FDA Approves the Roll-Over Combination Study with Checkpoint Inhibitor Immunotherapies to Allow Continued Access to BriaVax™ in Patients with Advanced Breast Cancer

The FDA has approved the roll-over combination study of the investigational breast cancer vaccine, BriaVax™ with pembrolizumab {Keytruda; manufactured by Merck & Co., Inc. or ipilimumab {Yervoy; manufactured by Bristol-Myers Squibb Company for patients previously treated with BriaVax™ from the ongoing Phase I/IIa Clinical Trial in Advanced Breast Cancer.

BriaVax™ is a whole-cell breast cancer vaccine genetically engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), a substance that activates the immune system by allowing the body to recognize and eliminate cancerous cells by inducing tumor-directed T cell and potentially antibody responses.

This roll-over combination study allows the patients who did not respond to BriaVax™ (monotherapy) treatment to be treated and continue to receive the potential clinical benefits of the vaccine in combination with either pembrolizumab or ipilimumab. This approach is based on the hypothesis that both pembrolizumab and ipilimumab may improve the anti-tumor activity of vaccine in patients with advanced breast cancer. Safety and efficacy data will be evaluated.

“We are very excited to evaluate the effects of BriaVax™ with other approved anti-tumor immunotherapeutic agents. We expect this study to extend and potentiate the clinical benefits of BriaVax™ in advanced breast cancer patients,” stated Dr. Williams, BriaCell’s President & CEO in a press release. “We look forward to expanding our clinical study and exploring potential immunotherapy partnerships with leading pharmaceutical companies in the future, and we are pleased with the FDA decision,” Dr. Williams added.

The clinical investigators will work closely with Cancer Insight, LLC, BriaCell’s contract research organization, to manage the clinical and regulatory aspects of the clinical trial for the roll-over combination study of BriaVax™ on behalf of BriaCell. More information on the roll-over combination study of BriaVax™ with either ipilimumab or pembrolizumab will be available on ClinicalTrials.gov (Study identifier: BRI-ROL-001).

Manufactured by Merck & Co., Inc., KEYTRUDA® (pembrolizumab) is a prescription medicine that may treat certain cancers by working with the immune system. It has been approved for the treatment of a number of cancer indications excluding breast cancer.

Manufactured by Bristol-Myers Squibb Company, YERVOY® (ipilimumab) is a prescription medicine used in adults and children 12 years and older to treat melanoma (a kind of skin cancer) that has spread (metastatic) or cannot be removed by surgery (unresectable). It is a monoclonal antibody that works to activate the immune system and enabling them to recognize and destroy cancer cells.

BriaVax™ is a whole-cell breast cancer vaccine genetically engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), a substance that activates the immune system. Previously, a small Phase I study documented very prompt and near complete regression of metastatic breast cancer deposits in the breast, lung, soft tissue, and even the brain.

The ongoing open-label Phase I/IIa study will evaluate BriaVax™ in up to 40 advanced breast cancer patients. This trial is listed in ClinicalTrials.gov as NCT03066947. The trial is being conducted along with the co-development of BriaDx™, our companion diagnostic test. The interim data for the first 10 patients is expected by the first quarter of 2018.

BriaCell is an immuno-oncology focused biotechnology company developing a targeted and safe approach to the management of cancer. BriaCell’s mission is to serve late-stage cancer patients with no available treatment options.

Immunotherapy has come to the forefront of the fight against cancer, harnessing the body’s own immune system in recognizing and selectively destroying the cancer cells while sparing normal ones. Immunotherapy, in addition to generally being more targeted and less toxic than commonly used types of chemotherapy, is also thought to be a strong type of approach aimed at preventing cancer recurrence.

The results of two previous Phase I clinical trials (one with the precursor cell line not genetically engineered to produce GM-CSF and one with BriaVax™) have been encouraging in patients with advanced breast cancer. Most notably, one patient with metastatic breast cancer responded to BriaVax™ with substantial reduction in tumor burden including lung and brain metastases. The company is currently conducting a Phase I/IIa clinical trial for BriaVax™ in patients with advanced breast cancer whose disease has progressed following at least one prior treatment course.

This trial is listed in ClinicalTrials.gov as NCT03066947.  The trial is being conducted along with the co-development of BriaDx™, our companion diagnostic test. The interim data for the first 10 patients is expected by the first quarter of 2018.

In a previous Phase I setting, a patient with metastatic breast cancer responded to BriaVax™ with objective reduction in tumor burden. To expand on this finding, after updating the clinical protocol of the original investigational new drug (IND) application, an open-label Phase I/IIa clinical trial enrolling up to 40 late stage breast cancer patients with recurrent and/or metastatic disease has been launched. Patients will be administered BriaVax™ every two weeks for the first month of treatment, then monthly up to one year.

The primary objective of the Phase I/IIa clinical trial is to evaluate the safety of BriaVax™ in study subjects, and the principal secondary objective is an evaluation of the tumor size reduction. Tumor response will be monitored every three months during the study. The trial will also evaluate progression-free survival (PFS) and overall survival (OS).

For additional details regarding the clinical trial, please visit:
https://www.clinicaltrials.gov/ct2/show/NCT03066947

Public-Private Consortium Aims to Cut Preclinical Cancer Drug Discovery from Six Years to Just One

Scientists from two U.S. national laboratories, industry and academia today launched an unprecedented effort to transform the way cancer drugs are discovered by creating an open and sharable platform that integrates high-performance computing, shared biological data from public and industry sources and emerging biotechnologies to dramatically accelerate the discovery of effective cancer therapies.

The goal of the consortium – Accelerating Therapeutics for Opportunities in Medicine (ATOM) – is to create a new paradigm of drug discovery that would reduce the time from an identified drug target to clinical candidate from the current approximately six years to just 12 months. ATOM aims to transform cancer drug discovery from a time-consuming, sequential and high-risk process into an approach that is rapid, integrated and with better patient outcomes — using supercomputers to pretest many molecules simultaneously for safety and efficacy.

The consortium comprises the Department of Energy’s Lawrence Livermore National Laboratory (LLNL), GSK, the National Cancer Institute’s Frederick National Laboratory for Cancer Research (FNLCR), and the University of California, San Francisco (UCSF). ATOM welcomes additional public and private partners who share the vision.

“The goals of ATOM are tightly aligned with those of the 21st Century Cures Act, which aims in part to enable a greater number of therapies to reach more patients more quickly,” said FNLCR Laboratory Director David Heimbrook. “Although initially focused on precision oncology – treatments targeted specifically to the characteristics of the individual patient’s cancer – the consortium’s discoveries could accelerate drug discovery against many diseases.”

ATOM will develop, test and validate a multidisciplinary approach to drug discovery in which modern science, technology and engineering, supercomputing simulations, data science and artificial intelligence are highly integrated into a single drug-discovery platform that can untimately be shared with the drug development community at large.

“As we have learned more about what modern supercomputers can do, we’ve gained confidence that this approach can make a big difference in creating medicines,” said John Baldoni, senior vice president, R&D at GSK. “We must do all that we can to reduce the time it takes to get medicines to patients. GSK is working to set a precedent with pharmaceutical companies by sharing data on failed compounds.”

GSK will initially contribute chemical and in vitro biological data for more than 2 million compounds from its historic and current screening collection, as well as preclinical and clinical information on 500 molecules that have failed in development but could help accelerate development of new compounds by providing knowledge about the underlying biology of candidate compounds and that of the human body. Combined with data on successful drugs, GSK’s offering represents a broad base of information for ATOM researchers. In addition, GSK will provide expertise in drug discovery and development, computational chemistry and biology.

The ATOM team will combine data provided by GSK with publicly available data, and that of future consortium members, to generate new dynamic models that can better predict how molecules will behave in the body compared to the current iterative and time-consuming practices. In this effort, LLNL will contribute its best-in-class supercomputers, including its next-generation system Sierra, as well as its expertise and innovative approaches to modeling and simulation, cognitive computing, machine learning and algorithm development. More broadly, by tackling the ambitious challenge of cancer therapies, ATOM will drive technologies vital to the core missions of the Department of Energy and National Nuclear Security Administration (NNSA).

