2014 Archives - Page 3 of 5

Michael B. Major, Ph.D., D. Neil Hayes, M.D., MPH, Gary Johnson, Ph.D.

Protein kinases are a family of 518 human proteins which receive and transmit information within the cell, often from one kinase to another. The information flow within the network governs all aspects of cell biology, including cell growth, movement and survival. Not surprisingly, cancer very often re-wires kinase activity and connectivity to support its uncontrolled growth and metastasis. Indeed, protein kinases are the most commonly mutated protein family in human cancer. Protein kinases are also exceptionally ‘druggable’ and constitute the most tractable class of new therapeutic targets. Two significant challenges exist. First, we know a great deal about very few protein kinases. There is no doubt that targeting understudied kinases in cancer will benefit patients, but what kinases and for which patients? Second, several kinase inhibitors have proven immensely effective in certain cancers, however not all patients respond and for those that do respond, resistance inevitably emerges. We now know that cancer reprograms the kinase network to bypass chemotherapy. To tackle these challenges, we have developed a new technology that allows us to identify and quantify the activity of nearly all kinases in a single experiment. This allows us to comparatively study kinase activity in normal cells and in cancer cells, in chemotherapy-sensitive and resistant cancers, and in tumors before and after relapse. We hypothesize that the responsiveness of cancer to targeted therapy is determined by the baseline activity of specific kinases and the nature by which these activities adapt to therapeutic challenge. We will test this hypothesis in tumors of the lungs and head and neck. Together, our experiments may lead to the identification of specific kinase activities which: 1) predict cancer disease progression, 2) predict response to therapy, and 3) suggest new and rationally designed therapeutic strategies for patients with naïve and relapsed cancer.

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.

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).

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.

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.

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.

Julie E. Bauman, M.D., Ph.D., Jennifer Grandis, M.D., Michelle Ozbun, Ph.D.

Head and neck cancer (HNC) is a painful, disfiguring cancer of the mouth or throat that affects more than 50,000 people in the United States and 600,000 people worldwide each year. Recently, oral infection with human papillomavirus (HPV) has become the primary cause of HNC in North America and Europe. This epidemic affects people from every walk of life. Although HPV(+) HNC is sensitive to the intensive combination of surgery, radiation and/or chemotherapy, survivors commonly face permanent changes in uniquely human functions, including facial expression, swallowing, and voice. A national priority is the investigation of tailored, less aggressive treatments for HPV(+) HNC, where current approaches represent overtreatment. Progressive insight into the unique biology of HPV(+) HNC creates an unprecedented opportunity to develop HPV-selective therapies with fewer side effects.

Leading scientists at the University of Pittsburgh Cancer Institute (UPCI) recently demonstrated that HPV(+) cancers accumulate significantly fewer genetic mutations compared with HPV(-) cancers. Nonetheless, alterations of the gene PIK3CA, the master regulator of the PI3K cell growth pathway, are unusually common and represent the primary genetic changes in HPV(+) HNC. Overall, DNA changes that turn “on” the PI3K pathway are present in about half of HPV(+) HNC. Our collaborators have traced the importance of the PI3K pathway back to early HPV infection, where HPV directly activates the PI3K pathway to promote its own life cycle. In established cancers, PIK3CA alterations increase tumor growth. Moreover, PI3K-activated tumors obtained from HPV(+) HNC patients are very sensitive to novel drugs that inhibit PI3K, including the selective compound, BYL719.

Our collaborative network of outstanding clinicians and scientists brings together expertise in HNC clinical trial design (J. Bauman), HNC translational science (J Grandis), and HPV biology (M. Ozbun). We will test the idea that PI3K pathway activation, both directly by HPV oncoproteins, and indirectly through accumulated genetic changes in PIK3CA, drive benign HPV infections to transform into cancers. Detecting such PI3K pathway alterations in HPV(+) HNC may predict which patients will respond to BYL719, in the context of an innovative clinical trial. The trial will evaluate the addition of BYL719 to pre-operative chemotherapy in HPV(+) HNC, followed by minimally-invasive transoral robotic surgery, and risk-adapted radiation. We will perform comprehensive genetic and viral analysis of PI3K pathway alterations in treated patients, with particular focus on features that predict complete response. We expect that PI3K inhibitors will restore normal cell functions that can block cell growth, and render tumor cells more responsive to chemotherapy.

