilimumab as tested in the kidney cancer study described here is already FDA-approved for treatment of melanoma, and is being tested for other cancers.

The Kidney Cancer Program at UTSW is one of two programs in the U.S. recognized with a Specialized Program of Research Excellence award by the National Cancer Institute. Discoveries at the Kidney Cancer Program have led to a new understanding of how kidney cancer develops and are leading to new treatments.

The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 48 NCI-designated Comprehensive Cancer Centers in the nation. Simmons Comprehensive Cancer Center includes 13 major cancer care programs. In addition, the Center’s education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Comprehensive Cancer Center is among only 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site.

Promising new therapeutic approach for debilitating bone disease

An Australian-led research team has demonstrated a new therapeutic approach that can re-build and strengthen bone, offering hope for individuals with the debilitating bone cancer, multiple myeloma.

The findings were published today in the medical journal Blood, and were presented at an international meeting of bone biology experts in Brisbane earlier this month.

The researchers tested a new type of treatment that specifically targets a protein called sclerostin, which in healthy bones is an important regulator of bone formation. Sclerostin halts bone formation, and the researchers speculated that if they could inhibit the action of sclerostin, they could reverse the devastating bone disease that occurs with multiple myeloma.

Dr Michelle McDonald and Professor Peter Croucher, of the Bone Biology Division of the Garvan Institute of Medical Research in Sydney, led the study.

“Multiple myeloma is a cancer that grows in bone, and in most patients it is associated with widespread bone loss, and recurrent bone fractures, which can be extremely painful and debilitating,” says Dr McDonald.

“The current treatment for myeloma-associated bone disease with bisphosphonate drugs prevents further bone loss, but it doesn’t fix damaged bones, so patients continue to fracture. We wanted to re-stimulate bone formation, and increase bone strength and resistance to fracture.”

The new therapeutic approach is an antibody that targets and neutralises sclerostin, and in previous clinical studies of osteoporosis, such antibodies have been shown to increase bone mass and reduce fracture incidence in patients.

The researchers tested the anti-sclerostin antibody in mouse models of multiple myeloma, and found that not only did it prevent further bone loss, it doubled bone volume in some of the mice.

Dr McDonald says, “When we looked at the bones before and after treatment, the difference was remarkable – we saw less lesions or ‘holes’ in the bones after anti-sclerostin treatment.

“These lesions are the primary cause of bone pain, so this is an extremely important result.”

The researchers have a biomechanical method to test bone strength and resistance to fracture, and found that the treatment also made the bones substantially stronger, with more than double the resistance to fracture observed in many of the tests.

They then combined the new antibody with zoledronic acid, a type of bisphosphonate drug, the current standard therapy for myeloma bone disease.

“Bisphosphonates work by preventing bone breakdown, so we combined zoledronic acid with the new anti-sclerostin antibody, that re-builds bone. Together, the impact on bone thickness, strength and resistance to fracture was greater than either treatment alone,” says Dr McDonald.

The findings provide a potential new clinical strategy for myeloma. While this disease is relatively rare, with approximately 1700 Australians diagnosed every year, the prognosis is extremely poor, with less than half of those diagnosed expected to survive for more than five years.

Prof Croucher, Head of the Bone Biology Division at Garvan, says that preventing the devastating bone disease of myeloma is critical to improve the prognosis for these people.

“Importantly, myelomas, like other cancers, vary from individual to individual and can therefore be difficult to target. By targeting sclerostin, we are blocking a protein that is active in every person’s bones, and not something unique to a person’s cancer. Therefore, in the future, when we test this antibody in humans, we are hopeful to see a response in most, if not all, patients,” Prof Croucher says.

“We are now looking towards clinical trials for this antibody, and in the future, development of this type of therapy for the clinical treatment of multiple myeloma.

“This therapeutic approach has the potential to transform the prognosis for myeloma patients, enhancing quality of life, and ultimately reducing mortality.

“It also has clinical implications for the treatment of other cancers that develop in the skeleton.”

