Tyler Endowed Professor in Cancer Research and KBA Eminent Scholar
PhD, University of Guelph, Ontario, Canada
Cancer biology, angiogenesis, metastasis, transgenic animals, stem cells, biomarkers, transcription factors, drug discovery and development
Cancer biology, angiogenesis, metastasis, autophagy, nanotechnology, transgenic animals, stem cells, biomarkers, transcription factors, drug discovery and development
The main focus of my laboratory is to examine the molecular mechanisms of apoptosis, angiogenesis and metastasis, and develop novel drugs for the treatment and prevention of various cancers.
We have used biochemical, molecular and transgenic animal approaches to identify novel death receptor agonists. These small molecules bind to death receptors and induce apoptosis in cancer cells, while sparing normal cells. Inhibition of survival pathways have been shown to enhance the therapeutic potential of death receptor agonists.
Chromatin modification has emerged as a new fundamental mechanism for gene transcriptional activity and has been associated with many cellular processes like proliferation, growth, apoptosis, and differentiation. It is increasingly recognized that epigenetic modifications constitute important regulatory mechanisms for the pathogenesis of malignant transformations. The role of epigenetics in diagnosis and treatment is likely to increase as mechanisms leading to the transcriptional silencing of genes involved in human cancers are revealed. Drugs that inhibit methylation are used both as a research tool to assess reactivation of genes silenced in cancer by hypermethylation and in the treatment of malignancies. In addition, the molecular mechanisms by which histone deacetylase inhibitors induce changes in gene expression are being examined. Furthermore, the clinical potentials of HDAC inhibitors and death receptor agonists are being evaluated in several models of human cancer.
Recent breakthroughs in stem cell biology, especially the development of induced pluripotent stem cell technique, have generated tremendous enthusiasm and efforts to explore the therapeutic potential of stem cells in human diseases. Progress in stem cell research and the identification of potential stem cells provides hope for the use of stem cells in regenerative medicine, treatment and prevention. The goal is to use adult or tissue-restricted stem cells as a possible approach for the treatment of cancer. We are using small molecules to target specific signaling pathways and/or mechanisms in manipulating cell fate and function. These small molecules are starting to play increasingly important roles in both elucidating the fundamental biology of stem cells and facilitating the development of therapeutic approaches. Such approaches could involve cell replacement therapies using homogenous functional cells produced under chemically defined conditions in vitro and the development of small-molecule based drugs for the treatment of human diseases.
Srivastava, R.K., Y.N. Lee, K. Noguchi, Y.G. Park, M.J.C. Ellis, J.-S. Jeong, S.N. Kim and Y.S. Cho-Chung. 1998. The RIIb regulatory subunit of protein kinase A binds to cAMP-response element: An alternative cAMP signaling pathway. Proc. Natl. Acad. Sci. 95: 6687-6692.
Srivastava R.K., Sasaki C.Y., Hardwick J.M. and Longo D.L. 1999. Bcl-2-mediated drug resistance: Inhibition of apoptosis by blocking nuclear factor of activated T lymphocytes (NFAT)-induced Fas ligand transcription. J. Exp. Med. 190: 253-265.
Srivastava R.K., Qing-Sheng M., Hardwick J.M. and Longo D.L. 1999. Deletion of loop region of Bcl-2 completely blocks paclitaxel-induced apoptosis. Proc. Natl. Acad. Sci. 96: 3775-80.
Suliman A., Lam A., Datta R., and Srivastava R.K. 2001. Intracellular Mechanisms of TRAIL: Apoptosis through Mitochondrial-Dependent and -Independent pathways. Oncogene 20: 2122-2133.
Kandasamy K. and Srivastava, R.K. 2002. Role of the Phosphatidyl 3'-Kinase/PTEN/Akt Kinase Pathway in TRAIL-induced Apoptosis in Non-Small Cell Lung Cancer (NSCLC) cells. Cancer Res. 62: 4929-4937.
Chen X., Kandasamy K. and Srivastava R.K. 2003. Differential roles of RelA (p65) and c-Rel subunits of nuclear factor kappa B (NFkB) in tumor necrosis factor-related apoptosis-inducing ligand signaling. Cancer Res. 63:1059-66.
Kandasamy K., Srinivasula S.M., Alnemri E.S., Thompson C.B., Korsmeyer S.J., Bryant J.L. and Srivastava R.K. 2003. Involvement of proapoptotic molecules Bax and Bak in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced mitochondrial disruption and apoptosis: Differential regulation of cytochrome c and Smac/DIABLO release. Cancer Res. 63:1712-21.
Singh T.R., Shankar S., Chen X., Asim M., and Srivastava R.K. 2003. Synergistic interactions of chemotherapeutic drugs and TRAIL on apoptosis and on regression of breast carcinoma in vivo. Cancer Res. 64: 6675-6686.
