Larry Norton, MD

2012-2013 BCRF Projects:
1) The Peter Jay Sharp Foundation Award
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 BCRF through generous donations from the Peter Jay Sharp Foundation 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 during this past year this team has been able to complete accrual of the third cohort to a clinical study evaluating the DNA vaccine against HER positive (HER+) breast cancer, and all patients enrolled in the study have completed all vaccinations with no significant toxicity. The investigators have also evaluated the efficacy of HER2/neu antibody (equivalent of Herceptin) in combination with anti-CTLA-4 (equivalent of Ipilimumab). They have also evaluated the combination of gemcitabine in combination with anti-CTLA-4. Furthermore, women with early-stage breast cancer have accrued to a clinical trial of ipilimumab and/or cryoablation, also as part of the study.

In the upcoming year, these researchers will continue their investigation of the optimal means to use the immune system to treat breast cancer.

Mid-year Progress: Patient accrual to the last cohort of a clinical study evaluating the HER2/neu DNA vaccine in patients with breast cancer continues. The research team is also evaluating the efficacy of HER2/neu antibody in combination with anti-CTLA-4. Their assessment of the combination of gemcitabine in combination with anti-CTLA-4 continues as well as accrual of women with early-stage breast cancer to a clinical trial of ipilimumab and/or cryoablation.

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

Drs. Rachel Hazan and Larry 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.

Drs. Hazan and Norton began their research with the hypothesis that N-cadherin promotes metastasis at two levels, by increasing the invasiveness of tumor cells and by providing access to blood vessels, which serve as an energy source fueling cancer growth. They sought to demonstrate in the laboratory setting that each mechanism depends on a different part of the N-cadherin protein and to map out key biological processes leading to malignant progression. Drs. Hazan and Norton have now collected evidence suggesting that N-cadherin can not only change a benign tumor cell into an aggressive one capable of healthy tissue invasion by activating critical metastatic cellular pathways but may also be a possible cause for resistance to the widely-used drug, Herceptin® (trastuzumab).

In 2012-2013, Drs. Hazan and Norton will continue to characterize the effects of N-cadherin on ErbB2/ErbB3 signaling, which is found to be hyper-activated in a subtype of breast cancer called HER2 positive disease, for which the targeted therapies Herceptin® (trastuzumab) and Tykerb® (lapatinib) were developed. This team's data to date suggest that N-cadherin may trigger resistance to this type of therapy. They will compare cell lines that have shown to be resistant to either Herceptin or Tykerb and determine whether these cell lines differ in their N-cadherin expression. The researchers will also test whether inhibiting the functions of N-cadherin would make these two targeted therapies effective again.

Mid-year Progress: Drs. Hazan and Norton's team found that a subset of breast cancers expresses N-cadherin and the FGF receptor (FGFR) in the context of HER2/neu. This causes tumor cells to behave like cancer stem cells and produce more metastatic cells. The researchers have found that FGFR inhibition is effective in attenuating HER2 positive metastatic tumors, but they predict that the combination of an FGFR inhibitor together with an HER2 inhibitor, such as lapatinib or trastuzumab, would more efficacious in subsiding aggressive breast tumors. Their study will continue to focus on these aspects of HER2 tumor biology.

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 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.

On March 22, 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.