Professor, Department of Medicine (Oncology)
The most recent focus of my lab is the discovery of new targets for drug design and development for the treatment of lung cancer. Three areas of current interest are drugs which inhibit autophagy in cancer cells, induce apoptosis in the cells, and inhibit angiogenesis in tumors.
Autophagy is an emerging therapeutic target in cancer chemotherapy. It is a regulated catabolic process that degrades cellular proteins and organelles, allowing the recycling of their biochemical components for use in energy production and biosynthetic reactions. Autophagy has a role in a number of critical cell functions, including stress response, cellular quality control, tissue homeostasis and energy production. Autophagy is induced upon treatment with chemotherapy in cancer cells, apparently as a protective and/or survival mechanism against the cell damage caused by chemotherapeutic agents or radiation. When autophagy is inhibited, either by pharmacologic or genetic means, cancer cells are less able to contend with the damage from concurrent chemotherapy and undergo cell death, generally by activating pro-apoptotic pathways. We have shown activity for the autophagy inhibitors chloroquine (CQ) and hydroxychloroquine (HCQ) in combination with the EGFR-targeted drug erlotinib in non-small cell lung cancer. However, the low potency of CQ and HCQ may limit their clinical efficacy. We have designed and synthesized lead compounds which are greater than 15-fold more potent than CQ and HCQ, and are currently conducting preclinical development, and evaluation of the molecular mechanisms of action, of the compounds.
The formation of new blood vessels (angiogenesis) is a critical process in the growth of tumors and provides a means by which they can spread to distant sites. My laboratory explores the mechanisms by which certain angiogenic factors stimulate blood vessel-forming endothelial cells, studies the molecular actions of experimental and established cancer chemotherapeutic drugs which inhibit the angiogenic process, and participates in the design and testing of new agents which could provide novel clinical approaches to inhibit angiogenesis in cancer. Among our current interests are the understanding of signal transduction pathways which mediate migration in the endothelial cell, including the formation of focal adhesions, the activation of cell surface integrins, the phosphorylation and activation of regulatory proteins, and the interaction of these components with microtubules and the cell cytoskeleton.
Cheng H, Zou Y, Ross JS, Wang K, Liu X, Halmos B, Ali SM, Liu H, Verma A, Montagna C, Chachoua A, Goel S, Schwartz EL, Zhu C, Shan J, Yu Y, Gritsman K, Yelensky R, Lipson D, Otto G, Hawryluk M, Stephens PJ, Miller VA, Piperdi B, Perez-Soler R. RICTOR amplification defines a novel subset of lung cancer patients who may benefit from treatment with mTOR1/2 inhibitors. Cancer Discovery, 2015, in press.
Nordstrøm LU, Sironi J, Aranda E, Maisonet J, Perez-Soler J, Wu P and Schwartz EL. Discovery of autophagy inhibitors with antiproliferative activity in lung and pancreatic cancer cells. ACS Medicinal Chem. Letters 2015; 6:134-9.
Zou Y, Ling YH, Sironi, J, Schwartz EL, Perez-Soler R, Piperdi B. (2013) The autophagy inhibitor chloroquine overcomes the innate resistance to erlotinib of non-small cell lung cancer cells with wild-type EGFR. J. Thoracic Oncology, 8:693-702.
Pula G, Dunn WB, Garonna E, Watson KE, Hirano M, Pizzorno G, Schwartz EL, el Kouni MH, Wheeler-Jones CPD. (2010) Paracrine stimulation of endothelial cell motility and in vitro wound repair by platelet-derived deoxyribose-1-phosphate. Arteriosclerosis, Thrombosis, and Vascular Biology. 30:2631-8.
Lu H, Klein RS and Schwartz EL (2009) Anti-angiogenic and anti-tumor activity of a novel thymidine phosphorylase inhibitor, 6-(2-aminoethyl)amino-5-chlorouracil (AEAC), in combination with the VEGF-Trap. Clinical Cancer Research, 15: 5136-5144.
Schwartz EL (2009) Anti-vascular actions of microtubule-binding drugs. Clinical Cancer Research 15:2594-2601.
Murtagh J, Lu H and Schwartz EL (2006) Taxotere-induced inhibition of endothelial cell migration is a result of Hsp90 degradation. Cancer Research 66:8192-8199.
Lu, H, Murtagh J and Schwartz EL (2006) The microtubule binding drug laulimalide inhibits VEGF-induced human endothelial cell migration, and is synergistic when combined with Taxotere. Molecular Pharmacology 69:1207-1215.
Hotchkiss, KA, Ashton AW and Schwartz EL (2003) The angiogenic factors thymidine phosphorylase and 2-deoxyribose stimulate human endothelial cell migration by activation of integrins alpha-5 beta-1 and alpha-v beta-3. J. Biological Chemistry 278:19272-19279.
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Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
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Bronx, NY 10461