E. Premkumar Reddy, PhD
- PROFESSOR | Pharmacological Sciences
- PROFESSOR | Oncological Sciences
Research Topics:Autophagy, Cancer, Cancer Genetics, Cell Cycle, Cytokines, Drug Design and Discovery, Knockout Mice, Leukemia, Lymphoma, Oncogenes, Protein Kinases, Signal Transduction, Stem Cells, Transcription Factors, Transgenic Mice, Tumor Suppressor Genes, Viruses and Virology
Dr. E. Premkumar Reddy obtained his Ph.D. in 1971 and carried out his post-doctoral training at the UCLA School of Medicine from 1972-1974 and later at the National Cancer Institute from 1974-75. He worked at the National Cancer Institute first as an independent investigator and later as a section chief between 1975 and 1984. In 1984, he moved to Hoffmann La Roche and held appointments at Hoffmann La Roche and the Roche Institute of Molecular Biology as a Full Member. In 1986, he joined the Wistar Institute as a Professor and Deputy Director. From 1992 to 2010, he served as the Director of the Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia. He joined the Mount Sinai School of Medicine in March of 2010 as a Professor in the Departments of Oncological Sciences and the Department of Structural and Chemical Biology and as the Director of Experimental Cancer Therapeutics.
While working at the National Cancer Institute, he made a number of seminal discoveries that provided a clear understanding of the molecular basis of cancer. He cloned and sequenced a number of viral oncogenes which included abl, ras, fgr, mos, myb, myc and sis oncogenes and their cellular homologues which pinpointed the precise changes that cellular proto-oncogenes undergo to produce cancer-causing viral oncogenes. He extended this work to human cancers and was responsible for the seminal discovery that point mutations in the cellular ras genes result in their oncogenic activation. His work also showed the mechanisms associated with the activation of Abl and Myb oncogenes, which are associated with the development of human myelogenous leukemias. His recent work on cell cycle regulator, Cdk4 has shown that this gene is very critical for the development of ErbB2 and ras oncogene-induced tumors and inhibition of expression of Cdk4 causes ablation of breast cancers caused by ErbB2 and Ras oncogenes.
Dr. Reddy has pioneered the development of small molecule inhibitors targeted against oncogenes and cell cycle regulators for cancer therapy. One of the drugs developed by Dr. Reddy, ON01910 is currently in Phase III clinical trials and has shown profound clinical activity in MDS (Myelodysplastic Syndrome) patients as a single agent. In combination with Oxaliplatin and Gemcitabine, ON01910 was found to have remarkable efficacy in reducing the tumor burden of several metastatic cancers including breast, ovarian and pancreatic cancers. In addition to ON01910, Dr. Reddy has developed six different cancer drugs, two of which (ON013100, and ON01210) have entered clinical trials and the other three are expected to enter clinical trials in the next one year. Two of these drugs, a small molecule inhibitor of Plk2, ON1231320 and a second compounds ON123300 which is a dual inhibitor of Cdk4 and AKT pathways arecurrently undergoing pre-clinical evaluation.
Dr. Reddy founded the cancer journal Oncogene in 1986 and served as its Editor from 1986 to 2009. In 2010, he founded a second cancer journal, Genes & Cancer for which he currently serves as the Editor-in-Chief.
Multi-Disciplinary Training AreasBiophysics and Systems Pharmacology [BSP], Cancer Biology [CAB]
PhD, Regional Research Laboratories/Osmania University
National Cancer Institute
University of California, School of Medicine
Laura H. Carnell Professor of Medicine
Scientific Achievement Award
Our laboratory is interested in the study of genes that control cell homeostasis and how these controls are dysregulated during the neoplastic process. We use a combination of biochemistry, molecular biology and synthetic organic chemistry approaches and in close collaboration with the clinical community develop and test small molecule anti-cancer compounds.
We are interested in studying basic biological processes, such as development of the organism through the study of oncogenes such as the myb gene family and cell-cycle regulatory genes such as Cdk4. We have generated a collection of transgenic and gene knock-out animal models for study of the myb gene family. Through our studies of the myb gene family, we have begun to understand its role in hematopoietic stem cell development and maintenance and their role in the development of mammary tissue. We also study the G1 cyclin-dependent kinase, CDK4. We have developed a nullizygous CDK4 mouse, which displays a phenotype that mimics Type I diabetes, and a CDK4 knock-in mouse that expresses the CDK4R24C protein. We are using both models to study the role of Cdk4 in the development of cancer.
We also study mechanisms of mitogen activated protein (MAP) kinase signaling through scaffolding proteins belonging to the JIP/JSAP/JLP family. In 2002, we reported the identification of a MAP kinase scaffolding proteins, JLP, which binds to and coordinately regulates the activities of MEKK3, MKK4, p38MAPK, JNK, Max, c-myc, the kinesin light chain, the stathmin-like protein SCG10, the alpha subumit of the heterotrimeric G protein G13, and the E3 ubiquitin ligase, CHIP. We are currently undertaking a number of projects aimed at understanding the role of JLP in cell growth and differentiation.
Our basic biology efforts are coordinated with a translational research program to develop and test small molecule anti-cancer therapeutics. Our chemical biology group has designed and produced a library of nearly 10,000 unique small molecules from approximately 120 individual chemical backbones, or “chemotypes.” This chemical library has been screened for cytotoxic activity toward cancer cells, while leaving non-malignant tissue intact. Several of these compounds exhibit kinase inhibitory activities while others seem to inhibit the function of heat shock proteins. At the present time, we are studying at least 10 such molecules, all with differing mechanisms of action. Some of these compounds have demonstrated dramatic activity in clinical trials and one of these molecules, ON01910 has been found to have a profound clinical activity in MDS (Myelodysplastic Syndrome) patients. In combination therapy with Oxaliplatin and Gemcytabine, ON01910 has also been found to have excellent activity in pancreatic and ovarian cancer patients. Several other kinase inhibitors developed in our laboratory that inhibit Plk2, BCR-ABL, PI3K-a, CK2 have shown pre-clinical activity in cultured cells lines and in animal tumor xenograft models and are being processed for Phase I clinical trials.
The Reddy Laboratory
Rane SG, Dubus P, Mettus RV, Galbreath EJ, Boden G, Reddy EP, Barbacid M. Loss of CDK-4 expression causes infertility and insulin deficient diabetes while its activation results in pancreatic islet hyperplasia. Nature . Nature Genetics 1997; 22: 44-52.
Lieu YK, Reddy EP. Conditional c-myb knockout in adult hematopoietic stem cells leads to loss of self-renewal due to impaired proliferation and accelerated differentiation.. Proc Natl Acad Sci U S A 2009; 106: 21689-21694.
Xu H, Dhanasekaran DN, Lee CM, Reddy EP. Regulation of neurite outgrowth by interactions between the scaffolding protein, JNK-associated leucine zipper protein, and neuronal growth-associated protein superior cervical ganglia clone 10. Journal of Biological Chemistry 2010; 285: 3548-3553.
Reddy HK, Graña X, Dhanasekaran DN, Litvin JJ, Reddy EP. Requirement of Cdk4 for v-Ha-ras–Induced Breast Tumorigenesis and Activation of the v-ras–Induced Senescence Program by the R24C Mutation. . Genes & Cancer 2010; 1: 69-80.
Reddy MV, Mallireddigari MR, Cosenza SC, Pallela VR, Iqbal NM, Robell KA, Kang AD, Reddy EP. Design, synthesis, and biological evaluation of (e)-styrylbenzylsulfones as novel anticancer agents. . Journal of Medicinal Chemistry 2008; 51: 86-100.