Study shows biomarkers can predict which ER-positive breast cancer patients respond best to first-line therapy

Two challenges in treating patients with estrogen-positive breast cancer (ER+) have been an inability to predict who will respond to standard therapies and adverse events leading to therapy discontinuation. A study at The University of Texas MD Anderson Cancer Center revealed new information about how the biomarkers retinoblastoma protein (Rb) and cytoplasmic cyclin E could indicate which patients will respond best to current first-line therapies.

The study also discovered that combining the current therapy with autophagy inhibitors will result in using one-fifth of the dosage of the standard treatment, which could significantly reduce side effects associated with this therapy. Findings were published in the June 27 issue of Nature Communications.

Standard treatment, consisting of palbociclib, often has adverse side effects and not all ER+ patients respond to the therapy. Palbociclib inhibits proteins called CDK4 and CDK6 (CDK4/6) and tumor cells escape this inhibition by activating autophagy, a process allowing cancer cells to thrive even when starved of nutrients. By combining palbocicilb with autophagy inhibitors in cells that express normal Rb and nuclear cyclin E, the dose of palbociclib was significantly reduced.

Khandan Keyomarsi, Ph.D., professor of Experimental Radiation Oncology, led a team that demonstrated how CDK4/6 and autophagy inhibitors synergistically induce cell senescence in Rb-positive cytoplasmic cyclin E-negative cancers. CDK4/6 inhibitors are approved by the Food and Drug Administration (FDA).

“Our findings could impact the majority of ER+ and HER2-negative breast cancers accounting for about 60 percent of advanced breast cancers,” said Keyomarsi. “We demonstrated for the first time evidence that Rb and cytoplasmic cyclin E status have a very strong effect on predicting response to the current standard first-line therapy for this population of patients, hormonal therapy plus palbociclib.We also discovered that by inhibiting the pathway such as autophagy that causes tumor cells to escape palbociclib growth inhibition, CDK4/6 inhibitor was more effective.”

Deregulation of cell cycle checkpoint proteins, such as CDK4/6, is a key hallmark of cancer, resulting in uncontrolled cellular growth and tumor formation. Some CDK4/6 inhibitors, including palbociclib, ribociclib and abemaciclib, have shown potential in pre-clinical and clinical studies in numerous solid tumors. Palbociclib has demonstrated benefits in Phase II and III trials in advanced ER+ breast cancers, doubling progression-free survival compared to drugs such as letrozole or fulvestrant, and is currently being evaluated clinically in other solid tumors.

“Data provided through The Cancer Genome Atlas revealed alterations in the CDK4/6/cyclin D pathway in about 35 percent of the patients, making them an ideal population for targeting CDK4/6,” said Keyomarsi. “Our study revealed that inhibition of CDK4/6 and autophagy pathways cooperate to induce sustained growth inhibition and senescence in vitro and in vivo, in breast and other solid tumors and showed how autophagy inhibition can significantly decrease the dose of palbociclib required to treat breast cancer patients. We believe this new strategy can improve the efficacy of other CDK4/6 inhibitor treatments like ribociclib and abemaciclib.”

The team’s findings indicated how Rb and cyclin E status predicts response to a combination of CDK4/6 and autophagy inhibition in pre-clinical models and that autophagy blockade is successful in reversing resistance to palbociclib.

“Palbociclib resistance is a significant limitation of this treatment which is not curative and does not prolong survival even though transient responses and prolongation of response have formed the basis of FDA approval,” said Keyomarsi. “Our study provides evidence that models of hormone receptor-negative cancer and even non-breast cancer malignancies can respond to the combination of palbociclib and autophagy inhibition, when selected based on Rb and cyclin E isoform status, representing a completely new therapeutic opportunity for these cancers.”

Keyomarsi and colleagues anticipate future clinical studies based on this pre-clinical and clinical evidence with the aim of developing translational and clinical applications.

