Shanu Modi, MD

2009-2010 BCRF Project:
ASCO Cancer Foundation Advanced Clinical Research Award

Triple-negative breast cancers (TNBCs) are defined by a lack of expression of estrogen, progesterone, and HER2 receptors. They account for 15% of all breast cancers and are associated with clinically aggressive behavior. Lacking hormone receptors and overexpression of HER2, these tumors can't be treated with available targeted therapies and standard treatment is limited to conventional chemotherapy agents, possibly combined with other novel therapeutics. While effective for some, this approach is not curative for metastatic disease and can be relatively more toxic. To improve treatment for this subtype of breast cancer we need to better understand what drives its growth so that appropriate targeted therapies can be developed.

HSP90 inhibitors are a new class of agents which work by inducing the degradation of critical proteins expressed within cancer cells. If these proteins are overexpressed in cancer or if their degradation is particularly destructive to cancer cells, then HSP90 inhibition can represent a significant advance. HER2 is a particularly sensitive client protein and Dr. Modi’s group previously demonstrated activity for a first generation HSP90 inhibitor in patients with HER2 positive disease.

There are now a variety of Hsp90 inhibitors in Phase 1/2 clinical trials. While TNBC tumors appear relatively resistant to the action of these agents, Dr. Modi's group has developed a novel Hsp90 inhibitor PU- H71, which exhibits potent activity in TNBC tumors because its client proteins include a variety of signaling molecules that appear to play a special role in TNBC. Using PU-H71 they observed high rates of complete tumor regressions in pre-clinical models and these are the most impressive pre-clinical responses seen in triple negative breast tumors after the administration of any single agent targeted therapy, including other Hsp90 inhibitors. They now propose the first phase 1 trial to evaluate the safety and feasibility of PU-H71 therapy for patients with advanced cancer, with focus on TNBC. In addition, the researchers will use non-invasive radiolabelled 124I-PU-H71 PET imaging to allow them to deliver the optimal dose to patients. Finally, they will correlate activity with the results of tumor tissue testing.

Mid-Year Progress Report:
Dr. Modi reports that her group has begun testing various subtypes of human breast cancers, including triple negative tumors, for their sensitivity to PU-H71 (a novel heat shock protein 90 inhibitor) treatment. They are looking to see if they can identify which tumor types are most sensitive to this agent and also to identify the specific proteins in the tumors that correlate with response or resistance to this drug. This will allow the researchers to appropriately select the best patients for studies using this type of therapy based on the characteristics of their cancers. To date, they have collected breast cancer tissues from seven patients and are in the process of testing these samples for factors that identify the best candidates for PU-H71 therapy. They have observed evidence of substantial cancer cell death after treatment with PU-H71 in one case of triple negative breast cancer, as predicted by the pre-clinical studies performed by Dr. Modi's collaborator, Dr. Chiosis's lab. They plan to accrue 50 patient cases for this project over the next 4-6 months.

Bio:
Dr. Shanu Modi is an Assistant Member of the Breast Cancer Medicine Service of Memorial Sloan-Kettering Cancer Center, and specializes in the treatment of breast cancer. She is a member of the Cancer and Leukemia Group B and the Translational Breast Cancer Research Consortium, and is a recipient of an ASCO Advanced Clinical Research Award.

Dr. Modi graduated from the University of Alberta (Edmonton, Canada) and pursued her Oncology residency at the Cross Cancer Institute before coming to Memorial Sloan-Kettering Cancer Center in 2001 for a clinical breast cancer research fellowship. She took a faculty position on the breast service in 2005. Dr. Modi’s research interests focus on the development of new treatments for patients with HER2-positive breast cancer and she is leading several clinical trials evaluating the use of HSP90 inhibitors for this subtype of disease. Her work is highly translational and collaborative and involves efforts to develop non-invasive radiological imaging to facilitate individualized drug dose selection and scheduling.

Dr Modi is an active member of various national and international scientific groups, including the American Society of Clinical Oncology and the American Association for Cancer Research. Dr Modi has numerous publications to her name and has presented her data at international meetings.