Singh T.R., Shankar S. and Srivastava R.K. 2005. HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma. Oncogene 24: 4609-23.
Shankar S., Chen Q., Ganapathy S., Singh K.P., and Srivastava R.K. 2008. Diallyl trisulfide increases the effectiveness of TRAIL and inhibits prostate cancer growth in an orthotopic model: molecular mechanisms. Mol. Cancer Therapeutics 7: 2328-38.
Shankar S., Ganapathy S. and Srivastava R.K. 2008. Sulforaphane enhances the therapeutic potential of TRAIL in prostate cancer orthotopic model through regulation of apoptosis, metastasis and angiogenesis. Clinical Cancer Res. 14: 6855-66.
Shankar S., Davis, R., Singh K.P., Kurzrock R., Ross D.D. and Srivastava R.K. 2009. Histone deacetylase inhibitor SAHA (vorinostat, zolinza) sensitizes TRAIL-resistant breast cancer cells orthotopically implanted in Balb c nude mice. Mol. Cancer Therapeutics. 8: 1596-605.
Ganapathy S, Chen Q, Singh KP, Shankar S, Srivastava RK. 2010. Resveratrol enhances antitumor activity of TRAIL in prostate cancer xenografts through activation of FOXO transcription factor. PLoS One. 5:e15627.
Srivastava RK, Kurzrock R, Shankar S. 2010. MS-275 sensitizes TRAIL-resistant breast cancer cells, inhibits angiogenesis and metastasis, and reverses epithelial-mesenchymal transition in vivo. Mol Cancer Ther. 9: 3254-66.
Shankar S, Nall D, Tang SN, Meeker D, Passarini J, Sharma J, Srivastava RK. 2011. Resveratrol inhibits pancreatic cancer stem cell characteristics in human and KrasG12D transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. PLoS One. 6:e16530.
Nalls D, Tang S-N, Rodova M, Srivastava RK, Shankar S. 2011. Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells. PLOS One. 6(8): e24099.
Tang SN, Fu J, Nall D, Rodova M, Shankar S, Srivastava RK. 2012. Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics. Int J Cancer.131: 30-40.
Tang S-N, Fu J, Shankar S, Srivastava RK. 2012. EGCG enhances the therapeutic potential of gemcitabine and CP690550 by inhibiting STAT3 signaling pathway in human pancreatic cancer. PLoS One 7(2): e31067.
Singh BN, Kumar D, Shankar S, Srivastava RK. 2012. Rottlerin induces autophagy which leads to apoptotic cell death through PI3K/Akt/mTOR/caspase-dependent pathway in human pancreatic cancer stem cells. Biochem Pharmacol. 84(9):1154-63.
Rodova M, Fu J, Watkins DN, Srivastava RK, and Shankar S. 2012. Sonic hedgehog signaling inhibition provides opportunities for targeted therapy by sulforaphane in regulating pancreatic cancer stem cell self-renewal. PLoS One. 2012;7(9): e46083.
Shankar S, Kumar D, Srivastava RK. 2013. Epigenetic Modifications by Dietary Phytochemicals: Implications for Personalized Nutrition. Pharmcology & Therapeutics. 138: 1-17.
Nanta R, Kumar D, Meeker D, Rodova M, Van Veldhuizen PJ, Shankar S, Srivastava RK. 2013. NVP-LDE-225 (Erismodegib) inhibits epithelial-mesenchymal transition and human prostate cancer stem cell growth in NOD/SCID IL2Rϒnull mice by regulating Bmi-1 and microRNA-128. Oncogenesis. 2013 Apr 8;2:e42.
Fu J, Rodova M, Roy SK, Sharma J, Singh KP, Srivastava RK, and Shankar S. 2013. GANT-61 inhibits pancreatic cancer stem cell growth in NOD/SCID/IL2Rgammanull mice. Cancer Letters. 330: 22-32.
Gojo I, Tan MT, Fang H-B, Sadowska M, Lapidus R, Baer MR, Carrier F, Beumer JH, Anyang BN, Srivastava RK, Espinoza-Delgado I, and Ross DD. 2013. Translational phase I trial of vorinostat combined with cytarabine and etoposide in patients with relapsed, refractory, or high-risk acute myeloid leukemia. Clinical Cancer Research. 19: 1838-51.Fu J, Rodova M, Nanta R, Meeker D, Van Veldhuizen PJ, Srivastava RK, and Shankar S. 2013. NPV-LDE-225 (Erismodegib) inhibits epithelial mesenchymal transition and self-renewal of glioblastoma initiating cells by regulating miR-21, miR-128, and miR-200. Neuro Oncol. 15: 691-706.
Rakesh K Srivastava, PhD
4031 Wahl Hall East; MS-1018
3901 Rainbow Blvd.
Kansas City, Kansas 66160
F: (913) 945-6831