“ATOM is a novel public-private partnership that draws on the lab’s unique capabilities to create a paradigm change in drug development,” said LLNL Director Bill Goldstein. “It will help to strengthen U.S. leadership in high-performance computing and, by speeding the discovery of therapeutics, contribute to biosecurity.”

For its part, FNLCR will contribute from its wealth of scientific expertise in precision oncology, computational chemistry and cancer biology, as well as support for open sharing of data sets and predictive modeling and simulation tools. UCSF will provide expertise from a long history of innovation in drug discovery and medicine to improve the lives of patients.

“We at UCSF are eager to lend our expertise to this effort,” said UCSF Chancellor Sam Hawgood, MBBS. “UCSF scientists and clinicians have long been leaders in drug discovery, therapeutics, and cancer biology with the UCSF Helen Diller Family Comprehensive Care Center among the top-ranked cancer institutes in the country. Our role with ATOM is therefore in lock step with UCSF’s mission of advancing health worldwide.”

ATOM welcomes additional public and private partners who share the vision of the consortium, which will have physical headquarters in the Mission Bay neighborhood of San Francisco, adjacent to UCSF’s newest campus.

Researchers quantify breast cancer risk based on rare variants and background risk

Rare variants combined with background genetic risk factors may account for many unexplained cases of familial breast cancer, and knowing the specific genes involved could inform choice of prevention and treatment strategies, according to findings presented in a plenary session at the American Society of Human Genetics (ASHG) 2017 Annual Meeting in Orlando, Fla.

Researchers Na Li, MD, who presented the work; Ian Campbell, PhD, lead investigator; and their colleagues at the Peter MacCallum Cancer Centre in Melbourne, Australia, focused their study on patients at high risk of breast cancer: those with a personal or family history who were seeking an explanation.

“When you know which gene is conferring the risk of breast cancer, you can provide a more precise estimate of risk, know what to expect and watch out for, and tailor risk management strategies to the patient,” said Dr. Campbell. Unfortunately, in about half of these high-risk patients, no known genetic cause was found, suggesting a more complicated explanation. In such cases, cancer geneticists had long suspected that polygenic risk (risk conferred by a combination of genetic variants) was involved.

Genes do not work on their own, but rather as part of one’s overall genetic context, explained Dr. Li. “That ‘polygenic risk’ background is like a landscape full of hills and valleys, with each risky variant like a house on top of it,” she said. “If you inherit a high-risk variant – a tall house – but live in a valley, your overall risk of breast cancer may end up being average because your genetic landscape pulls it down.”

The concept of background genetic risk is not new, but for many years, scientists did not have the tools to collect and analyze the thousands of genomes needed to quantify it. Recent improvements in next-generation sequencing technology have addressed this challenge. As a result, Dr. Li and colleagues were able to sequence up to 1,400 candidate breast cancer genes in 6,000 familial breast cancer patients and 6,000 cancer-free controls. In this large sample, they searched for potential cancer-associated genes suggested by the literature, collaborators, and their own previous results, and identified at least 46 genes that were at least twice as likely to have mutations among participants with breast cancer than in those without.

They also used the data to calculate a polygenic risk score for each patient, and combined this score with data on their high and moderate-risk variants to estimate each patient’s overall risk of developing breast cancer. In the coming years, the researchers plan to expand the study internationally to further test and refine their findings across populations. They also hope to bring these more precise risk estimates into the clinic, to more accurately reassure women about their personal risk of cancer, or – if risk is high – advise preventive strategies such as screening at a younger age.

According to William V. Williams, MD, FRCP, CEO of BriaCell Therapeutics Corp. news on new variants are essential and extremely useful in tailoring and customizing their BriaVax™ breast vaccine technology with those variants in order to teach the body to recognize and eliminate cancerous cells. Their whole-cell breast cancer vaccine is genetically engineered to release granulocyte macrophage colony-stimulating factor (GM-CSF), a substance that activates the immune system. “Breast cancer is an evolving field, there are different sub types of breast cancer. As we know more about the genetics of breast cancer this will allow us to develop novel therapies to treat those different variants, that is part of what we are doing with our vaccines,” he told Modern Wall Street.

Blood Test for HPV May Help Predict Risk in Cancer Patients

A blood test for the human papillomavirus, or HPV, may help researchers forecast whether patients with throat cancer linked to the sexually transmitted virus will respond to treatment, according to preliminary findings from the University of North Carolina Lineberger Comprehensive Cancer Center.

HPV can cause oropharyngeal cancer, which is a cancer of the throat behind the mouth, including the base of the tongue and tonsils. Studies have shown that patients with HPV-positive oropharyngeal cancer have better outcomes than patients whose cancer is not linked to the virus.

Preliminary findings presented at this year’s American Society for Radiation Oncology Annual Meeting suggest a genetic test for HPV16 in the blood could be useful to help assess risk for patients, and could help identify patients suitable for lower treatment doses.

“Our work on this blood test is ongoing, but we are optimistic that ‘liquid biopsy’ tests such as ours may be useful in the personalization of therapy for many patients with HPV-associated oropharyngeal cancer,” said the study’s senior author Gaorav P. Gupta, MD, PhD, UNC Lineberger member and assistant professor in the UNC School of Medicine Department of Radiation Oncology.

To avoid over-treating patients and to spare them from toxic treatment side effects, UNC Lineberger’s Bhisham Chera, MD, an associate professor in the radiation oncology department, led studies testing whether favorable-risk patients with HPV-positive oropharyngeal cancer can be treated successfully with lower doses of radiation and chemotherapy. A phase II clinical trial using this de-intensified regimen have shown “excellent” cancer control, Chera said.

The researchers used a number of selection criteria to identify patients who can benefit from lower-doses: patients had to be positive for HPV, and they had to have smoked fewer than 10 pack years. Chera said this system is not perfect, however. The researchers have seen cancer recur in non-smoking patients as well as “excellent” cancer control in longtime smokers.

“This has led us to question whether we can get better prognostication with other biomarkers,” Chera said.

They developed a test that can detect HPV16 circulating in the blood, and found that circulating HPV16 DNA was detectable using the test in the majority of a group of 47 favorable-risk oropharyngeal cancer patients.

In a finding that seems counterintuitive, they discovered that very low or undetectable HPV16 pretreatment levels in their blood actually had higher risk of persistent or recurrent disease for chemotherapy and radiation treatment. In contrast, patients with high pretreatment levels of HPV16 in their blood had 100 percent disease control.

They hypothesized that, potentially, the patients with undetectable/low pre-treatment HPV16 levels in the blood may have different, more radiation/chemotherapy resistant cancers.

“Our current theory is that these patients with low or undetectable levels of HPV16 have a different genetic makeup—one that is perhaps less driven purely by HPV, and thus potentially less sensitive to chemotherapy and radiation,” Gupta said. “We are performing next generation sequencing on these patients to search for additional genetic markers that may give us a clue regarding why they have a worse prognosis.”

They also identified a subset of patients who rapidly cleared the HPV16 from their blood. Researchers hypothesize that they could use their findings to further stratify patients who may be eligible for lower intensity treatment.

“A tantalizing – and yet currently untested – hypothesis is whether this subset of ultra-low risk patients may be treated with even lower doses of chemoradiotherapy,” Gupta said.

Genetic Targets to Chemo-Resistant Breast Cancer Identified

Research led by Dr. Carlos Arteaga, Director of the Harold C. Simmons Comprehensive Cancer Center, has identified potential targets for treatment of triple negative breast cancer, the most aggressive form of breast cancer.

Increased activity of two genes, MCL1 and MYC, is associated with the development of chemotherapy resistance. The increased action of these two genes boosts mitochondrial oxidative phosphorylation, which promotes the growth of chemotherapy-resistant cancer stem cells, the research showed.

