Larry Norton, MD

2009-2010 BCRF Projects:

1) The Peter Jay Sharp Foundation Award
Co-Investigator: Alan Houghton, MD, PhD, Memorial Sloan-Kettering Cancer Center

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 has opened.

Specifically, with support from Peter Jay Sharp Foundation/BCRF, during this past year the researchers have been able to: (1) complete accrual of the first cohort to a clinical study evaluating the HER2/neu DNA vaccine in patients with breast cancer, (2) evaluate the efficacy of antibody plus DNA vaccine therapy in combination with anti-CTLA-4 in a melanoma model (this therapy will be tested in a breast cancer model within the next funding year), (3) test the combination therapy of an immunomodulatory molecule and a chemotherapeutic drug which promoted the regression of established tumors and/or significantly prolonged survival in a breast cancer model, (4) explore the mechanism by which the anthrax receptor functions in immune responses.

Although the process of creating a new experimental therapy, such as a vaccine, including the basic research, preclinical studies, protocol development, safety evaluation and manufacturing, normally takes many years, Peter Jay Sharp Foundation/BCRF support has allowed the researchers to move rapidly, shaving years off of this process. The future direction of their work will focus on completing accrual to the HER2 clinical trial. They will also further optimize an immunotherapeutic approach in the treatment of breast cancer by combining their DNA vaccines with immunomodulatory molecules.

Mid-Year Progress Report:
With support from Peter Jay Sharp Foundation/BCRF, during this past year Dr. Norton's team has been able to: (1) complete accrual of the first cohort to a clinical study evaluating the HER2/neu DNA vaccine in patients with breast cancer and all patients in this cohort have completed all vaccinations with no significant toxicity, (2) evaluated alphavirus replicon particle based vaccines alone and in combination with antibodies, (3) evaluated the efficacy of the antibody TA99 in combination with immunomodulatory antibodies (this therapy will be tested in a breast cancer model once the schedule of antibody administration is optimized in the melanoma model and the mechanism underlying the anti-tumor effects are known.) Although the process of creating a new experimental therapy, such as a vaccine, including the basic research, preclinical studies, protocol development, safety evaluation and manufacturing, normally takes many years, Peter Jay Sharp Foundation/BCRF support has allowed us to move rapidly, shaving years off of this process. In the future Dr. norton and colleagues will continue their investigation of the optimal means to use the immune system to treat breast cancer.

2) The First Step Award, made possible by generous support from QVC and the Fashion Footwear Charitable Foundation
Co-Investigator: Rachel Hazan, PhD, Albert Einstein College of Medicine, New York

Aggressive breast cancers abnormally express the cell-cell adhesion molecule N-cadherin, and Dr. Hazan and her colleagues showed that this expression stimulates metastasis although it reduces primary tumor growth. This relationship implies that N-cadherin targeted therapies might eradicate metastasizing cells and be useful at a clinically intractable stage. New data suggest that N-cadherin induces a phenotypic switch to an aggressive phenotype, known as epithelial to mesenchymal transition, due to activation of the FGF receptor signaling pathway, leading to the expression of transcription factors, which render cells metastatic. Dr. Hazan proposes to investigate this relationship and evaluate available drugs that may disrupt the cooperation of N-cadherin with the FGF receptor as a therapeutic modality for metastasis. The information gained will have important clinical implications for treatment of late-stage breast cancer.

Mid-Year Progress Report:
Aggressive breast cancers abnormally express the cell-cell adhesion molecule N-cadherin that causes the cells to become invasive and metastatic. Dr. Hazan's data suggest that N-cadherin induces an acutely aggressive behavior due to its cooperation with the FGF receptor. She and her team have in their last report shown that N-cadherin leads to a switch from a benign to a metastatic phenotype due to signaling via the FGF receptor which results in higher levels of transcription factors that cause such malignant switch. Their most recent findings add to this picture by showing that N-cadherin causes breast cancer cells to have elevated oncogenic signaling by the MAPK and STAT3 pathways which may be responsible for the generation of these transcription factors. The researchers will test this hypothesis and will test inhibitors to either the FGF receptor alone or in combination with Her2/neu inhibitors to inhibit invasion and metastasis of the tumor cells.

Bio:
Dr. Larry Norton is currently the Deputy Physician in Chief, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, for Breast Cancer Programs, and The Medical Director of MSKCC's Breast and Imaging Center, which contains the Evelyn H. Lauder Breast Center. He is the founding incumbent of the Norna S. Sarofim Chair of Clinical Oncology at MSKCC and a Professor of Medicine in the Weill Medical College of Cornell University. Dr. Norton is a founder of The Breast Cancer Research Foundation and has served as its Scientific Director and chairman of its Executive Board of Scientific Advisors since the Foundation's inception in 1993. 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.

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. 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, 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.