Dr. Malachi Griffith – Research in Action
Read moreType: Translational
Facilitate the transition of projects from the laboratory to the clinic. Translational researchers seek to apply basic knowledge of cancer and bring the benefits of the new basic-level understandings to patients more quickly and efficiently. These grants are $600,000, three-year commitments
Linzhao Cheng, Ph.D., Hyam I. Levitsky, M.D., Martin G. Pomper, M.D. , Ph.D. Richard Wahl, M.D.
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.
Amar Gajjar, M.D., Richard J. Gilbertson, M.D., Ph.D., Helen Poppleton, Ph.D.
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.
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.
Paul Dent, Ph.D., Steven Grant, M.D., John Roberts, M.D.
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.