Targeted drug shows promise in rare advanced kidney cancer

Some patients with a form of advanced kidney cancer that carries a poor prognosis benefited from an experimental drug targeted to an abnormal genetic pathway causing cancerous growth, according to research led by a Dana-Farber Cancer Institute scientist.

The drug, savolitinib, showed clinical activity in patients with metastatic papillary renal cell carcinoma (PRCC) whose tumors were driven by overactivity of the MET signaling pathway, but was not effective for patients whose tumors lacked the MET abnormality, said the investigators, led by Toni Choueiri, MD, director, Lank Center for Genitourinary Oncology, and director, Kidney Cancer Center, both of Dana-Farber.

These results from a single-arm, multicenter phase II clinical trial, reported in the Journal of Clinical Oncology, suggest that savolitinib holds promise as a personalized treatment for a subgroup of patients with metastatic papillary renal cell carcinoma, the researchers said.

In the US alone, about 6,400 cases of PRCC are expected to be diagnosed in 2017, compared to a total of 64,000 cases of kidney cancers. The majority of them are classified as clear cell renal cell cancers. Papillary renal cell carcinoma are non-clear cell kidney cancers. No good treatments exist for advanced or metastatic PRCC.

The current trial tested savolitinib, a potent and selective MET inhibitor, in 109 patients with locally advanced or metastatic PRCC. Of the 109 patients, 40 percent had tumors driven by MET, 42 percent had tumors that did not rely on MET, and MET status was unknown in 17 percent of patients.

When the results were analyzed, 18 percent of patients with MET-driven cancers had significant shrinkage of their tumors, and 50 percent had stable disease. By contrast, none of the patients with MET-independent tumors had shrinkage response, and only 24 percent had stable disease.

In addition, the length of time after treatment before the cancer began growing was significantly longer in the MET-driven tumor group – 6.2 months versus 1.4 months.

“These data support the hypothesis that savolitinib has antitumor activity in patients with MET-driven papillary renal cell carcinoma,” the authors wrote. “Our study identified a defined molecular group and highlights the prevalence of MET-driven disease in this rare population of RCC patients.”

Although some patients had their dosage of savolitinib reduced and two patients discontinued treatment because of side effects, the researchers said the drug was generally well-tolerated.

Combination approach improves power of new cancer therapy

An international research team has found a way to improve the anti-cancer effect of a new medicine class called ‘Smac mimetics’.

The team discovered how a protein called MK2 helps to keep cancer cells alive, making them resistant to the anti-cancer effects of Smac mimetics. The findings provide a rationale for combining inhibitors of MK2 with Smac mimetics as a potentially powerful new combination therapy for cancers with few treatment options, such as acute myeloid leukaemia (AML).

The research, recently published in the journal Molecular Cell, was the outcome of a research collaboration between Dr Najoua Lalaoui, Professor John Silke and colleagues at the Walter and Eliza Hall Institute, Australia; Professor Pascal Meier and colleagues at the Institute of Cancer Research, UK; and Professor Manolis Pasparakis and colleagues at the Cluster of Excellence CECAD at University of Cologne, Germany.

Dr Lalaoui said the research helped to advance her team’s previous discovery that combining the Smac mimetic agent birinapant with another new class of anti-cancer agents, called p38 inhibitors, could offer a new approach to treating AML.

“We knew these two agents could be combined, but didn’t fully understand the how they worked together at the molecular level,” Dr Lalaoui said.

“This latest study has pinpointed the MK2 protein as critical for the combination of Smac mimetics and p38 inhibitors to have a potent anti-cancer effect. As well as understanding our previous discovery better, it also highlights MK2 as an exciting new target for anti-cancer therapies, particularly in combination with Smac mimetics.”

Professor Silke said the research was part of a growing trend in the field, taking ‘rational’ approaches to treating cancer better, particularly through selecting combinations of anti-cancer agents.

“By understanding precisely which molecules are helping cancer cells to survive and evade treatment, we can develop smarter ways to kill these cells,” Professor Silke said.

“In the first place, the rational development of combination therapies has the potential to provide new treatments for cancers, such as AML, that have previously had poor outcomes.”