“Alterations in these two genes are easily detectable with tumor gene tests in current use. Combinations of drugs that inhibit MCL1 or MYC, or both, have the potential to reduce the development of chemotherapy resistance and should be studied in clinical trials,” said Dr. Arteaga, Professor of Internal Medicine at UT Southwestern Medical Center. Dr. Arteaga holds The Lisa K. Simmons Distinguished Chair in Comprehensive Oncology.

Most breast cancers can be treated with hormone therapy, but about 15 percent of cases are triple negative breast cancer, meaning the cancer cells are not influenced by hormones like estrogen or progesterone. These triple negative breast cancers must, therefore, be treated with chemotherapy, which is toxic to healthy cells as well as cancer cells. Furthermore, most triple negative breast cancers eventually become resistant to chemotherapy and the cancer then spreads unchecked.

Drugs that inhibit activity of the MCL1 or MYC genes are in development, Dr. Arteaga said. These drugs, given in conjunction with standard chemotherapies, could potentially slow or even prevent the development of chemotherapy resistance, improving the outlook for this aggressive form of breast cancer.

The research was conducted at Vanderbilt-Ingram Cancer Center and appears in the journal Cell Metabolism. The research was supported by the Susan G. Komen for the Cure Foundation, the Breast Cancer Research Foundation, a National Institutes of Health Breast Cancer SPORE grant, and a Vanderbilt-Ingram Cancer Center Support Grant.

The Simmons Cancer Center at UT Southwestern is one of 49 NCI-designated Comprehensive Cancer Centers in the U.S. and the only one in North Texas. It is also one of 30 U.S. cancer research centers to be designated by the National Cancer Institute as a National Clinical Trials Network Lead Academic Site.

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 100,000 hospitalized patients, 600,000 emergency room cases, and oversee approximately 2.2 million outpatient visits a year.

By Decoding How HPV Causes Cancer, Researchers Find a New Potential Treatment Strategy

A study that teases apart the biological mechanisms by which human papillomaviruses (HPV) cause cancer has found what researchers at Georgetown University Medical Center say is a new strategy that might provide targeted treatment for these cancers.

HPVs are responsible for the majority of cervical cancer and a substantial portion of head and neck and anal cancers, but therapy available to date is surgery and non-specific chemotherapy.

The new study, published Oct. 2 in the journal Oncotarget, found that E6, an oncoprotein produced by the virus, interacts with several other molecules in host cells in a manner that ensures infected cells cannot die. If they are immortal and continue to multiply, cancer develops.

“There is no targeted treatment now for these cancers since German virologist Harald zur Hausen, PhD, discovered in 1983 that HPV can cause cervical cancer. Recently, the numbers of HPV-linked head and neck cancers have increased in the U.S. Now we have a chance to develop and test a very specific, potentially less toxic way to stop these cancers,” says the study’s lead author, Xuefeng Liu, MD, associate professor of pathology at Georgetown University Medical Center.  Liu is director of Telomeres and Cell Immortalization for the medical center’s Center for Cell Reprogramming.

Liu and his team have previously found that the HPV E6 oncoprotein interferes with the well-known p53 tumor suppressor to increase telomerase activity that extends the life span of infected cells. A telomerase is a protein that allows a cell to divide indefinitely when it would have stopped after a certain number of divisions.

In this study, researchers found that E6 also interacts with myc, a protein produced by the Myc gene, which controls gene expression in all healthy cells. They concluded that telomerase activity is dependent on E6-myc proteins hooking on to each other.

This means, says Liu, that designing a small molecule that stops E6 from joining up with myc should shut down persistent activation of telomerase. A small molecule could bind to E6 in the same spot that myc would, or bind on to myc in the same spot that E6 would, thus preventing an E6-myc complex.

“This small molecule would not be toxic to all normal cells or, importantly, to master stem cells, because myc would not be affected,” says Liu. “It could be a unique treatment, targeted specifically to HPV cancers.”

Georgetown researchers are now working on a prototype chemical to interfere with E6/Myc binding.

New research on probiotics in the prevention and treatment of colon cancer

In an innovative approach to colorectal cancer (CRC) prevention and treatment, scientists are studying ways to replace missing metabolites in patients prone to gut inflammation and CRC. A new study in The American Journal of Pathology describes how administration of histamine-producing gut microbes to mice lacking the enzyme histidine decarboxylase (HDC) reduced inflammation and tumor formation. These results suggest that alteration of the gut microbiome with probiotics may become a new preventative or therapeutic strategy for patients at risk for inflammatory bowel disease (IBD)-associated CRC.

“We are on the cusp of harnessing advances in microbiome science to facilitate diagnosis and treatment of human disease,” explained James Versalovic, MD, PhD, pathologist-in-chief at Texas Children’s Hospital, and Milton J. Finegold Professor of pathology & immunology at Baylor College of Medicine (Houston). “By simply introducing microbes that provide missing life substances, we can reduce the risk of cancer and supplement diet-based cancer prevention strategies.”

Researchers conducted a series of experiments using mice that were deficient in HDC, the enzyme required to convert histidine to histamine. Experimental mice were orally administered the probiotic Lactobacillus reuteri 6475, which is known to possess the histidine decarboxylase gene (hdc+) and is able to convert histidine to histamine; control animals received a placebo. The probiotic was administered both before and after the mice received a single dose of a colonic carcinogen (azoxymethane) plus an inflammation-inducing chemical (DSS) to induce tumor formation. Fifteen weeks later, the mice were sacrificed and the tissues removed for study.

The probiotic increased expression of bacterial HDC and amounts of histamine in the colons of the mice. Using positron emission tomography (PET) to visualize the tumors, control-treated mice showed evidence of tumors and increased glucose uptake in colon walls. In contrast, mice administered the probiotic had fewer and smaller tumors and significantly diminished areas of glucose uptake.

Inactive L. reuteri strains (those deficient in HDC activity) did not provide protective effects. These mice showed increased numbers of “hot spots” indicative of tumor formation and increased abdominal glucose uptake.

The active probiotic also reduced inflammation induced by the carcinogen plus DSS, as indicated by suppressed pro-inflammatory cytokine gene expression (i.e., those encoding KC, interleukin (IL)-22, IL-6, tumor necrosis factor (TNF), and IL-1α) and reduced cytokine concentrations in plasma (i.e., KC, IL-22, and IL-6). The active probiotic also counteracted an increase in immature myeloid cells induced by the carcinogen. According to Dr. Versalovic, “These observations are consistent with the conclusion that histamine-generating probiotic L. reuteri may attenuate AOM+DSS-induced colon carcinogenesis, at least in part, via enhanced maturation of circulating myeloid cells and concomitant reduction of pro-inflammatory cytokines.”

The role of histamine in human cancer is still unclear. However, when investigators analyzed data obtained from 2,113 CRC patient samples taken from 15 datasets, results showed better survival in patients with elevated patterns of HDC and histamine receptor gene expression. These findings indicate that histamine-generating probiotics, in the presence of sufficient protein (L-histidine) intake, may improve outcomes for patients with sporadic and IBD-associated CRC.

“Our results suggest a significant role for histamine in the suppression of chronic intestinal inflammation and colorectal tumorigenesis. We have also shown that cells, both microbial and mammalian, can share metabolites or chemical compounds that together promote human health and prevent disease,” said Dr. Versalovic.

Cell Surface Protein May Offer Big Target in Treating High-Risk Childhood Cancers

Oncology researchers studying high-risk children’s cancers have identified a protein that offers a likely target for immunotherapy–harnessing the immune system in medical treatments. In cell cultures and animal models, a potent drug attached to an antibody selectively zeroes in on cancer cells without harming healthy cells.

“We have built a strong foundation for developing a completely new and hopefully much less toxic treatment for neuroblastoma, the most common cancer in infants,” said study supervisor John M. Maris, MD, a pediatric oncologist at Children’s Hospital of Philadelphia (CHOP). “Furthermore, our findings may also lend support to the development of other immune-based therapies, such as CAR T-cells, in children with multiple aggressive cancers in addition to neuroblastoma.”

Maris, along with study leader and first author Kristopher R. Bosse, MD, and colleagues published their study today in Cancer Cell, which featured their findings as the cover story.

