Medical Director of Evelyn H. Lauder Breast Center Memorial Sloan Kettering Cancer Center New York, New York BCRF Scientific Director
1) Project 1: Co-Investigators: Alan Houghton, MD, PhD, Memorial Sloan Kettering Cancer Center, New York, NY; Jedd Wolchok, MD, PhD, Memorial Sloan Kettering Cancer Center, New York, NY
Effective vaccination against breast cancer is difficult because breast cancer arises from cells that were once normal and our bodies have elaborate controls to stop the immune system from attacking our own tissues. However, research supported by the Peter Jay Sharp Foundation/BCRF has discovered a way to trick the immune system by vaccinating against cancer using a vaccine from a different species. The immune system recognizes the vaccine as “foreign” and generates an immune response to destroy breast cancer cells as if they were foreign invaders. This research has moved from the laboratory to patients— the Investigational New Drug (IND) application for a vaccine created under this support was approved by the Food and Drug Administration (FDA) and the clinical trial to test the first-generation vaccine against breast cancer is accruing patients. Specifically, with support from Peter Jay Sharp Foundation/BCRF, during this past year this team has been able to: (1) continue to accrue patients to the last cohort of a clinical study evaluating the HER2/neu DNA vaccine in patients with breast cancer and all patients in these cohorts have completed all vaccinations with no significant toxicity, (2) evaluate the efficacy of HER2/neu antibody (Equivalent to Herceptin) in combination with anti-CTLA-4 (equivalent of Ipilimumab), (3) Evaluate the combination of gemcitabine in combination with anti-CTLA-4, and (4) continue to accrue women with early-stage breast cancer to a clinical trial of ipilimumab and/or cryoablation. In the future, this group will continue their investigation of the optimal means to use the immune system to treat breast cancer. In addition to completing accrual to the HER2/new DNA vaccine study, in the coming year the researchers plan to further evaluate the efficacy of the combination therapy of the monoclonal antibody to HER2/neu (the equivalent of Herceptin in clinic) in combination with immunomodulatory antibodies (CTLA-4, CD137, PD-1, OX40, GITR) and determine the mechanism of action for the optimal combination; investigate radiation in combination with immune modulation in a laboratory model of breast cancer; and evaluate the effects of immunomodulatory antibodies in combination with chemotherapy. Further, they will continue accrual to the ipilimumab trial. Assuming that the primary end-point of safety and tolerability is met, which seems reasonable a larger randomized phase 2 study will be undertaken.
2) Project 2: Co-Investigator: Rachel Hazan, PhD, Albert Einstein College of Medicine, New York, NY
Drs. Hazan and Norton’s project focuses on the N-cadherin molecule, which is often found to be hyperactive in aggressive breast cancers. N-cadherin in breast cancers, driven by the HER2/neu oncogene, causes tumor cells to become more metastatic. Drs. Hazan and Norton observed in the laboratory that this molecule stimulates the spread of cancer cells -- a finding that implies the targeting of N-cadherin might prevent the spread of tumor cells, and new therapies could be developed. Since relatively little is known about N-cadherin and its functions, this team set out to delineate the exact mechanisms of N-cadherin action on breast cancer metastasis. Their ultimate aim is to turn that information into new clinical strategies for metastasis prevention.
Dr. Hazan has found in a survey of 99 invasive breast cancers that N-cadherin was co-expressed with HER2/neu in poorly differentiated tumors. This combination of HER2 and N-cadherin caused the breast tumor cells to behave like cancer stem cells. These stem cells were readily eradicated by FGFR or MEK inhibitors. They recently found that the switch from the benign E-cadherin molecule to the malignant N-cadherin is facilitated by a molecule called Akt3. Therefore understanding how Akt 3 is regulated in breast cancer will allow understanding of how to reverse the adhesion molecule switch in favor of an anti‐cancer state. In 2013-2014, Drs. Hazan and Norton will further investigate these findings to decipher the role of N-cadherin in breast cancer.
