Arnold J. Levine, PhD
Professor, Pediatrics and Biochemistry
Rutgers Cancer Institute of New Jersey
2013-2014 BCRF Project:
1) (The Estée Lauder Companies Brands Award)
Co-Investigator: Kim Hirshfield, MD, PhD, The Institute for Advanced Study, Princeton, and The Cancer Institute of New Jersey, New Brunswick, NJ
Dr. Levine is renowned for his work in establishing p53 as a tumor suppressor gene, one of the body's most important defenses against many forms of cancer. Genetic variations between individuals can confer a risk upon a person for the development of breast cancer, the age of onset of a breast cancer, the response to treatment for a breast cancer and the risk of developing a reoccurrence of a breast cancer. Employing the Framingham Study containing three generation of individuals and thousands of families, Drs. Levine and Hirshfield have identified single nucleotide polymorphisms in the p73 and MRE-11 genes (which respond to DNA damage from environmental mutagens) that result in early onset breast cancers in the next generation. They have also identified a unique polymorphism in chromosome 17q21.3 encoding a fusion protein that behaves as an oncogene altering epigenetic marks and DNA damage responses. Their findings help to explain why some cancers have genomic instability and suggest that two sets of drugs (HDAC inhibitors and PARP inhibitors) could be a useful treatment of those cancers with the fusion protein expressed. They are testing these ideas in cell culture and their research focus in 2013-2014 will continue to pursue these lines of inquiry. cancers.
2) Further contributing to our understanding of the molecular basis of cancer, Dr. Levine is currently studying the potential correlations between p53 mutations and breast cancer stem cells, also characterized as tumor initiating cells. Over the past few years the concept of a breast cancer stem cell has arisen that produces a tumor and a more differentiated set of cell types. It is thought that the stem cell is required for the malignant state. A great deal of evidence has suggested that cells can undergo efficient epigenetic reprograming to become induced pluripotent stem cells but this requires the loss of a functional p53 protein. Based upon this observation Dr. Levine’s group tested the hypothesis that breast cancer stem cells arise efficiently in tumors with p53 mutations. Employing RNA micro arrays they showed that breast cancers with p53 mutations had stem cell signatures. Central to these signatures was the over-expression of two proteins MELK and TMEM97. Dr. Levine’s team has produced antibodies directed against these proteins and obtained cell lines that over-express these proteins and produce tumors in laboratory models. They have obtained a small molecule inhibitor of the MELK protein kinase and are testing it and other derivatives to determine if MELK activity drives the growth of these tumors. Monoclonal antibodies directed against the cell surface protein TMEM97 are being prepared. This trans-membrane protein inserts cholesterol into the membrane of these cancer cells, and we are testing whether or not the monoclonal antibodies inhibit tumor cell growth. The goal of this project is to develop novel potential therapeutic agents that inhibit or kill cells from triple negative and Her2/neu breast cancers.