Neuroblastoma is a cancer of the developing peripheral nervous system that usually occurs as a solid tumor in a child’s chest or abdomen, and is the most common cancer in infants. It accounts for a disproportionate share of cancer deaths in children. Over decades, CHOP clinicians and researchers have built one of the world’s leading programs in neuroblastoma.

The study team used sophisticated sequencing tools to first discover molecules that are much more commonly found on the surface of neuroblastoma cells than on normal cells. “Our rationale was to identify a cell-surface molecule that an immune-based therapy could target without damaging healthy tissues,” said Bosse. “Using this approach, we identified a protein called glypican-2, or GPC2.” GPC2 is one of a family of glypicans—cell-surface proteins that interact with growth factors and cell surface receptors, influencing many intracellular signaling pathways important in development and cancer.

In addition to GPC2’s presence on neuroblastoma cells, the study team also found that GPC2 is necessary for a neuroblastoma tumor to proliferate. Both of those facts implied that a compound that acted against GPC2 might kill cancer cells, spare healthy cells, and limit the possibility of these tumors developing “immune escape” mechanisms, in which cancer cells resist an immunotherapy by shedding the target. “Given GPC2’s critical role in the growth of neuroblastomas, we hope that tumors will not be able to simply downregulate this protein in order to escape recognition by our immunotherapies that target GPC2,” said Bosse.

After pinpointing GPC2 as a very promising target for therapy, the researchers next worked with their colleagues at the National Cancer Institute to search for a weapon. They developed an antibody-drug conjugate (ADC) called D3-GPC2-PBD, which combined a very specific antibody that recognizes GPC2 with a potent chemotherapy drug that is internalized specifically by cancer cells. The drug payload damages DNA in tumors, while sparing healthy tissues from its toxic effects.

In cell cultures and mouse models of neuroblastoma, the ADC robustly killed neuroblastoma cells with no discernible toxicity to normal cells. “These findings establish that this type of immunotherapy could be potentially safe and effective against neuroblastoma,” said Maris. “Our next steps will be to further evaluate this ADC and also develop other immune-based therapies directed against GPC2. Because other glypicans in addition to GPC2 are overexpressed in other childhood cancers, it may also be possible to apply this approach across various types of high-risk pediatric cancers.”

Accelerating the Development of Next-Generation Cancer Therapies

To accelerate the development of next-generation cancer therapies, the Gene Editing Institute of the Helen F. Graham Cancer Center & Research Institute at Christiana Care Health System has agreed to provide genetically modified cell lines to Analytical Biological Services, Inc. (ABS) of Wilmington, Delaware.

Under a three-year agreement, the Gene Editing Institute will act as sole provider of gene editing services and genetically modified cell lines to ABS for replication, marketing and distribution to leading pharmaceutical and biomedical research companies worldwide.

“This agreement with ABS will speed the progress in the discovery of effective cancer therapies and accelerate the path to prevention, diagnosis and treatment of many forms of cancer,” said Nicholas J. Petrelli, M.D., the Bank of America endowed medical director of the Helen F. Graham Cancer Center & Research Institute at Christiana Care Health System.

“This partnership greatly enhances our capability to provide the highest quality genetically engineered cells for drug discovery,” said ABS President and CEO Charles Saller, Ph.D. “Our partners at the Gene Editing Institute are advancing molecular medicine, and their expertise adds a new dimension to our efforts to speed up drug discovery.”

“One goal of The Gene Editing Institute is to develop community partnerships that can advance translational cancer research,” said Eric Kmiec, Ph.D., founder and director of the Gene Editing Institute. “The Gene Editing Institute is driving innovation in gene engineering, and ABS has the know-how to grow and expand the cells in sufficient quantities, as well as to market them to pharmaceutical and biotechnology clients for drug screening and research.”

The Gene Editing Institute is a worldwide leader in the design of the tools that scientists need to manipulate and alter human genetic material easier and more efficiently than ever before. Scientists at the Gene Editing Institute have designed and customized an expanding tool-kit for gene editing, including the renowned CRISPR-Cas9 system, to permanently disrupt or knock out genes, add or knock in DNA fragments and create point mutations in genomic DNA. Last year, scientists at the Gene Editing Institute described in the journal Scientific Reports how they combined CRISPR and short strands of synthetic DNA to greatly enhance the precision and reliability of the CRISPR gene editing technique. Called Excision and Corrective Therapy, or EXACT, this new tool acts as both a Band-Aid and a template during gene mutation repairs.

Genetically modified cells can help advance cancer research. By inactivating a single gene, scientists can test if it affects tumor formation or somehow alters the response to cancer therapies. Similarly, inserting a gene into a cell can produce a gene product that is a target for potential new drugs.

“Gene editing and the CRISPR technology is having a major impact on anticancer drug development because it allows us to validate the target of the candidate drug,” said Dr. Kmiec. “Pharmaceutical companies want to use gene editing tools to identify new targets for anti-cancer drugs and to validate the targets they already have identified.”

The Delaware BioScience Association helped connect the Gene Editing Institute with ABS. “The collaborative agreement between the Gene Editing Institute and ABS exemplifies the power of building a strong biotech community, flourishing further innovation, and keeping businesses engaged and thriving in the state of Delaware,” said Helen Stimson, president and CEO of The Delaware BioScience Association. “The Delaware BioScience Association is committed to fostering meaningful relationships, such as this one, among its members, and establishing strategic partnerships that bolster the state’s innovation economy,” she said.

“This is one of those times when the forces of nature align to bring two perfectly matched skill sets together,” said Dr. Kmiec. “There is no question that our collaboration with ABS will accelerate the pace of drug discovery around the world.”

About The Gene Editing Institute

The Gene Editing Institute of Christiana Care Health System’s Helen F. Graham Cancer Center & Research Institute is unlocking the genetic mechanisms that drive cancer that can lead to new therapies and pharmaceuticals to revolutionize cancer treatment. Gene editing in lung cancer research has already begun setting the stage for clinical trials.

The Gene Editing Institute is integrated into the Molecular Screening Facility at The Wistar Institute in Philadelphia, PA, where its innovative gene-editing technologies are available to research projects at Wistar and to external users. Working with Wistar scientists, the Gene Editing Institute has begun research to conduct a clinical trial in melanoma. With funding from the National Institutes of Health, the Gene Editing Institute is partnering with A.I. duPont/Nemours to develop a gene editing strategy for the treatment of sickle cell anemia and leukemia. Under a grant from the U.S.–Israel Binational Industrial Research & Development Foundation, the Gene Editing Institute is working with Jerusalem-based NovellusDx to improve the efficiency and speed of cancer diagnostic screening tools. This work could lead to earlier identification of genetic mechanisms responsible for both the onset and progression of many types of cancers and the development of individualized therapeutics.

Gene Editing Institute scientists also provide instruction in the design and implementation of genetic tools. Partnerships with Bio-Rad Inc. and the Delaware Technical and Community College are producing gene editing curricula and teacher training workshops for both community colleges and secondary schools.

Study Suggests that Zika Virus Could Be Used to Treat Brain Cancer Patients

Recent outbreaks of Zika virus have revealed that the virus causes brain defects in unborn children. But in a study to be published September 5 in The Journal of Experimental Medicine, researchers from Washington University School of Medicine in St. Louis and the University of California, San Diego report that the virus could eventually be used to target and kill cancer cells in the brain.

Glioblastoma is the most common form of brain cancer and is frequently lethal; most patients die within two years of diagnosis. Just like normal, healthy tissues, the growth and development of glioblastomas is driven by stem cells that proliferate and give rise to other tumor cells. Glioblastoma stem cells are hard to kill because they can avoid the body’s immune system and are resistant to chemotherapy and radiation. But killing these cells is vital to prevent new tumors from recurring after the original tumor has been surgically removed.

“It is so frustrating to treat a patient as aggressively as we know how, only to see his or her tumor recur a few months later. We wondered whether nature could provide a weapon to target the cells most likely responsible for this return,” says Milan Chheda from Washington University School of Medicine in St. Louis.