He said another potential benefit of combined anti-cancer therapies could be using each agent at lower doses.

“With a combined approach, the agents could still kill the cancer cell but with fewer harmful side effects on healthy tissues. Our goal is to develop cancer treatments that are both safer and more powerful than are currently available” Professor Silke said.

HPV Testing Leads to Earlier Detection and Treatment of Cervical Precancer

Women who receive human papillomavirus (HPV) testing, in addition to a pap smear, receive a faster, more complete diagnosis of possible cervical precancer, according to a study of over 450,000 women by Queen Mary University of London (QMUL) and the University of New Mexico (UNM) Comprehensive Cancer Center.

HPV is a virus that can cause cervical, vaginal, penile and anal cancers. More than 520,000 cases of cervical cancer are diagnosed worldwide each year, causing around 266,000 deaths. A common screening procedure for cervical cancer is the Pap smear, which tests for the presence of precancerous or cancerous cells on the cervix.

The study, published in JAMA Oncology, used data from the New Mexico HPV Pap Registry in the United States. It is the first comprehensive evaluation of HPV testing on the long-term outcomes of women who had received a borderline abnormal Pap test result.

A total of 457,317 women were included in the study. Of these, 20,677 women (4.5 percent) received a borderline abnormal result through a Pap smear and were followed in the study for five years. Some of the women with borderline abnormal Pap smear results had an HPV test.

HPV testing led to a 15.8 percent overall increase in the detection of cervical precancers and time to detection was much shorter (a median of 103 days versus 393 days).

Virtually all cervical pre-cancers were detected in women who tested positive for HPV, suggesting HPV testing to be a good additional screening method after the Pap smear. Colposcopy, which is a medical examination of the cervix, could then be focused on women who would need it most: those with a positive HPV test.

At the same time, however, HPV testing of women resulted in 56 percent more biopsies and a 20 percent increase in surgical treatment procedures performed. Most of the additional biopsies were for low grade lesions which could have regressed, indicating some overtreatment due to HPV testing.

Professor Jack Cuzick from QMUL said: “This study shows that knowing a woman’s HPV status can help determine her likelihood of needing additional procedures, and prioritise immediate treatment and medical resources to the women who need them most.”

Professor Cosette Wheeler from the UNM Comprehensive Cancer Center said: “The benefits of HPV testing outweigh the harms observed but it’s important to understand and quantify the harms as well.”

The authors warn that, as this was an observational study, the use of HPV testing was not randomised. So, it is also possible that there could be socioeconomic or other relevant differences among health care facilities that have not been measured.

UTHealth’s Lenard Lichtenberger Tests Effectiveness of Lipidic Aspirin Formulation Against Cancer

Scientists at The University of Texas Health Science Center at Houston (UTHealth) are testing the effectiveness of a soy-enriched aspirin formulation designed to fight colorectal cancer with fewer side effects.

Lenard Lichtenberger, Ph.D., professor of integrative biology and pharmacology at McGovern Medical School at UTHealth, is the principal investigator for the preclinical study funded with a $1.9 million grant from the National Cancer Institute (NCI). The grant was awarded to PLx Pharma Inc., the specialty pharmaceutical company developing this new form of aspirin.

While aspirin reduces the risk of colorectal cancer, daily use can cause ulcers and stomach bleeding. Colorectal cancer is a leading cause of cancer death in the United States claiming more than 50,000 lives in 2013, according to the Centers for Disease Control and Prevention.

First synthesized more than a century ago and hailed as a wonder drug, aspirin has been long known to reduce a person’s likelihood of heart disease and stroke. But, the research into its cancer protection benefits is relatively new.

For example, a popular medical search engine (PubMed) has less than 100 entries for the words aspirin and cancer between 1971 and 1974 compared to more than 4,000 since 2011.

The research into the chemopreventive action of aspirin is so conclusive that the U.S. Preventive Services Task Force recommends that people between the ages of 50 and 69 take low-dose aspirin on a daily basis to prevent colorectal  cancer so long as they consult with their physician first.

