Massachusetts Archives - Page 9 of 13

Nikhil Wagle, M.D. & Pingping Mao, Ph.D.

Funded in Collaboration With Stand Up To Cancer (SU2C)

Clinical oncology has entered an era of personalized molecular diagnosis and targeted therapy. This means treatments are tailored to each patient based her tumor’s histopathological and genetic characteristics. Such personalized treatment often involves a combination of multiple active agents to treat one tumor. In estrogen receptor positive (ER+) breast cancers, the three most promising classes of treatments are hormonal therapy, PI3K pathway inhibitors and cell cycle inhibitors.

Although patients derive benefit from such treatment, for most of the advanced ER+ breast cancers, the tumors respond initially but then stop responding, which is called “resistance” to therapy. Unfortunately, this resistance results in death in most cases of advanced breast cancer. Treating these cases requires developing novel therapeutic strategies to overcome the resistance based on an understanding of the mechanisms of resistance.

In this project, we leverage the leading edge technology of high-throughput whole-genome screening to discover mechanisms of resistance to each of three classes of drugs and all of their combinations. We also characterize the identified genes and their function in a variety of breast cancer cell types and mouse models. The knowledge of resistance to treatment obtained through this project will guide our effort to design more effective combinational therapeutics to overcome resistance. Ultimately, this work will be translated to benefit most of the patients with ER+ breast cancers.

Anthony Letai, M.D., Ph.D. & Joan Montero, Ph.D.

Funded in Collaboration with Stand Up To Cancer (SU2C)

Every cancer is unique pointing to the need for personalized medicine. In oncology, a fundamental challenge is to assign the right treatment to every patient due to cancers’ biological complexity and the lack of effective predictive biomarkers. At the Letai lab we developed a functional predictive assay called Dynamic BH3 Profiling to rapidly test different treatments prior to giving them to the patient. It has already been successfully proved as an excellent predictor in different types of cancer, including melanoma. We aim to combine sophisticated genomic analyses with this novel test to improve melanoma treatment, improving patients’ clinical outcome, clinical trials and drug development.

Rebecca Chin, Ph.D.

Albert Wyrick V Scholar

Triple negative breast cancer (TNBC) is aggressive and has a poor prognosis. Currently, chemotherapy is the only treatment option. Therefore there is unmet need to identify novel therapeutic targets for TNBC. Acquired resistance to targeted therapy, a newer treatment type with drugs targeting specific molecules necessary for tumor growth, poses another major clinical problem. We have recently identified a major mechanism that TNBC cells utilize to promote tumor growth. This proposal aims at deciphering this mechanism in cancer growth and drug resistance, as well as discovering novel therapeutic targets for TNBC.

Akt1, Akt2 and Akt3 are a “family” of proteins with both overlapping and unique functions. Akt plays critical roles in tumor growth, and a number of drugs targeting Akt are being tested in clinical trials. Our recent findings indicate that Akt3 has an increased expression in ~30% of TNBC. Importantly, Akt3, but not Akt1/2, is critical for regulating TNBC growth. Moreover, Akt3 is implicated in drug resistance to Akt inhibitors. We propose that Akt3 regulates tumor growth and resistance by activating specific downstream targets and upregulating receptors on cell surface. To identify novel Akt3 targets, we will use a discovery-based proteomics approach. For drug resistance study, we will analyze Akt3 signaling in tumor samples, and test if certain receptor inhibitors effectively eliminate resistant cells. In the short term, our results will provide rational combination treatment strategy to combat drug resistant breast tumors. In the long term, we anticipate developing effective therapeutics targeting Akt3 or its substrates to treat TNBC.

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.

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.