One approach to killing cancer stem cells involves using viruses that specifically target tumor cells. Zika virus appears to disrupt fetal brain development by preferentially targeting neural stem and progenitor cells. The virus’ effects on adult brains—which contain fewer active stem cells that developing fetal brains—are generally much less severe.

“We hypothesized that the preference of Zika virus for neural precursor cells could be leveraged against glioblastoma stem cells,” says Michael Diamond, also from Washington University School of Medicine in St. Louis, who co-directed the study with Milan Chheda and with Jeremy Rich, from the University of California, San Diego and the Cleveland Clinic Lerner Research Institute.

The researchers found that Zika virus preferentially infected and killed patient-derived glioblastoma stem cells compared with other glioblastoma cell types or normal neural cells. When mice with aggressive glioma were injected with a mouse-adapted strain of Zika virus, the virus slowed tumor growth and significantly extended the animals’ lifespan.

The researchers then tested a mutant strain of Zika that is less virulent than naturally occurring strains of the virus. This “attenuated” strain, which is more sensitive to the body’s immune response, was still able to specifically target and kill glioblastoma stem cells and was even more effective when combined with a chemotherapy drug, temozolomide, that usually has little effect on these cells. “This effort represents the creative synthesis of three research groups with complementary expertise to attack a deadly cancer by harnessing the cause of another disease,” says Jeremy Rich. “Adults with Zika may suffer less damage from their infection, suggesting that this approach could be used with acceptable toxicity.”

“Our study is a first step towards the development of safe and effective strains of Zika virus that could become important tools in neuro-oncology and the treatment of glioblastoma,” says Diamond. “However, public health concerns will need to be addressed through pre-clinical testing and evaluations of the strains’ ability to disseminate or revert to more virulent forms.”

A blood test can predict early lung cancer prognosis

Cancer cells obtained from a blood test may be able to predict how early-stage lung cancer patients will fare, a team from the University of Michigan has shown.

This information could be used to determine which patients are most likely to benefit from additional therapies to head off the spread of the cancer to other areas of the body.

With a new single cell analysis service in U-M’s Comprehensive Cancer Center, the researchers are making the necessary technology more widely available in the university system. They hope these “liquid biopsies” will be offered to patients within the next five years.

Circulating tumor cells, representing only about one in a billion cells in the bloodstream, are largely untapped sources of information about tumors, but new methods are bringing their diagnostic value ever closer to patient care.

Sunitha Nagrath, U-M professor of chemical engineering who designs devices that can capture these rare cells, led a team including oncologists and surgeons to explore how cancer cells escape tumors and travel through the body in the bloodstream. This is how metastases, or satellite tumors elsewhere in the body, are thought to form.

“The tumors were constantly shedding cells even when they were small–that’s one thing we learned,” Nagrath said. “Although we define the tumors as early stage, already they are disseminating cells in the body.”

Early-stage lung cancer patients, whose tumors may only measure a few millimeters in diameter, are typically treated with surgical removal of the tumor, but the study results suggest that this may not be enough. A handful of patients had tumors that were shedding hundreds or thousands of tumor cells into the lung.

“Even though you removed the tumor, you left behind these hundreds and hundreds of cells,” Nagrath said. “If you know this patient walking out of the clinic is going to relapse after less than a year because of these cells, why don’t we treat them now?”

With a relatively small sample of 36 patients, the team can’t definitively say that an actively shedding tumor will lead to metastasis within a year, but Nagrath is exploring the predictive power of cancer cells drawn from the blood. In particular, the study showed that clusters of two or more tumor cells indicated shorter survival times. Six of the nine patients whose cancer returned during the two to 26 months of follow-up had circulating tumor cells appearing in clusters.

“Ultimately, this method will help us look for and find potential markers for either metastatic spread or cancer detection,” said Rishindra Reddy, U-M associate professor of surgery who coordinated the blood samples and designed the study with Nagrath and Nithya Ramnath, an associate professor of medical oncology at the U-M Medical School.

Gangs of aggressive cells

Genetic analysis confirmed that clusters showed higher expression of aggressive traits. They were better at moving, evading the immune system, recruiting blood cells to help them and resisting treatments. In other words, clustered tumor cells were better suited to spreading cancer to distant locations.

“These are drivers of tumor progression and resistance, and they are more important to target with therapy,” Nagrath said.

To gather the data underpinning these findings, the team took blood samples before, during and after tumor removal surgery. At each stage, surgeons collected blood from a vein in the patient’s arm, far from the tumor. Early in surgery, before disturbing the tumor, the surgeon also drew blood from the lung vein that drained from the tumor, where tumor cells are expected to be more concentrated.

And they were–as Vasudha Murlidhar, then a doctoral student in the Nagrath lab, showed by analyzing all the samples using a microfluidic chip of her own design. While tumor cells from the arm had a median count of around 1.3 per 3 milliliters, it was 7.5 per 3 ml of blood from the lung. Among the patients whose lung blood samples revealed hundreds or even thousands of tumor cells, the numbers fell sharply by the time the cells reached the vein in the arm.

It couldn’t be explained by mere dilution. The researchers hypothesize that the larger clusters are getting stuck in capillaries–potentially the start of a new tumor–or that many of these cells can’t survive in the bloodstream.

Toward monitoring cancer with blood tests

Nagrath is impatient to see liquid biopsy begin to benefit patients at U-M. Already, this study demonstrates that capturing cancer cells from the bloodstream can indicate which patients are most in need of a second treatment, such as chemotherapy, to go after the cells that have already dispersed in the body. It could also help doctors choose drugs that will be better at exploiting the weaknesses of these aggressive cells.

Nagrath is advancing the technology at U-M by co-directing a new service arm within the Cancer Center. The new Single Cell Analysis Core will isolate cancer cells from blood using many different microfluidic chips, developed by Nagrath’s group and others.

Evan Keller, a professor of urology in the Medical School, will lead the cell analysis techniques. This effort will primarily help cancer researchers better understand the disease for now, but Nagrath is hopeful that it won’t be long before liquid biopsies are part of routine patient care at Michigan Medicine.

“With a simple blood draw, we can tell the dynamic state of the disease during the treatment and after the treatment, monitoring it closely. If something has to show up on a CT scan, it may already be too late,” Nagrath said.

The study is titled “Poor prognosis indicated by venous circulating tumor cell clusters in early stage lung cancers” and will appear in Cancer Research.

The microfluidic chips for isolating cancer cells were produced at the Lurie Nanofabrication Facility at U-M. Captured cells were analyzed with the help of the Microscopy and Image Analysis Laboratory and the Cancer Center’s DNA Sequencing Core at U-M. This study was funded by the National Institutes of Health Director’s New Innovator Award, the U-M Lefkofsky Scholarship and the U-M Rackham International Student Fellowship.

Vasudha is now a postdoctoral scholar in biomedical engineering at the University of California, Davis.

Novartis garners first ever FDA approval for a CAR-T cell therapy, Kymriah(TM), for children and young adults with B-cell ALL that is refractory or has relapsed at least twice

Novartis announced today that the US Food and Drug Administration (FDA) has approved Kymriah(TM)(tisagenlecleucel) suspension for intravenous infusion, formerly CTL019, the first chimeric antigen receptor T cell (CAR-T) therapy, for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Kymriah is a novel immunocellular therapy and a one-time treatment that uses a patient’s own T cells to fight cancer. Kymriah is the first therapy based on gene transfer approved by the FDA.

“At Novartis, we have a long history of being at the forefront of transformative cancer treatment,” said Joseph Jimenez, CEO of Novartis. “Five years ago, we began collaborating with the University of Pennsylvania and invested in further developing and bringing what we believed would be a paradigm-changing immunocellular therapy to cancer patients in dire need. With the approval of Kymriah, we are once again delivering on our commitment to change the course of cancer care.”

The FDA has approved a Risk Evaluation and Mitigation Strategy (REMS) for Kymriah. The REMS program serves to inform and educate healthcare professionals about the risks that may be associated with Kymriah treatment. To support safe patient access, Novartis is establishing a network of certified treatment centers throughout the country which will be fully trained on the use of Kymriah and appropriate patient care.

