From Patient to Healthcare Hero: Carey is Riding for Research
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V Foundation Grants
Selina Chen-Kiang, Ph.D., Lewis C. Cantley, Ph.D., John Leonard, M.D., Peter Martin, M.D., Maurizio DiLiberto, Ph.D.
The development of drug resistance is a major challenge in cancer therapy. Mantle cell lymphoma (MCL), like many other human cancers, remains incurable mainly due to acquired drug resistance. Ibrutinib received approval from the U.S. Food and Drug Administration (FDA) for treatment of MCL in November 2013, and has shown promise in treating many MCL patients. Unfortunately, about one-third of patients are resistant to ibrutinib and many patients become resistant after the initial response. The tumors grow faster than before and there are no effective therapeutic options. The underlying mechanism is unknown. By longitudinal genomic and RNA sequencing analysis of both MCL tumors and healthy tissue we have identified a relapse-specific genetic mutation, C481S, in Burton’s Tyrosine Kinase (BTK), which ibrutinib specifically targets. This is the first identified mutation specific to MCL patients who relapse from ibrutinib after a durable response. However, this BTK mutation is not found in MCL patients who do not respond to ibrutinib or become resistance after transient response, suggesting two patterns of ibrutnib resistance.in MCL.
Ibrutinib resistance appears to correlate to an increased activation of a number of other molecular mechanisms known to contribute to lymphoma growth, among them the protein CDK4, and signaling along the PI3K-AKT pathway. We further discovered that targeting CDK4 with palbociclib (PD 0332991), a selective CDK4-inhibitor, made the MCL tumor cells sensitive to inhibitors of PI3K regardless of BTK mutation. These findings suggest that a combination therapy of palbociclib and PI3K inhibitor may overcome ibrutinib resistance. To address this exciting possibility, we will 1) investigate the mechanism by which inhibition of CDK4 sensitizes lymphoma cells to PI3K inhibitor, focusing on the disruption of glucose metabolism based on preliminary evidence; and 2) determine the clinical efficacy of overriding ibrutinib resistance by dual targeting of CDK4 and PI3K in a Phase I clinical trial in MCL, and discover genes and pathways that discriminate sensitivity and resistance by integrative longitudinal genomic and RNA sequencing analysis of serial biopsies before, during and after therapy.
This novel study not only suggests new approaches for treating MCL but also has implications for treatment of other B cell lymphomas, such as chronic lymphocytic leukemia and a diverse group of non-Hodgkin lymphomas. It is also exciting because CDK4 is a new kind of drug target; it controls the cell cycle, which is a central cancer pathway. As such, targeting CDK4 is not just important for MCL but for many forms of cancer. For example, when combined with letrozole, palbociclib more than doubled the progression free survival of metastatic breast cancer patients. Since PI3K is commonly mutated or over-activated in human cancers, including breast cancer, the palbociclib and PI3K combination represents a novel therapy for other human cancers as well.
Diane M. Da Silva, Ph.D., W. Martin Kast, Ph.D., I. Caroline Le Poole, Ph.D., Laila Muderspach, M.D., Jeffrey S. Weber, M.D., Ph.D.
David Cheresh, Ph.D., Razelle Kurzrock, M.D., Karen Messer, Ph.D., Hatim Husain, M.D.
We have recently discovered that tumors cells with integrin αvβ3 on their surface are particularly difficult to treat because αvβ3 triggers reprogramming events that make tumors immune to certain anti-cancer therapies. Because we identified the pathways by which integrin αvβ3 drives these changes, we were able to reverse this behavior in preclinical research models by re-purposing FDA-approved drugs developed for other indications. Now, funding from the V Foundation will allow us to test whether this strategy can be translated to improve the response to therapy for patients with non-small cell lung cancer.
To do this, we will first look for the presence of integrin αvβ3 on circulating tumors cells that may be present in blood samples from patients who have become resistant to a targeted form of cancer therapy called Erlotinib. Once optimized, this assay could be used as a non-invasive blood test to identify the earliest emergence of drug resistance in lung cancer patients. Next, we will conduct a Phase II clinical trial to test if patients who have developed resistance to Erlotinib can be “re-sensitized” to the drug by adding a second drug, an inhibitor of the NFκB pathway known as VELCADE. According to our preclinical animal studies, we expect the addition of this FDA-approved drug will allow patients to respond to Erlotinib therapy for a much longer time.
