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ICC 2019

Ramzi M Mohammad

Ramzi M Mohammad, Speaker at Cancer Congress
Wayne State University, United States
Title : Targeting nuclear protein export inhibitors machinary in cancer

Abstract:

Nuclear export is an evolutionary conserved mechanism that regulates the balanced nuclear expression of tumor suppressor proteins (TSPs). Overexpression of the major exportin protein chromosome region maintenance 1 (CRM1) results in nuclear exclusion of TSPs and is considered the underlying cause for low efficacy of drugs that target TSP activation. CRM1 overexpression has been linked to poor prognosis of pancreatic cancer (PC). Recently, we showed that inhibition of CRM1 by our specific inhibitors of nuclear export (SINEs) can suppress PC cell proliferation and induce tumor growth arrest in mice (Gastroenterology; 2013). Further, our large scale screening of gemcitabine (GEM) refractory PC patient tissue showed consistent over-expression of CRM1 that was concurrent with nuclear exclusion of major TSPs. These important findings suggest that CRM1 inhibition is could be an attractive strategy against GEM refractory PC. Here we show that SINEs synergize with GEM (CI<1) in a panel of PC cell lines and spheroid models that over express CRM1 [GEM resistant (GR) MiaPaCa-2-GR and AsPC-1-GR]. We also found that SINE-GEM can inhibit the proliferation of two recently identified stem cell models of PC (CD24+;CD44+;EpCam+). Mechanistically, SINEs were found to reverse GEM mediated expulsion of major TSPs and induce nuclear re-alignment of IκB, FOXO3a, p73, Par-4 and p27. Systems analysis of microarray expression datasets from SINE-GEM treated PC cells showed enrichment of gene networks in the nucleus of PC cells. Functional ontology of activated gene networks linked them to pathways that were relevant to stem cell and EMT inhibition and cancer fibroblast cell death associated signaling. These studies indicate that SINE-GEM can interfere with the EMT, stemness and fibroblast promoting signaling. Based on these important findings, we are initiating a SINE-GEM based multi-center Phase I/bII clinical trial in PC patients

Biography:

As a Director of GI-Cancer Research and Scientific Member of the Molecular Therapeutics Program at the Oncology Department, Karmanos Cancer Institute, Wayne State University with a track-record of cancer research for more than 34 years. I am one of the pioneers in developing animal models such as the Orthotopic Pancreatic Cancer animal model in 1990’s and the establishment of several unique cancer cell lines such as WSU-DLCL, WSUBL, WSU-NHL, WSU-FSCCL, WSU-WM, KCI-Pan, WSU-AML and more. I have published over 190 original scientific articles in peer-reviewed journals, review articles and book chapters (PubMed shows 146 articles under Mohammad RM and 190 under Mohammad R). I have been continuously and for 34 years funded by NCI, NIH and pharmaceutical companies and I have directed NIH funded research effectively. I have trained 52 pre-doctoral and post-doctoral students, and contributed to the research and education mission of the Cancer Center. I have taught second medical students’ immunology, bacteriology and virology for the last 27 years at WSU Medical School-Department of Immunology and Microbiology. I have extensive experience in physiology, cancer biology, animal models including Pancreatic Cancer, Colon Cancer, Sarcoma and NHL (xenografts and transgenic models), tissue culture and statistical analysis. My current research interest is focused on drug discovery. Utilizing my established cell lines and animal models, I study the effects of new anticancer agents, marine products as well as standard chemotherapeutic drugs. My research is translational in nature and through my close work with clinicians I was able to introduce several experimental drugs into the clinic among which include Bryostatin-1, Aurastatin-PE & PYE, Dolastatin-10 & 15 and Cambertastatin-4 and small molecule inhibitors such as AT-101 (gossypol), Bcl2/BclX, MDM2, Bcl2-DNAi and CRM1.

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