There has been an urgent need for novel treatment options that improve outcomes for patients with relapsed or refractory (r/r) B-cell precursor ALL, whose prognosis is poor. Patients often undergo multiple treatments including chemotherapy, radiation, targeted therapy or stem cell transplant, yet less than 10% of patients survive five years [2], [3].

Kymriah is an innovative immunocellular therapy that is a one-time treatment. Kymriah uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular expansion and persistence. In 2012, Novartis and the University of Pennsylvania (Penn) entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including Kymriah, for the investigational treatment of cancers.

“This therapy is a significant step forward in individualized cancer treatment that may have a tremendous impact on patients’ lives,” said Carl June, MD, the Richard W. Vague Professor of Immunotherapy, Director of the Center for Cellular Immunotherapies in Penn’s Perelman School of Medicine, who is a pioneer of this new treatment. “Through our collaboration with Novartis, we are creating the next wave of immunocellular cancer treatments, and are eager to progress CAR-T therapy in a host of hematologic and other cancer types.”

In close collaboration with Novartis and Penn, Children’s Hospital of Philadelphia (CHOP) was the first institution to investigate Kymriah in the treatment of pediatric patients leading the single site trial.

“Tisagenlecleucel is the first CAR-T therapy to demonstrate early, deep and durable remission in children and young adults with relapsed or refractory B-cell ALL,” said Stephan Grupp, MD, PhD, the Yetta Deitch Novotny Professor of Pediatrics at the Perelman School of Medicine at Penn, and Director of the Cancer Immunotherapy Frontier Program at Children’s Hospital of Philadelphia (CHOP). “We’ve never seen anything like this before and I believe this therapy may become the new standard of care for this patient population.”

Novartis is committed to ensuring eligible patients have access to Kymriah, and is working to ensure payers understand the value of Kymriah and provide coverage for patients. To address the unique aspects of the therapy, Novartis has also developed various patient access programs to support safe and timely access for patients. Novartis is also providing traditional support to patients by helping them navigate insurance coverage and providing financial assistance for those who are uninsured or underinsured.

Novartis plans additional filings for Kymriah in the US and EU later this year, including applications with the FDA and European Medicines Agency (EMA), for the treatment of adult patients with r/r diffuse large B-cell lymphoma (DLBCL). Additional filings beyond the US and EU are anticipated in 2018.

Spider peptides battle superbugs and cancer

As antibiotic resistance rises and fears over superbugs grow, scientists are looking for new treatment options. One area of focus is antimicrobial peptides (AMPs), which could someday be an alternative to currently prescribed antibiotics, many of which are becoming increasingly useless against some bacteria. Now, a team reports in ACS Chemical Biology that they have improved the antimicrobial — and anticancer — properties of an AMP from a spider.

According to the U.S. Centers for Disease Control and Prevention, 2 million people become infected with antibiotic-resistant bacteria in the U.S. each year. Because no known antibiotics work against these bacteria, patients simply have to hope that their natural defenses eventually overcome the infection. But some patients experience severe symptoms, landing them in a hospital, and in extreme cases, they could die. Researchers are trying to find alternatives to traditional antibiotics, and one such possibility is a group of peptides called AMPs. These peptides are found in all plants and animals as a type of immune response and have been shown to be potent antibiotics in the laboratory. Gomesin, an AMP from the Brazilian spider Acanthoscurria gomesiana can function as an antibiotic, but it also has anticancer activity. When gomesin was synthesized as a circle instead of as a linear structure, these characteristics were enhanced. Sónia Troeira Henriques and colleagues wanted to further boost the peptide’s traits.

The team made several variations of the cyclic gomesin peptide and found that some of these were 10 times better at killing most bacteria than the previously reported cyclic form. In other experiments, the new AMPs specifically killed melanoma and leukemia cells, but not breast, gastric, cervical or epithelial cancer cells. The researchers determined that the modified peptides killed bacteria and cancer cells in a similar way — by disrupting the cells’ membranes. The group also notes that the modified AMPs were non-toxic to healthy blood cells.

Prostate Cancer Cells Become ‘Shapeshifters’ to Spread to Distant Organs

Johns Hopkins Kimmel Cancer Center scientists report they have discovered a biochemical process that gives prostate cancer cells the almost unnatural ability to change their shape, squeeze into other organs and take root in other parts of the body. The scientists say their cell culture and mouse studies of the process, which involves a cancer-related protein called AIM1, suggest potential ways to intercept or reverse the ability of cancers to metastasize, or spread.

Results of the research are described in the July 26 issue of Nature Communications.

For the study, the Johns Hopkins scientists mined publically available research data on the genetics and chemistry of hundreds of primary and metastatic cancers included in five studies of men with prostate cancer. They found that a gene called AIM1 (aka “absent in melanoma 1”), which makes proteins also called AIM1, is deleted in approximately 20 – 30 percent of prostate cancers confined to the gland and about 40 percent of metastatic prostate cancers. In addition, the scientists found, on average, two- to fourfold less amounts of AIM1 expression in metastatic prostate cancers compared with normal prostate cells or those from men with prostate cancers confined to the prostate, suggesting that reduction of AIM1 proteins is somehow linked to tumor spread.

Aside from its link to the development of melanoma, a deadly skin cancer, scientists knew little about the function of AIM1.

“Our experiments show that loss of AIM1 proteins gives prostate cancer cells the ability to change shape, migrate and invade. These abilities could allow prostate cancer cells to spread to different tissues in an animal and presumably a person,” says Michael Haffner, M.D., Ph.D., a pathology resident and former postdoctoral fellow at the Johns Hopkins Kimmel Cancer Center who is involved in the research. “It’s not the whole story of what is going on in the spread of prostate cancer, but it appears to be a significant part of it in some cases.”

Looking more closely at the AIM1 gene and its protein levels in prostate cancer tissues, the Johns Hopkins scientists found that many times, even when the gene isn’t completely deleted and its protein production is reduced, its location in the prostate cancer cell is highly abnormal compared with normal prostate cells. This occurs even in primary prostate cancer cells, which have invaded the local structures to form invasive cancer within the prostate gland, say the scientists.

The research team used dyes to track the location of AIM1 proteins in human cells grown in the lab and followed where they appear in normal and cancerous prostate tissues. In normal prostate cells, AIM1 was located along the outside border of each cell and paired up with a protein called beta-actin that helps form the cell’s cytoskeleton, or scaffolding. However, in prostate cancer cells, the protein spread away from the outer border of the cells and no longer paired up with beta-actin.

The scientists found this pattern among a set of human prostate tissue samples including 81 normal prostates, 87 localized prostate cancers and 52 prostate cancers that had spread to the lymph nodes.

“It appears that when AIM1 protein levels drop, or when it’s abnormally spread throughout the cell instead of confined to the outer border, the prostate cancer cells’ scaffolding becomes more malleable and capable of invading other tissues,” says Vasan Yegnasubramanian, M.D., Ph.D., associate professor at the Kimmel Cancer Center and a member of the research team. With AIM1, the scaffold, Yegnasubramanian says, keeps normal cells in a rigid, orderly structure. Without AIM1, cells become more malleable, shapeshifting nomads that can migrate to other parts of the body, he says.

To track how these shapeshifting cancer cells move, the Johns Hopkins scientists, with Steven An, Ph.D., an expert in cellular mechanics and an associate professor at the Johns Hopkins Bloomberg School of Public Health, took a close-up look at AIM1-lacking prostate cancer cells, using sophisticated and quantitative single-cell analyses designed to probe the material and physical properties of the living cell and its cytoskeleton.

They found that cells lacking AIM1 remodeled their scaffolding more than twice as much as cells that had normal levels of AIM1, and that they exert three- to fourfold more force on their surroundings than cells with normal levels of the protein. Such cellular properties are reminiscent of cells with high potential to invade and migrate, An notes.

In addition, the scientists found that AIM1-lacking prostate cells were capable of migrating to unoccupied spaces on a culture dish or invading through connective tissue-like materials at rates fourfold higher than cells with normal levels of AIM1.