Since there is no clearly defined standard of care therapy for Erlotinib-resistant lung cancer, our project will address this unmet need and, if successful, would change the way lung cancer patients are diagnosed and treated.
John M. Chirgwin, Ph.D., Theresa A. Guise, M.D., Michelle Heine, R.N., M.S., Aileen Heras-Herzig, M.D., Wende M. Kozlow, M.D., Richard Santen, M.D.
Funded by the Jimmy V Celebrity Golf Classic Benefactor Grant
In honor of GlaxoSmithKline
Michael Deininger, M.D., Ph.D., Thomas O’Hare, Ph.D.
Chronic myelomonocytic leukemia (CMML) is a cancer of the bone marrow that is typically observed in patients over 65 years of age and has no known cause. CMML patients have a short survival, with only ~20% of patients alive five years following diagnosis. Dr. Deininger is a leader of a clinical trial testing a CMML drug called 5-azacytidine and we have many samples from the patients enrolled from across the country. The drug was highly effective in a minority of patients but eventually lost effectiveness for most. The first major objective of our project will focus on specimens collected from patients prior to and throughout 5-azacytidine treatment to allow comparisons between those for whom the drug was effective and for those it was not.
Recent work makes it clear that many genes are mutated in CMML and that no single mutation is the source of the disease. Our laboratory utilizes an advanced, highly accurate DNA sequencing technique called whole exome sequencing to sequence every gene in the genome. We have performed this analysis on specimens from 21 CMML patients. Importantly, we conducted the analysis side-by-side on leukemic and healthy cells from each patient. After careful mathematical analysis of the results, we then directed our attention to the mutated genes found only in leukemic cells. We will compare the mutation profile of each patient with the clinical outcomes to understand whether certain mutation profiles correlate with better or worse responses to drug treatment. To further this understanding, we will assemble the mutation patterns in such a way that we can estimate the number of leukemia initiating cells, also called clones, present in each patient. This yields a quantification of the population diversity and complexity and allows us to provide a scheme for predicting patient outcomes. It is critical to understand not only which genes are mutated but also whether the mutations are located in the same or different cells. Such a high resolution visualization of the disease will enable the first thorough understanding of this genetically complex disease and direct us towards the genetic events that initiate CMML. Altogether, this predictive information will aid physicians in understanding which patients are at high risk for transformation to terminal leukemia and who is most vs. least likely to respond to treatment. In the longer term, deciphering the genetic blueprints of CMML will be instructive for design and implementation of safer and more effective drugs.
Our second goal is to uncover new molecular pathways required by CMML cells but not healthy cells and to develop precision drugs that interrupt these critical processes. The most important requirement for drug design is a well-defined molecular target that is essential only in the cancer cells. While the requirement is selfevident, there are a staggering number of possibilities. To contend with this complexity, we use a ‘function-first’ approach, meaning that we impose an experimental condition on CMML cells and ask whether their ability to survive is compromised. For instances in which we observe compromised survival, we then work backward to understand the molecular pathways involved. We rely on a powerful new tool called an shRNA library to interrupt the function of one gene per cell and determine whether the absence of that gene’s function makes that cell more likely to die. The term ‘library’ in the context of our experimental design refers to an inventory of thousands of different gene-interrupting shRNA molecules that allow us to interrogate the function of thousands of genes, one gene at a time, in one study. We also mimic the bone marrow environment in our experimental design, providing a more realistic proving ground for drug discovery. This novel type of analysis, applied to leukemia cells from CMML patients, has the capability to unveil novel molecular pathways in CMML.
The two complementary objectives of our study will vastly improve our understanding of molecular pathways that are uniquely important for the survival of CMML cells. With this knowledge, we can design drugs that precisely interrupt key components of survival pathways specific for CMML cells. The long-term, overarching goal of our work is to discover novel therapeutic targets in CMML, and based on these insights, to develop precision drugs for translation into the clinic.
Andrew Feinberg, M.D., MPH, Philip Cole, M.D., Ph.D.
