Lewis C. Cantley, PhD

2012-2013 BCRF Project:
Co-Investigator: Gerburg Wulf, MD, PhD, Beth Israel Deaconess Medical Center, Boston, MA

With support from BCRF, Drs. Cantley and Wulf have discovered a surprisingly strong anti-cancer effect when they combined two agents that target specific proteins that govern cell division and metabolism, PI3Kinase and PARP. Based on these data, they have now launched an early phase clinical trial of this combination in patients with metastatic triple negative breast cancer, including patients with BRCA1-related breast cancer. Going forward, they will expand their arsenal of combinations of targeted therapies and perform randomized clinical studies in laboratory models that will directly compare these new combinations with treatments currently considered standard of care. This team's goal is to use the pre-clinical setting for the development of combination treatments with the greatest efficacy that can then go forward into clinical trials.

Mid-year Progress: Endocrine-resistant breast cancer presents a therapeutic dilemma: responses to both chemotherapy and targeted agents are incomplete and short-lived. Patients whose tumors progress through endocrine therapy or who have triple negative breast cancer will receive chemotherapy that targets a tumor cell's DNA replication machinery. Single or combination treatments with chemotherapeutic agents, such as taxanes, anthracyclines or alkylating agents, typically induce partial remissions, invariably followed by recurrence, and with each successive treatment regimen, remissions become shorter. Treatments that target only signal transduction pathways such as rapalogs, on the other hand, frequently lead to incomplete and short remissions. The recurring tumor frequently develops mechanisms to evade the activity of the signal transduction inhibitor, and is able to recruit the required mitogenic signaling through alternate, parallel pathways. The goal of Drs. Cantley and Wulf's work is to discover how an enzyme that plays a key role for the transmission of signals in cells, phosphoinositide 3-kinase (PI3K), regulates DNA synthesis and repair. This team intends to exploit this dual function of PI3K to design combination treatments for endocrine-resistant breast cancer, because endocrine-resistant breast cancer cells are frequently driven by signals emanating from the PI3K pathway. Their approach will be to combine PI3K-inhibitors with inhibitors of DNA synthesis and repair. A pilot clinical trial with this approach is already under way, and the investigators are currently analyzing specimens from patients on the ongoing study to understand mechanisms of responsiveness or resistance to this treatment approach.

Bio:
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).