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Function Based Therapeutic Strategies to Human cancers (Functionotherapeutics): Study of the Functional Role of ETS-fusion genes in Prostate cancer, Ewing Sarcoma, Breast cancer, Melanoma and leukemias
We have discovered and cloned several oncogenes and studied their functions (close to twenty genes). The most notable genes discovered include ERG-1, ERG-2 and ERG-3 genes (we have named the gene as ETS Related Gene, published in prestegious Science and PNAS journals). This gene is involved in 40-80% of Prostate cancers, Ewing sarcoma and also leukemias (AML). Other notable genes discovered and studied by Dr Reddy include human Fli-1 (involved in Leukemias), EWS-Fli-1 (involved in Ewing Sarcoma) , EWS-erg (involved in Ewing Sarcoma), TLS-erg (involved in Acute Myeloid Leukemia), EWS (involved in multiple cancers), TLS/FUS (involved in multiple cancers), ELK-1 (ETS Like Gene, published in prestegious Science journal, involved in breast and ovarian cancers), BRCA2a (involved in breast, ovarian and prostate cancers) and EWS-ATF-1 (involved in malignant Melanoma of Soft Parts). We have identified the DNA binding, trans-activation domains and other regulatory domains of ERG, ELK-1, Fli-1, EWS-Fli-1, EWS-erg, TLS-erg, EWS-ATF-1, etc. We have successfully targeted EWS-fusion proteins and shown that this approach can be used as a therapy for Ewing family of tumors. Dr Reddy and his colleagues are identifying the function of these oncogenes and also developing strategies to target these oncoproteins or their functions to develop novel targeted therapeutic agents. Using this Function based therapeutic strategy, we have developed several novel drugs (patent being submitted) that target Prostate, Ewing Sarcoma, Breast cancer (triple negative breast cancer), Pancreatic cancer, Ovarian, cervical cancers and colorectal cancers. Dr Reddy and his colleagues have identified ERG/ETS-target genes and are studying the novel mechanism by which it regulates the signaling pathways. These studies will revolutionize our understanding of tumorigenesis and provide new approaches to therapeutic intervention.
Dr Reddy and his colleagues have also shown that anti-epileptic drug Valproic acid (VPA) targets ERG-positive Prostate cancers and Ewing Sarcoma and identified the molecular mechanism of action of VPA on ERG/Fli-1 associated cancers. Recently, they have identified novel ways by which ERG/ETS oncoproteins target different signaling pathways that leads to prostate and other cancers (leukemias, lymphomas and sarcomas). Dr Reddy and his colleagues have identified novel molecular mechanism of activation of TGF beta–signaling pathway by ERG oncoprotein in prostate cancer. Recently, Dr Reddy and his colleagues have shown that ETV1 onco-protein induces certain kinases in cancer cells which deregulate the critical Wnt/beta catenin pathway. They have also identified therapeutic agent that interferes with this process. They have also demonstrated that this therapeutic agent targets these cancer cells effectively (manuscript in press, 2016). These therapeutic agents will have a profound impact on prevention and treatment of prostate cancer which may help to reduce health disparity seen in minority prostate cancer patients. Recently, Dr Reddy’s group decoded non-coding DNA and it’s non-coding RNA, which will revolutionize the future biology (manuscript In press, 2016). (Please see www.reddyesp.com)
We have recently discovered novel post-translational mechanism in Breast cancer cells that will have global effect on the gene expression, differentiation, protein turnover, cell death, cancer and other Human diseases. Majority of N-linked glycosylation of proteins occurs in secretary and membrane proteins. This typical N-glycosylation of a protein takes place upon entry of the protein into the lumen of endoplasmic reticulum (ER) where, there is a transfer of carbohydrate moiety to asparagine residue present in the protein. In bacteria, N-glycosylation can occur independent of this protein translocation (Science, 314, 1148, 2006). Here, Dr Reddy and his group find that such protein modifications (protein translocation-independent N-glycosylation) can also occur even in eukaryotic cells. They show that transcriptional cofactor CBP interacts with BRCA2 protein (involved in breast cancer, ovarian cancer and prostate cancer) and mediates its N-glycosylation both in vitro and in vivo. This is the first report that a transcription cofactor like CBP may be involved in protein translocation-independent N-glycosylation.
Dr Reddy predicts that this CBP/p300-mediated post-translational modification may be a signal for the regulation of CBP interacting proteins. Interestingly, BRCA2 protein is known to be ubiquitinated and degraded by the proteosomal pathway in breast cancer cells. Dr Reddy is presently testing this hypothesis. Since CBP/p300 cofactor interacts with many onco-proteins, tumor suppressors and transcription factors, such a signal may be vital to regulate the expression of these interacting proteins which play an important role in cell growth, differentiation and cell death. Therefore, this post-translational N-glycosylation can have global effect on gene function, cell growth and differentiation.
Dr Reddy conducted Cancer Colloquiums to teach MD and Ph.D. students. He also taught and trained Ph.D. students, MD students, residents, MPH students, undergraduate students and also high school students in cancer research.
Dr Reddy received many personal distinguished awards such as LIFETIME ACHIEVEMENT AWARD by IIFS; prestigious MAHATMA GANDHI PRAVASI GOLD MEDAL at the HOUSE OF LORDS, PARLIAMENT, LONDON; Outstanding Advisor Ph. D. class of 2014, Morehouse School of Medicine, "MOTHER TERESA EXCELLENCE AWARD" by ICSEP; "BHARAT AWARD for EXCELLENCE", “RASHTRYA JEWEL AWARD” and GOLD MEDAL, prestigious INTERNATIONAL GOLDSTAR AWARD 2012, prestigious BEST PERSONALITIES OF INDIA AWARD and Gold Medal, Super achievers of India Award with Gold medal, BHARAT EXCELLENCE AWARD with Gold Medal 2012, CPDR Distinguished Visiting Professor Recognition Award 2011, Prestigious BHARAT GAURAV AWARD (Pride of India award) (Previous winners of this honor - Late Mother Teresa, Noble Laureate, actor Dev Anand, Lord Parekh, S. Gavaskar), TAMA award for outstanding efforts and leadership in medicine 2011, GCC Distinguished Cancer Scholar Award from the Governor, Georgia, USA, chosen to receive the prestigious Glory of India award, ATA Outstanding Science Achievement award, USA, MSM Dean's Outstanding Research award, Outstanding Grantsmanship Award and induction into the million dollars club of Drexel – University, INSA Young Scientist award from the Prime Minister of India, several NIH RO1 grants, PO1 awards, DOD Prostate Cancer idea awards, DOD Breast Cancer idea awards, DOD Breast Cancer concept award (blind review), Twice recipient of Swebelius Cancer Research Award, Yale University, First Margaret Memorial award, UK and W.W. Smith Foundation Charitable Trust award. Dr Reddy is also appointed as Editor of Journal of Pharmaceutical Sciences and Pharmacology, and editorial member of seven journals. 1. American Journal of Cancer Science; 2. American Journal of Cancer Biology; 3. American Journal of Cancer Review; 4. Speciality Editor Cancer on WebmedCentral plus Cancer; 5. Gastroenterology and Hepatology (GH), CSC Canada; 6. J. Hematology & Thromboembolic Diseases; 7. British Biotechnology Journal.
Dr Reddy is also chosen as Board of Director of Carcinogenesis Foundation.
WEB: www.reddyesp.com
http://www.linkedin.com/pub/e-shyam-p-reddy/22/b99/3a
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