Custom built molecule shows promise as anti-cancer therapy

Scientists at the University of Bath funded by Cancer Research UK have custom-built a molecule which stops breast cancer cells from multiplying in laboratory trials, and hope it will eventually lead to a treatment for the disease.

But perhaps even more importantly the method they used to create the molecule has potential to be applied to develop new treatments for a wide range of cancers and other diseases.

The team, from the Department of Biology & Biochemistry, working with colleagues at the University of Queensland in Australia and the University of Bristol, modified a protein which can interfere with cell multiplication in many cancers, including breast cancer, by binding with another protein and rendering it inactive.

They took a small piece of the protein, called a peptide, that is known to be important in binding, and modified it to retain the structure otherwise lost when cut out. The modification has the additional advantage of protecting the peptide from being broken down within cells. The resulting molecule still binds to its target protein and inhibits cancer cell multiplication, but crucially can travel across cell membranes to get at it. The full-sized proteins, which the peptides are taken from, are usually too large to protect from breakdown or to cross protective cell membranes so this removes a literal barrier to developing treatments.

The study is published in the journal ACS Chemical Biology

Dr Jody Mason, one of the lead researchers on the project, said: “Peptides have the potential to be incredibly potent drugs which are exquisitely specific for their target. However they are easily broken down in the body, much like when we eat a steak. We have modified the peptides so that they retain the structure they have within the full-size protein and can therefore bind to the target “

Professor David Fairlie, from the University of Queensland added “This is a particularly challenging cancer target involving intertwined proteins and large surfaces that must be blocked. International collaborations like this one have the potential to combine resources and scientific skills from multiple disciplines to conquer difficult problems in targeting human disease.”

Dr Justine Alford, Cancer Research UK’s senior science information officer, said: “This early study may have laid the groundwork for a potential new treatment for certain cancers by creating a sophisticated designer molecule that can effectively block a cancer-fuelling target in cells.

“Cancer survival is improving, but people still die from their disease, so we need to develop innovative ways such as this that could help more people survive in the future.” The team now intend to continue to work on the molecule to improve its stability, with a long-term view to it eventually becoming a cancer drug, although this is still years away.

They are also interested in finding other candidate peptides for similar trials.

The researchers believe that other small peptides are a promising avenue of research to create new treatments for different types of cancer, and potentially other diseases such as Alzheimer’s disease

A patent study on the great new hope emerging from marine derived anticancer drugs

Microtubule dynamics govern crucial cellular functions and this is why microtubules are one of the most attractive anticancer drug targets. Microtubule targeting agents (MTAs) have the ability to treat a wide range of cancers. However, drug induced cytotoxicity and adverse side effects have hindered their development. Another major setback is multiple drug resistance in tumor cells. These limitations have prompted the need to develop novel MTAs from alternative sources, with better therapeutic efficacies. Recently, MTAs from marine sources have grabbed much attention due to their unique tubulin binding features and remarkable ability to reduce tumor progression.

The authors have summarized some of the most promising marine derived MTAs by systematically searching patent databases such as USPTO, Espacenet and WIPO for recent patents published from 2006 up to 2016. After a critical data analysis, only those patents focusing on the chemical synthesis and/or modifications of marine derived MTAs along with a significant demonstration of their in vitro and/or in vivo activity have been reviewed.

The survey of recent patents revealed that chemically modified versions of marine derived MTAs, overcoming drug resistance and their novel combination therapies increasing the overall efficacy, have positioned them as future anticancer blockbusters. Of particular interest are dolastatin, laulimalide, peloruside, hemiasterlin, halichondrin, eribulin mesylate, discodermolide, dictyostatin, cryptophycin and their analogs which have significant antiproliferative potency against a wide array of cancers and are also able to overcome multidrug resistance. A deeper understanding of the molecular mechanisms behind the specific drug interactions and of microtubule molecular biology in general, combined with innovative therapeutic regimen would lead to major advances in the field of cancer therapy.