Results will provide insight into how PIK3CA mutations cooperate with HPV to transform normal cells into cancer, reveal new targets for the treatment of HPV(+) HNC, determine whether genetic PI3K pathway alterations predict response to PI3K inhibition, and establish a novel paradigm for more effective, less toxic therapy for people with HPV(+) HNC.

Nabeel Bardeesy, Ph.D., Cyril Benes, Ph.D., Andrew Zhu, M.D., Ph.D.

Cancers that emerge from bile ducts and other part of the biliary tract are exceedingly difficult to treat. The subset of these tumors that are arise within the liver are called intrahepatic cholangiocarcinomas, which represent the second most common type of liver tumor. Unfortunately, the incidence of these cancers has risen worldwide for the past 3 decades. An estimated 80,000 patients die from this disease annually, although the actual rate is likely several times higher, as recent studies demonstrate that many tumors previously designated as “cancers of unknown origin” are in fact cholangiocarcinomas. In most cases, intrahepatic cholangiocarciniomas are diagnosed at advanced stage and have a poor prognosis. Despite the current standard chemotherapy with gemcitabine/cisplatin combination for patients with unresectable or metastatic biliary tract cancer, the median survival time remains less than one year. There are no standard treatments for patients who failed gemcitabine/platinum-based chemotherapy, and overall this remains among the most lethal of human cancers. Therefore, there is clearly an urgent need to identify better drugs against cholangiocarcinomas and to improve treatment of patients affected with this cancer today.

Our group has shown previously that mutations in two genes known to cause brain tumors and leukemias are also commonly found in intrahepatic cholangiocarcinoma. These genes, Isocitrate Dehydrogenase 1 and 2 (IDH1 and IDH2) are mutated in about 25% of intrahepatic cholangiocarcinomas. Our recent laboratory studies have shown that these mutations can convert mature specialized liver cells into a less differentiated (i.e. more primitive) state, raising the possibility that they might make them differentially sensitive to some targeted drugs.

To identify such drugs, we tested more than 1000 cell lines derived from many types of cancer including more than 20 bile duct cancers in large scale screens using several hundreds drugs. These studies identified that a type of drug (in the class of kinase inhibitors) already approved to treat another type of cancer is very efficient at killing IDH mutated intrahepatic cholangiocarcinoma cells compared to virtually all the other cells tested. This kinase inhibitor has been used in large number of patients already and much is known about the doses to use and its potential side effects. Our additional laboratory results suggest that the doses used in other cancers will be efficient to treat patients with IDH mutated intrahepatic cholangiocarcinomas.

We propose to initiate a clinical trial to evaluate the safety and efficacy is this drug in intrahepatic cholangiocarcinoma patients. Our proposal includes a parallel evaluation of responses in mice engineered to develop intrahepatic cholangiocarcinoma with IDH mutations and additional mutations that we believe might influence how well patient will respond. With these studies we will better understand how to treat different patients with IDH mutations. In addition, we propose to use cells derived from individual patients to identify potential mechanisms of resistance and drug combinations that might further improve treatment success.

In conclusion, we have identified a new exciting opportunity to treat patients with intrahepatic cholangiocarcinoma using an already approved drug in use in other cancers. We can readily identify patients that should be treated with this kinase inhibiting drug and we have a number of follow-up studies ongoing in the laboratory that will inform the results of the clinical trial proposed and further developed better ways to treat this cancer. We believe that we have a great opportunity to improve the care of a number of patients affected by biliary tract cancer today.

Scott Antonia, M.D., Ph.D., Amer Berg, Ph.D., Dung-Tsa Chen, Ph.D.

