Larry Norton, MD

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 and 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.

Mid-Year Progress Report:
Dr. Norton and his team reported in February that progress over the past year has enabled the researchers to1) open to accrual a clinical study evaluating the HER2 DNA vaccine in patients with breast cancer; 2) determine the efficacy of antibody plus DNA vaccine therapy; 3) explore the mechanism by which the anthrax receptor increases CD8+ T cell responses to HER2/neu; and 4) use peptide pools to identify antigens recognized by T cells; this novel method will be used to identify specific antigens in HER2 that are recognized by patients treated with HER2/neu DNA.

2) The First Step Award, made possible by generous support from the Fashion Footwear Charitable Foundation and QVC
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 Drs. Hazan and Norton and colleagues showed that this expression stimulates metastasis with no effects on primary tumors. This relationship implies that targeted therapies aimed at N-cadherin might eradicate metastasizing tumor cells and be useful at a clinically intractable stage. Since their c-neu model is a reliable model of metastasizing breast cancer, the researchers will use it to delineate the exact mechanism of N-cadherin action on metastasis. They hypothesize N-cadherin promotes metastasis at two levels, by increasing the invasiveness of tumor cells (signaling), and by localizing tumor cells to blood vessels (adhesion). Their studies will first demonstrate that each mechanism depends on a different part of the N-cadherin protein, and then examine new drugs that selectively target these distinct N-cadherin functions. The researchers believe that 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. N-cadherin in breast cancers driven by the Her2/neu oncogene causes tumor cells to become more metastatic. Dr. Norton and his team performed a thorough in vivo characterization of the c-neu-N-cadherin model for metastasis to map out key biological phenotypes leading to malignant progression. Their most recent studies show that N-cadherin accelerates the induction of breast neoplasms, enhances angiogenesis and activates lung metastasis. The researchers will continue to investigate the causal relationship between N-cadherin and breast cancer metastasis in order to gain novel insights into targeted therapies to eradicate metastasis.

Bio:
Since its inception in 1993, Dr. Norton has served as scientific director and chairman of the Executive Board of Scientific Advisors of The Breast Cancer Research Foundation. He is Past President of the American Society of Clinical Oncology, and past Chair of the ASCO Foundation. Dr. Norton was a Presidential Appointee to the National Cancer Advisory Board of the NCI (1998-2004.) He is the first incumbent of the Norna S. Sarofim Chair in Clinical Oncology at MSKCC and recipient of the American Society of Clinical Oncology's highest scientific award, The 2004 David A. Karnofsky Memorial Award.

Dr. Norton has served on or chaired numerous committees of governmental and professional organizations, including the Breast Committee of the Cancer & Leukemia Group B, the NCI's Cancer Clinical Investigations Review Committee, its Cooperative Breast Cancer Tissue Resource (Registry), and the Consensus Development Conference on Treatment of Early Stage Breast Cancer (1990). He has also served on committees of the Institute of Medicine of the National Academy of Sciences.

Dr. Norton is on the editorial board of several medical publications, and is an active clinical and laboratory investigator. He is the co-author of the Norton-Simon Model, which has broadly influenced cancer treatment and research for over thirty years.