Gerburg Wulf, MD, PhD
2012-2013 BCRF Project:
Assistant Professor of Medicine
Beth Israel-Deaconess Medical Center
Harvard School of Medicine
Co-Investigator: Lewis C. Cantley, 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.
Dr. Wulf's medical, graduate and early post-graduate training took place in Germany at the Universities of Muenster, Heidelberg and the Max-Planck Institute for Biochemistry in Munich. She came to the US as a post-doctoral fellow to perform hematological stem cell research in Dr. Bing Lim's laboratory at the Beth Israel Deaconess Medical Center (BIDMC) in Boston, followed by a residency in Medicine and a clinical fellowship in Oncology at BIDMC. In a second post-doctoral fellowship, Dr. Wulf was the first scientist to recognize and analyze the role that prolyl isomerization catalyzed by Pin1 plays in the initiation and progression of cancer, and especially breast cancer, and her work has since been referenced by over 300 scientists. Her current professional work is a combination of clinical practice and laboratory-based research. Dr. Wulf's overriding interest is to improve outcomes for patients with metastatic breast cancer with more precisely targeted therapies, and she sees the advent of more precisely targeted therapies as an opportunity for progress.