Associate Professor, Harvard Medical School
Attending Physician, Beth Israel Deaconess Medical Center
Co-Investigator: Lewis C. Cantley, PhD, Beth Israel Deaconess Medical Center, Boston, MA
With support of BCRF in the past three years, Drs. Cantley and Wulf have 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.
Dr. GerburgWulf is an Assistant Professor of Medicine at Harvard Medical School and an Attending Physician in the Breast Oncology Group at Beth Israel Deaconess Medical Center (BIDMC) and the Dana-Farber Harvard Cancer Center. She received her medical school and graduate training in Germany where she studied in Muenster and at the Max-Planck-Institute for Biochemistry in Munich. After a residency at the University in Heidelberg she came to the US in 1991 for a post-doctoral research fellowship in Hematology at Beth Israel Hospital. She received further post-graduate training at St. Elizabeth’s Medical Center in Internal Medicine and at Beth Israel Deaconess Medical Center (BIDMC) in Clinical Hematology/Oncology, as well as a second post-doctoral fellowship in Cancer Cell Biology. Her current professional work is a combination of clinical practice and laboratory-based research. As a board-certified oncologist, Dr. Wulf serves breast cancer patients from the greater Boston area in the Multidisciplinary Breast Cancer Clinic at BIDMC. She is an active clinical scientist and an investigator for the National Cancer Institute and the Eastern Cooperative Oncology Group. Her focus is laboratory-based research where she is interested in novel treatment concepts for endocrine-resistant breast cancer. She is collaborating closely with Dr. Lewis Cantley, Director of the Cancer Center at Weill Cornell Medical School in New York, to develop and test in preclinical models novel combination treatments that include the use of PI3Kinase inhibitors.