Lewis C. Cantley, PhD
Margaret and Herman Sokol Professor
Director, Weill Cornell Cancer Center
Weill Cornell Medical College
New York, New York
2013-2014 BCRF Project:
Dr. Cantley will evaluate the effect of combining PI3K inhibitors with other drugs to treat a series of pre-clinical models of triple negative breast cancers, including BRCA1 mutant breast cancer. In previous collaborations with researchers at Harvard Medical School, Dr. Cantley was able to translate an important observation made from an earlier BCRF-funded study associated with a clinical trial. He and colleagues had found that a combination of two new, targeted agents (i.e. a PARP inhibitor and a PI3K-inhibitor) showed a cooperative effect and was able to block tumor growth in BRCA1-related breast cancer with high efficacy. Consistent results in two different laboratory models gave Dr. Cantley’s team the confidence that they could move forward and convince the respective pharmaceutical companies to collaborate and help start an early phase clinical trial. This study is designed for women with metastatic triple negative breast cancer or high-grade ovarian cancer, and Dr. Cantley is currently actively accruing to this protocol. combination of a HER2-targeted drug and an inhibitor of a critical cell survival protein.
Dr. Cantley’s goal is to develop treatment strategies for triple-negative breast cancers that require medical treatments, i.e. that cannot be treated with surgery or radiation. Until now, the treatment of such cancers has relied heavily on the use of mono- or poly-chemotherapy. The researchers’ approach is to use combinations of targeted therapy, here the PARP-inhibitor BMN679 and the PI3K-inhibitors BYL719 and BKM120. They are conducting studies in laboratory models that have lost one or several tumor suppressor genes and that have developed triple-negative breast cancer that can serve as a model for human breast cancer. They are currently conducting a large treatment study to evaluate the efficacy of their treatment combinations. This project is a team effort; the group at Weill Cornell Medical Center continues to work with the Dr. Gerburg Wulf and the Beth Israel-Deaconess/Harvard-based group in Boston.
In a second study, supported by BCRF in the past three years, Dr. Cantley has collaborated with fellow BCRF grantee, Dr. Gerburg Wulf at Beth Israel Deaconess Medical Center and built a research infrastructure designed to prepare for early phase clinical studies. This infrastructure in Boston is laboratory-based and consists of a number of laboratory models for triple negative breast cancer, including genetically engineered models and patient-derived models, a research pharmacy for laboratory studies, core facilities for tumor imaging with ultrasound, radionucleotides and CT/MRI scanning, a mass spectrometry core facility able to perform pharmacokinetic studies as well as tumor metabolism and basic laboratories for mechanistic and genomic studies. Maybe most important of all, their pre-clinical research set-up is closely connected with clinical investigators at the Dana-Farber Harvard Cancer Center (DFHCC). This enhances all of the researchers’ ability to take clinical problems and examine the feasibility, schedule, and efficacy of novel drugs and their combinations in preparation for specific clinical trials. Drs. Cantley and Wulf believe that this type of pre-clinical in vivo work will increasingly become a necessity in preparation for early-phase clinical trials because the number of candidate drugs for cancer rapidly increases - and at the same time it has become clear that finding tolerable and effective combinations will be key to long-term disease control for cancer patients. With several hundred drugs now ready for clinical testing and limitless potential for combinations, pre-clinical in vivo assessments, performed by academic centers not tied to any one particular pharmaceutical company and their product, are essential to aid clinical trials design. Prototypical for this approach was this team’s recent work on the combination of a PI3Kinase-inhibitor and a Parp-inhibitor for triple-negative breast cancer. Drs. Cantley and Wulf’s first aim will therefore focus on learning from patients’ biospecimens what parameters best predict for the efficacy and potential adverse effects of this combination. They will collect archival tumor specimen, newly acquired biopsies and in addition plasma from the circulating blood to determine genetic changes and blood chemistry parameters of resistance and responsiveness. Their second aim will be to examine the efficacy of an optimized PI3K-inhibitor containing regimen in laboratory models that bear tumors directly derived from patients. They will share their results in real time with their clinical colleagues. Drs. Cantley and Wulf’s goal is to generate data that form the basis for a phase I/II clinical study that lead to substantially improved treatment strategies for TNBC.
The research team is making progress on three projects. They are leading a study aimed to examine the feasibility and obtain initial efficacy data of the combination of a PI3K-inhibitor (NVP-BKM120)and a PARP-inhibitor (Olaparib). To date, they have accrued 32 of 50 patients and are anticipating completion of the last dose-escalation cohort in February 2014. At that point they will open the expansion cohorts.
Genomic analyses to determine resistance patterns to PI3K- and Parp-inhibition studies on sensitive and resistant tumors are being done in collaboration with Dr. Joe Gray at the Oregon Health Center, and the bioinformatics analyses are done at Harvard Medical School. Resistance patterns are currently being identified.
It is well known that PI3K regulates the uptake and metabolism of sugar in cancer cells. The researchers asked experimentally if they could trace the metabolism of sugar all the way from the exterior of the cell the building blocks of DNA and found that PI3K-inhibition slowed the making of new DNA and thus interfered with cell division. In summary, their mechanistic studies have revealed alternative pathways that allow PI3K- and PARP-inhibitor resistant tumors to escape the growth-inhibitory effects of this combination.
All studies are being done in tight collaboration with Dr. Lewis C. Cantley at WCMC in New York.The clinical trial is on track with accrual likely to conclude in 2014.
In September 2012, Weill Cornell Medical College and NewYork-Presbyterian Hospital announced the appointment of Dr. Lewis Cantley as Director of the newly established Weill Cornell Cancer Center. Dr. Cantley is also the Margaret and Herman Sokol Professor at Weill Cornell Medical College. Prior to joining Weill Cornell in January 2013, Dr. Cantley was Director of the Beth Israel Deaconess Cancer Center and the William Bosworth Castle Professor of Medicine at Harvard Medical School.
Throughout his career, Dr. Cantley has been interested in the biochemical mechanisms by which growth factors and hormones control cell growth and cell metabolism and the defects in these control mechanisms that lead to diseases such as diabetes, immune disorders and cancers. In the course of this work, Dr. Cantley discovered a cell growth pathway involving the enzyme Phosphoinositide 3-Kinase (PI3K). This pathway is now known to be the most frequently mutated pathway in human cancers. His discoveries have led to the development of drugs to target this pathway for treating cancers.
In recognition of his contributions to the understanding of human diseases, Dr. Cantley was elected to the American Academy of Arts and Sciences (1999) and the National Academy of Sciences (2001). He has received numerous awards, including the ASBMB Avanti Award for Lipid Research (1998), the Heinrich Weiland Preis for Lipid Research (2000), the Caledonian Prize from the Royal Society of Edinburgh (2002) and the American Association of Cancer Research/Pezcoller Award for Cancer Research (2005).