Adenocarcinoma is the most common type of lung cancer, and the majority of people diagnosed with this disease will die from metastases. Chemotherapy is the standard way to treat this cancer, and this provides clear benefits including increasing the lifespan of patients. However this benefit is limited and all patients eventually become resistant to standard therapy. Therefore new types of treatment need to be developed. Immunotherapy is a type of treatment designed to get a patient’s own immune system to kill their cancer. Very recently it was demonstrated that an immunotherapy called anti-PD1 has surprisingly good activity in lung cancer. Rapid and prolonged regressions of tumors occur in about one quarter of patients. Now it is important to develop combination therapies with this agent that may help the three quarters of patients who do not respond to anti-PD1. One such approach would be to combine anti-PD1 with a therapeutic cancer vaccine. Vaccines are designed to increase the number of lymphocytes in patients that can recognize and kill cancer cells. Many of these sorts of vaccines have been developed that are very effective in accomplishing this lymphocyte expansion, but none have been very good at killing tumors. One reason for this is that tumor cells can produce a protein called PD-L1 that binds to PD1, another protein on the surface of the lymphocytes activated by the vaccines, which shuts down their ability to kill cancer cells. Anti-PD1 prevents this from happening. We propose to combine anti-PD1 with a cancer vaccine for the first time to treat patients with advanced stage lung adenocarcinoma. We will use a vaccine that activates lymphocytes that recognize a protein called mesothelin which is produced by many lung adenocarcinomas and has been shown previously to expand the number of mesothelin-specific lymphocytes in cancer patients. We expect that combining this vaccine with anti-PD1 will be synergistic, producing improved clinical outcomes. We will also comprehensively analyze the immune systems of the patients and characteristics of their tumors which may be responsible for producing resistance to anti-PD1 and/ or the vaccine. This information can then be used to suggest additional agents that can be added to the anti-PD1/ vaccine combination in the future to further improve the effectiveness of this therapy.

Kenneth D. Westover, M.D., Ph.D.

Funded by The Michael and Carole Marks Family

Multiple lines of evidence suggest that if achievable, inhibiting K-Ras signaling may have therapeutic advantages in cancer. Approximately 30% of all human cancers contain activating Ras mutations making them one of the most common identifiable molecular cancer drivers. Despite almost 30 years of effort, direct inhibitors of Ras family members have failed to achieve success in the clinical setting. Our immediate aim is to develop and evaluate GTP-competitive inhibitors of K-Ras. Our long term goal is to apply this concept to other cancer-related small GTPases and test it as a new therapeutic strategy.

Targeting the GTP binding site of Ras is difficult because it binds to GTP and GDP with high affinity and the intracellular concentrations of GTP and GDP are also high. We recently reported a concept to overcome these obstacles that involves using compounds that form a covalent bond with K-Ras after they enter the GTP binding site. This concept was motivated both by clinically important, time-tested covalent inhibitors like aspirin and penicillin and by recently developed, rationally designed covalent kinase inhibitors such as Ibrutinib and Afatinib which are now FDA approved. Our prototype compound, SML-8-73-1 (SML), is a GDP analogue containing a reactive warhead extending from the beta-phosphate which adds irreversibly to Cysteine 12, a cysteine found in the active site of an oncogenic mutant form of K-Ras that is common in people exposed to cigarette smoke, K-Ras G12C. We have shown that even in the presence of large excesses of GDP and GTP, quantitative complete irreversible binding of SML is observed.

We hypothesize that for non-G12C K-Ras mutants and other cancer-related GTPases the covalent strategy may be applied by targeting a conserved active site lysine. We already know that targeting this lysine with covalent chemistry is possible but we don’t know if this strategy can be adapted to make inhibitors that are selective for particular GTPases and what the impact of these compounds will be on GTPase-mediated signaling. The goal of our work supported by the V Foundation will be to explore this concept by generating and testing new compounds which target the conserved active site lysine.

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Year: 2014