Next, the scientific team implanted human prostate cancer cells engineered without AIM1 in five mice and found that the cells spread to other tissues at levels 10 to 100 times more than cells with normal levels of AIM1 that were implanted in five similar mice. However, the AIM1-lacking cells were not able to establish full colonies and tumors at those other tissues, suggesting that AIM1 depletion is not the whole story in the spread and growth of metastatic prostate cancer.

“AIM1 may help prostate cancer cells disseminate throughout the body, but something else may be helping them form full-blown metastatic tumors when they get there,” says Yegnasubramanian.

The Johns Hopkins scientists plan to further study what happens to the AIM1 protein to cause its abnormal location in prostate cancers and identify other proteins and genes that work with AIM1 to cause metastasis. Such studies could help scientists find new drug targets aimed at preventing or reversing prostate metastasis.

Study uncovers potential ‘silver bullet’ for preventing and treating colon cancer

In preclinical experiments, researchers at VCU Massey Cancer Center have uncovered a new way in which colon cancer develops, as well as a potential “silver bullet” for preventing and treating it. The findings may extend to ovarian, breast, lung, prostate and potentially other cancers that depend on the same mechanism for growth.

Led by Massey’s Deputy Director Steven Grossman, M.D., Ph.D., a team of scientists targeted the gene CtBP with a drug known as HIPP (2-hydroxy-imino phenylpyruvic acid) and were able to reduce the development of pre-cancerous polyps by half and return a normal lifespan to mice born with a predisposition to intestinal polyps. In humans, this condition is known as familial adenomatous polyposis, a devastating inherited disease that causes pre-cancerous polyps to grow in the intestine at a young age, often leading to the removal of portions of the colon to prevent cancer.

“This work opens up a whole new avenue for anti-cancer therapeutic development, as it shows that CtBP drives the actions of what are known as cancer stem cells, which are keys to cancer metastasis and resistance to chemotherapy,” says Grossman, who is also the Dianne Nunnally Hoppes Endowed Chair in Cancer Research and co-leader of the Developmental Therapeutics research program at Massey as well as professor and chair of the Division of Hematology, Oncology and Palliative Care in the Department of Internal Medicine at the VCU School of Medicine.

In contrast to other cancer-promoting genes, CtBP is not mutated in colon cancer; instead, it is overexpressed to the point where the cancer depends on it for growth. CtBP works to reprogram cells by repressing the expression of genes that typically prevent cancer through a form of cell suicide known as apoptosis while simultaneously promoting the expression of other genes that lead to cancer growth and metastasis.

The researchers found that CtBP can cause normal human cells to become cancerous when inserted into the cell’s DNA. In mouse models of familial adenomatous, treatment with HIPP significantly reduced intestinal polyps and increased survival while mice bred without the CtBP gene lived twice as long as those with it.

“In our experiments, HIPP acted almost as a chemical ‘silver bullet’ to prevent polyp formation, thereby reducing the risk of colon cancer,” says Grossman. “Also, we believe that anti-CtBP therapies such as HIPP may be able to complement current therapies to counter drug resistance and decrease metastasis, ultimately increasing our ability to control and cure colon cancer.”

This study is the latest in a line of research investigating CtBP by Grossman and his colleagues that began in 2010. Moving forward, they plan to continue testing derivatives of HIPP for the treatment of colon cancer and also see if their findings extend to breast, lung, ovarian and prostate cancers.

Risk-reducing mastectomy questioned for BRCA mutation carriers with prior ovarian cancer

Mutations in the BRCA gene correspond to a higher lifetime risk of developing breast and ovarian cancers, and many women who carry these mutations consider undergoing mastectomy or removal of the ovaries and fallopian tubes as preventive measures.

But for the subset of women with BRCA mutations who have already had ovarian cancer, risk-reducing mastectomy might not be worth the price tag. New research from the Duke Cancer Institute finds that for many women in this unique group, prophylactic mastectomy does not produce a substantial survival gain and is not cost-effective.

The finding is especially noteworthy because of updated National Comprehensive Cancer Network guidelines recommending that many women with ovarian cancer be considered for genetic testing regardless of family history. Now, more than ever before, some women with ovarian cancer are also learning that they carry a BRCA mutation.

“Risk-reducing mastectomy is costly and can require many months of follow-up and recovery,” said Charlotte Gamble, M.D., the study’s lead author and a resident physician at Duke University School of Medicine. “Our results emphasize that prophylactic mastectomy should be used selectively in women with both a BRCA mutation and a history of ovarian cancer.”

In the study, published online July 11 in the journal Annals of Surgical Oncology, Gamble and co-researchers constructed a statistical model comparing risk-reducing mastectomy to breast cancer screening, including mammogram and MRI. The model incorporated clinical factors such as the age at ovarian cancer diagnosis, time between ovarian cancer diagnosis and risk-reducing mastectomy, BRCA mutation status, cancer survival rates and treatment costs. Risk-reducing mastectomy was compared to breast cancer screening performed every six months following ovarian cancer diagnosis.

The study’s authors also considered a cost-effectiveness measurement called the incremental cost effectiveness ratio. Healthcare interventions where this ratio is less than $100,000 per year of life saved are commonly considered cost-effective in medical literature. The authors used the same threshold in this study.

According to the authors’ analysis, the benefit of risk-reducing mastectomy over screening alone largely depended on the patient’s age at the time of her ovarian cancer diagnosis and time to mastectomy:

For women diagnosed at any age with BRCA 1 and 2 gene mutations and within the first four years after ovarian cancer diagnosis, mastectomy was associated with a negligible gain in survival and was therefore not found to be cost-effective;

For women diagnosed at age 60 or older, regardless of time since ovarian cancer diagnosis, the gain in survival months was also negligible and the procedure was not cost-effective;

For women diagnosed at age 40 to 50 with BRCA 1 and 2 mutations and at least five years after an ovarian cancer diagnosis, the procedure was associated with a survival benefit of two to five months compared to screening and found to be cost-effective.

“Our study provides clarity on how a woman’s age and timing of a risk-reducing mastectomy after an ovarian cancer diagnosis impact the benefit of this procedure,” Gamble said. “Within the first five years, nobody benefited from risk-reducing mastectomy and after that threshold, survival gains were seen mostly in the youngest, healthiest ovarian cancer patients.”

“There is no right or wrong answer on how to manage breast cancer risk in this unique population,” added senior author Rachel Greenup, M.D., assistant professor of surgery at Duke. “However, we hope that our findings provide guidance to women and their doctors deciding if and when prophylactic mastectomy is beneficial following ovarian cancer treatment.”

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.

New cellular imaging paves way for cancer treatment

Researchers at the Universities of York and Leiden have pioneered a technique which uses florescent imaging to track the actions of key enzymes in cancer, genetic disorders and kidney disease.

Scientists hope this new development will aid drug design for new anti-cancer, inflammation and kidney disease treatments.

It will also provide diagnostic tools for disease identification and allow medical professionals to measure the effectiveness of drug treatment regimes in an easy laboratory manner.

Studying heparanase – a key enzyme in the development and metastasis of human cancers – scientists unveiled new fluorescent imaging agents that detect enzyme activity in healthy and diseased tissues.

The research, published this week in Nature Chemical Biology, builds upon previous work revealing heparanase’s three-dimensional structure.

Heparanase is a long-studied protein in human tissues involved in breaking down the complex sugars of the “extracellular matrix” – the material surrounding cells that provides structure and stability.

Heparanase dysfunction is linked to the spread of cancers both through the breakdown of this matrix and via the subsequent release of “growth factors” – chemicals that promote tumour development.

Through its remodelling of the matrix, heparanase is also a key player in inflammation and kidney disease. It is therefore a major drug, and diagnostic probe, target.

Gideon Davies, Professor of Structural Enzymology and Carbohydrate Chemistry at the University of York, said: “Heparanase is a key human enzyme. Its dysregulation is involved in inherited genetic disorders, and it is also a major anti-cancer target and increasingly implicated in kidney disease.