While genetic mutations, changes in DNA sequence, are central to the development of Cancer, it is increasingly recognized that associated alterations in the chemical structure of the DNA packing material, known as chromatin, are linked to cancer causation. These distinct chromatin states and the molecules that regulate then form the basis of the field of epigenetics. While epigenetics is generally understood to be important in oncology, it is not yet clear how specific epigenetic changes are generated by different environmental conditions such as UV light exposure. Moreover, it is not understood what epigenetic changes are most impactful for the progression of malignancy and what therapeutic approaches can be used to successfully intervene to prevent or cure cancer. Our team will address how UV exposure in patients can induce particular epigenetic changes in skin lesions, whether existing epigenetic therapies can achieve desired effects of preventing epigenetic changes and progression to cancer, and design and develop new epigenetic therapies that could be useful for skin cancer and other malignancies. We hope to illuminate the factors that dictate patiets’ skin cancer’s responsiveness to epigenetic therapies which could ultimately lead to a new standard of care for treatment. We also plan to synthesize at least one new dual action epigenetic modulator compound that can serve as a clinical candidate for patient cancer trials.
John Byrd, M.D., Ching-Shih Chen, Ph.D., Michael Freitas, Ph.D., Michael Grever, Ph.D., Samual Kulp, Ph.D., David Lucas, Ph.D., Mark R. Parthun, Ph.D., Amy Sklenar, B.S., Xiaodan Su, Ph.D.
Partially funded by Cardinal Health
Michael C. Heinrich, M.D.
Activating mutations of KIT are found in a number of human malignancies, including Gastrointestinal stromal tumors ( GIST, 80%), mast cell neoplasms (95-100%), melanoma (rare overall, but up to 25% of certain subtypes), seminoma (10-25%), and acute myeloid leukemia (<5% overall, but 20-40% of certain subtypes). Although KIT inhibitory drugs such as imatinib (Gleevec) have been effective for treating some of these cancers, the efficacy of these drugs is limited by primary as well as acquired drug resistance. Dr. Heinrich and his team have been leaders in the development of these targeted molecular treatments for KIT-mutant cancers. This proposal seeks to further improve treatment of GIST and other KIT-mutant cancers (e.g. melanoma), using combination therapy to simultaneously target KIT and other critical signaling pathways. Dr. Heinrich’s project will provide critical data that can be readily translated into the design and conduct of future clinical studies of the treatment of advanced KIT-mutant cancers. These studies will be conducted by a multidisciplinary team that includes: Dr. Michael Heinrich (Cancer Biology, Medical Oncology), Dr. Christopher Corless (Cancer Biology, Pathology, Animal Models), Dr. Jeffrey Tyner (Cancer Biology, Animal Models), Dr. Marc Loriaux (Cancer Biology, Pathology), and Dr. Harv Fleming (Animal Models of Cancer, Medical Oncology).
Darrell J. Irvine, Ph.D.
Vaccines that prime a patient’s own immune system to attack cancer are an attractive strategy, with the potential to promote durable regression of cancer that is not subject to rapid treatment resistance. However, to date cancer vaccines have generally failed in two important ways to optimally target cancer: First, cancer vaccines have typically targeted proteins that are over-expressed by tumor cells but not necessarily unique to tumor cells- this can lead to poor potency and the danger of autoimmune reactions. Second, vaccines based on peptides, proteins, or whole cell lysates have generally shown poor immunogenicity in patients, due in part to poor uptake of such vaccines by the immune system. We propose the translational development of a novel vaccine platform that addresses these two key limitations and could further be combined with promising immunomodulators such as checkpoint blockade therapies in patients to promote potent but safe anti-tumor immunity. In collaboration with the Broad Institute and the Dana Farber Cancer Institute (DFCI), we are pursuing cancer vaccines that are generated by sequencing the genome of individual patient tumors, and then forming vaccines that are chemically designed to traffic to lymph nodes following injection. We will carry out preclinical safety and manufacturing studies to enable clinical trials of this concept, which has shown great promise in small animal models of cancer therapy. We hypothesize that combining these two promising cancer vaccine technologies will lead to a highly potent, patient-targeted cancer vaccine strategy that could be broadly applied to diverse tumors.