1) Project 1: During this past six months this research team has been able to: (1) Finish accrual to the last cohort of a clinical study evaluating the HER2/neu DNA vaccine in patients with breast cancer, (2) optimize a schedule for combining anti-Her2/neu (equivalent to Herceptin) with anti-CTLA-4 (equivalent of ipilimumab) and gemcitabine that will result in the greatest tumor protection (3) Evaluate the combination of gemcitabine with other immunomodulatory antibodies (4) continue to collect safety data from patients enrolled on the clinical trial of ipilimumab and/or cryoablation, (5) conduct the immune monitoring of these patients. It is anticipated that a related abstract will be submitted for presentation at ASCO in June 2014. The researchers will continue their investigation of the optimal means to use the immune system to treat breast cancer.
2) Project 2: During the past several months, Drs. Hazan and Norton found that Akt3 expression is lost with progression from a normal/benign to a malignant breast cancer form, suggesting activating the expression of Akt3 in cancer can combat cancer formation. Their team is now testing this hypothesis in laboratory models using human cancer transplants.
Dr. Larry Norton is Medical Director of the Evelyn H. Lauder Breast Center at Memorial Sloan Kettering Cancer Center. He is a founder of The Breast Cancer Research Foundation and has served as its Scientific Director since the Foundation's inception in 1993.
Dr. Norton is the founding incumbent of the Norna S. Sarofim Chair of Clinical Oncology at MSKCC and a Professor of Medicine in the Weill Cornell Medical College. He received his AB with Highest Distinction from the University of Rochester and his MD from the College of Physicians and Surgeons of Columbia University. He trained in medicine and medical research at the Albert Einstein College of Medicine and the National Cancer Institute (NCI).
Dr. Norton has dedicated his life to the eradication of cancer by activities in medical care, laboratory and clinical research, advocacy, and government. He was a U.S. Presidential appointee to the National Cancer Advisory Board (the board of directors of the NCI) serving as Chair of the Budget Sub-Committee. A former Director of the American Society of Clinical Oncology, he served as President of ASCO and subsequently Chair of the ASCO Foundation. He has been Vice-Chair of the Lymphoma Committee and a long-serving Chair of the Breast Committee of the Cancer and Leukemia Group B (now the Alliance for Clinical Trials in Oncology). He has served on or chaired numerous committees of the National Cancer Institute, National Institutes of Health, and the Institute of Medicine of the National Academy of Sciences. He is an editorial board member or reviewer for numerous medical journals and on the advisory boards of many advocacy and medical institutions including the Cold Spring Harbor Laboratory Cancer Center and several Specialized Programs of Research Excellence.
Dr. Norton's personal research has focused on the use of medicines to treat cancer, particularly the application of mathematical methods to optimizing dose and schedule. He has been involved in the development of several effective agents including paclitaxel and trastuzumab. He co-invented the Norton-Simon Model of cancer growth, which has broadly influenced cancer therapy, and more recently the self-seeding concept of cancer metastasis and growth. He is the Principal Investigator of an NCI Program Project Grant in Models of Human Breast Cancer and an author of more than 350 published articles and many book chapters.
For his work Dr. Norton has received many honors including election to Phi Beta Kappa and Alpha Omega Alpha and recognition from the MD Anderson Cancer Center, the Society for MSKCC, the Italian-American Foundation for Cancer Research, the Don Shula Foundation, SHARE (NY), the Susan G. Komen Foundation, and The Breast Cancer Research Foundation. He received ASCO's highest honor, the David A. Karnofsky Award, in 2004, and was a McGuire Lecturer at the San Antonio Breast Cancer Symposium. He has served as a visiting professor throughout the U.S., Canada, South America, Europe, Israel, and Asia and has trained many cancer physicians and researchers. In 2010, Dr. Norton was one of three individuals honored for clinical excellence and presented with a National Physician of the Year Award by Castle Connolly Medical Ltd. Honorees for this award are selected based on an extensive process involving thousands of nominations by physicians listed in Castle Connolly's America's Top Doctors and America's Top Doctors for Cancer guides. More recently, Dr. Norton received the 2013 Gianni Bonadonna Award from ASCO, in recognition of his distinguished record of accomplishments in advancing the field of breast cancer.