“Our work allows us to probe the activity of heparanase in human samples – allowing early disease identification and a direct measure of the success of drugs in humans.

“This work is a great example of the power of EU collaboration and science funding from the European Research Council.”

Hermen Overkleeft, Professor of Bio-Organic Synthesis at Leiden University, added: “This work reveals the power of activity-based protein profiling: the probe described here at once enables screening for heparanase inhibitors from large compound collections and is a lead compound for drug development in its own right.

“While the road to heparanase-targeting clinical drugs is long and fraught with risks, with this work we believe to have taken a major step in realizing the therapeutic potential of this promising clinical target.”

Thorough Genotyping and Repurposed Drugs Key to Treating Small-Cell Lung Cancer, says Cancer Expert

Small cell lung cancer (SCLC) is an aggressive disease characterized by quick growth and spread. While there has been a gradual decrease in incidence of SCLC in recent years, likely reflecting the decreased prevalence of tobacco use, little progress has been made in treating SCLC due to its complex pathogenesis.

The majority of patients, including those with limited-stage disease and those who initially respond to chemo- and radiation- therapy (two traditional pillars of cancer therapy), become resistant to treatment resulting in a very small percentage (approximately 6%) who survive 5 years after being diagnosed.

Smoking is the main risk factor for SCLC, with only 2-3% of patients categorized as never-smokers.

Identifying Therapeutic Targets in Small-Cell Lung Cancer

From the molecular point of view, SCLC is characterized by a multitude of alterations, owing to the fact that cells are exposed to a myriad of carcinogens contained in cigarette smoke, which bind and mutate DNA. These alterations affect numerous genes and pathways, but among these there are few obvious therapeutic targets. This means that the driver genes responsible for most SCLC development and progression have yet to be identified with any certainty.

However, new high-throughput technologies, which allow comprehensive gene profiling, have revealed promising findings. For example, 20% of SCLC patient tumors bear alterations in the MYC gene family. This discovery has helped to identify a subset of patients sensitive to an oncogenic kinase downstream in the MYC pathway, allowing for better designed, biomarker-driven clinical trials for these, often repurposed, therapeutic agents.

Similarly, PARP1 and Notch have been found overexpressed in SCLC. In order to target PARP1, an enzyme which, when it malfunctions, leads to replication of damaged DNA, researchers are currently evaluating the efficacy of PARP inhibitors for treatment of SCLC. And, to investigate targeting of the Notch signaling pathway, which influences the cellular life-cycle, the FDA is in the process of approving Tarextumab, a selective Notch inhibitor, in the treatment of SCLC.

Another issue with SCLC tumors is that they are mostly characterized by the loss of two crucial oncosuppressor genes, named RB, RB2\p130 i and TP53, which are less actionable pharmaceutically because it is much more difficult to restore a loss of function rather than block an oncogenic gain of function. Although challenging, researchers are nonetheless trying to develop strategies in this direction.

Repurposing Existing Drugs

Also important to the progress of SCLC therapies, more effective drug identification and testing, through the use of powerful mouse models of the human disease, put researchers in a good position to tackle this cancer type and attempt better defined targeted approaches.

Recent immunotherapy approaches have emerged as a significant new pillar in cancer therapy and are being assessed in numerous clinical trials for a multitude of tumors, including SCLC. In particular, two new agents, nivolumab and ipilimumab, have recently been developed to treat other forms of cancer, such as unresectable or metastatic malignant melanoma, advanced non-small-cell lung cancer (NSCLC), and advanced renal-cell carcinoma. These agents have also been tested for applications in SCLC. Nivolumab and ipilimumab are constituted by monoclonal antibodies functioning through direct inhibition of CTLA4 and PD1, respectively, which are key negative regulators of the antitumoral immune function. Bristol-Myers Squibb (BMS) was able to obtain the National Comprehensive Cancer Network indication for use of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens. The indication was achieved upon the publication on Lancet Oncology by Scott Antonia and colleagues, who reported the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab, achieving antitumour activity with durable responses and manageable safety profiles in previously treated SCLC patients, enrolled in the CheckMate-032 clinical trial.

Data was also presented at the World Lung Cancer Congress on the immunotherapy drug pembrolizumab, another therapeutic antibody against PD1, already approved for other diseases, which showed good efficacy.

One additional drug in this category is rovalptizumab teserine, a first-in-class antibody-drug conjugate comprised of a humanized monoclonal antibody against DLL3 and a toxin. DLL3 is a Notch ligand found to be expressed on 80% of SCLC. There is a 3rd line trial which is biomarker driven, meaning that they test for DLL3 expression and patients are eligible if they have “high” DLL3.

 

First in Human’ Trial Defines Safe Dosage for Small Molecule Drug ONC201 for Solid Cancer Tumors

Research from Rutgers Cancer Institute of New Jersey examines oral drug that targets cancer cells and spares healthy tissue

A ‘first in human’ clinical trial examining the small molecule drug ONC201 in cancer patients with advanced solid tumors shows that this investigational drug is well tolerated at the recommended phase II dose. That’s according to Rutgers Cancer Institute of New Jersey investigators and colleagues whose research also showed early signs of clinical benefit in patients with advanced prostate and endometrial cancers. The work appears in the ‘OnlineFirst’ section of Clinical Cancer Research (DOI: 10.1158/1078-0432.CCR-16-2658).

At focus is the investigational drug ONC201 that targets a dopamine receptor, a member of the G protein-coupled receptor superfamily residing on the surface of cancer cells, to cause their destruction. ONC201 is the first of a new family of therapeutic compounds called imipridones. Previous research on the study drug conducted by Rutgers Cancer Institute and Oncoceutics, Inc. – which is also supporting this trial – suggests that ONC201 may be capable of turning off proteins that maintain tumor growth and and may help kill cancer cells while sparing normal ones. Pre-clinical study demonstrated ONC201 was effective in laboratory models against a number of solid tumors including colon cancer, brain cancer, triple-negative breast cancer and non-small cell lung cancer.

In this phase I dose-escalation study, 10 patients over age 18 with advanced solid tumors that were resistant to standard therapies were enrolled through Rutgers Cancer Institute between January and July 2015. Participants received a starting dose of 125mg of the study drug, which was taken orally via capsule every 21 days (one cycle). The dosage for this cohort was increased incrementally up to a maximum dose of 625mg, which is five-fold above the dose that was effective in laboratory models. An additional 18 patients were enrolled in an expansion phase between August 2015 and February 2016 and treated at the recommended phase II dose of 625mg in order to collect additional safety, pharmacokinetic and pharmacodynamic information.

There were no drug-related adverse events over Grade 1 in either the dose escalation phase or the expansion phase. The few low grade events that were recorded (nausea, fever) were resolved quickly, note the authors. While the study achieved the aim of identifying the recommended phase II dose of the drug, findings also showed tumor regression in patients with metastatic disease. Results also demonstrated prolonged stable disease following more than nine cycles (27 weeks) of treatment – particularly in prostate and endometrial cancer patients that had lymph node, bone and lung lesion involvement. Out of the 28 participants, 10 completed at least four cycles of treatment with two patients receiving at least nine cycles. The authors note while a 90-year old prostate cancer patient saw his primary tumor and metastatic bone lesion shrink by about 25 percent after taking two 625mg doses of ONC201, a 72-year old patient with advanced clear cell endometrial cancer had a mixed response after two doses, with multiple nodes decreasing by more than 30 percent but experiencing the development of new nodes.

“By exploring a novel agent that targets the cancer but leaves non-cancerous tissue untouched, we have an opportunity to not only provide a new treatment option for patients who have exhausted standard forms of therapy without the typical toxicities associated with anticancer treatment, but to also offer them a therapeutic that may result in a better quality of life since healthy cells are not impacted,” notes Rutgers Cancer Institute medical oncologist Mark Stein, MD, who is an associate professor of medicine at Rutgers Robert Wood Johnson Medical School and lead investigator of the work. “While meaningful to confirm the safety profile of this dosage for ONC201, it is noteworthy that our findings also showed some evidence of clinical benefit to some patients.”