Meenakshi Upreti, Ph.D.
The goal of my research is to transform scientific approaches and techniques developed in the laboratory into clinical applications to reduce cancer incidence, morbidity, and mortality.
My current research falls broadly under the following areas (1) Experimental Cancer Therapeutics and Impact of Tumor Microenvironment (2) Developing Novel in-vitro/ in-vivo Tumor Models (3) Targeted drug delivery and (4) Application of Systems Biology approaches to Cancer. I also collaborate with basic scientists and clinicians at UAMS that complement my expertise in addition to pursuing independent research.
Classical research in cancer for several decades has focused on understanding the biology of tumor cells in vitro. However, extending these findings to in vivo settings has been impeded due to limited insights on the effect of microenvironment on tumor cells. The communication between tumor cell and the vascular niche, a phenomenon termed neo-angiogenesis, plays a critical role in tumor progression. Folkman, in his seminal work on angiogenesis proposed a two-compartment system requiring both tumor cells and endothelial cells in the microenvironment to promote rapid tumor growth and vascular reconstruction. To that end we have developed a ‘hanging drop’ 3-D tumor/endothelial cell co-culture strategy without the incorporation of any extracellular matrix (ECM) mimics in vitro that can be subsequently transplanted to window chamber or rear limb in vivo for fluorescence imaging of vascularization, cancer progression and treatment response. This newly created pre-clinical model system is designed to better understand mechanisms governing tumor initiation, growth, angiogenesis, and disease progression. The response of these systems to experimental or established therapeutics will allow important observations about the cellular, molecular and physiological aspects of tumor response. In addition the importance of yet undefined modes of intercellular communication and support between tumor and endothelial cells may be uncovered, leading to identification of new targets for cancer control. Our efforts are directed towards developing and improving strategies for tumor specific radiation therapy and/or drug delivery, by identifying surrogate markers of tumor progression, before and after treatment.
Galectin-1 is one such tumor endothelial cell specific marker that is functionally important to tumor angiogenesis. We have made the novel discovery that galectin-1 expression further increases, is upregulated, after radiation exposure, particularly on the endothelial cell surface. It also serves as a receptor for the 33 Amino acid antiangiogenic peptide, Anginex. We believe that delivery of chemotherapy via a peptide targeted to radiation-induced and tumor-vasculature associated Galectin-1 will improve the therapeutic ratio for combination therapy strategies against solid tumors. Our in vitro and in vivo models of tumor-endothelial cell co-culture show increased levels of galectin-1 upon radiation exposure and therefore serve as appropriate models to understand radiation enhanced drug delivery. The long-term research goal is to develop targeting ligands, such as anginex, for conjugation to therapeutic payloads for highly selective, radiation therapy-amplified drug delivery to the tumor microenvironment.
LIST OF PUBLICATIONS
Williams BW, Koonce NA, Bischof JC, Song CW, Asur R, Upreti M. Griffin RJ  Vascular disrupting agent arsenic trioxide enhances thermoradiotherapy of solid tumors. Journal of Oncology.2012:934918. Epub 2012 Jan 4. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261488/?tool=pubmed
Upreti M, Jamshidi-Parsian A, Koonce NA, Webber JS, Sharma SK, Asea AA, Mader MJ, Griffin RJ.  Tumor-Endothelial Cell Three-dimensional Spheroids: New Aspects to Enhance Radiation and Drug Therapeutics. Translational Oncology. 2011 Dec; 4(6):365-76. Epub 2011 Dec 1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243660/?tool=pubmed
Nagarajan R and Upreti M.  Inferring functional relationships and causal network structure from gene expression profiles. Methods in Enzymology 487:133-46. PMID: 21187224 http://www.ncbi.nlm.nih.gov/pubmed?term=21187224
Upreti M, Koonce NA, Hennings L, Chambers TC, and Griffin RJ.  Pegylated IFN-α sensitizes melanoma cells to chemotherapy and causes premature senescence in endothelial cells by IRF-1-mediated signaling. Cell Death and Disease 1, e67 doi:10.1038/cddis.2010. PMID: 21197417 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010727/?tool=pubmed
Nagarajan R, Upreti M. Granger causality analysis of human cell-cycle gene expression profiles.  Statistical Applications in Genetics and Molecular Biology. 9(1):Article31. Epub 2010 Aug 13. PMID: 20812909 http://www.ncbi.nlm.nih.gov/pubmed?term=20812909
Terrano DT, Upreti M and Chambers TC.  CDK1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Molecular and Cellular Biology 30(3):640-56. [Epub 2009 Nov 16] PMID: 19917720 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812246/?tool=pubmed
David Bateman T, Joshi AL, Moon K, Galitovskaya EN, Upreti M, Chambers TC, and McIntosh MC.  Synthesis and anticancer activity of sclerophytin-inspired hydroisobenzofurans. Bioorganic & Medicinal Chemistry Letters 19(24); Dec, p6898-6901. PMID: 19896844 http://www.ncbi.nlm.nih.gov/pubmed?term=19896844
Chu R., Upreti M., Ding W. X., Yin X. M., and Chambers T. C.  Regulation of Bax by c-Jun NH(2)-terminal kinase and Bcl-xL in vinblastine-induced apoptosis. Biochemical Pharmacology 78(3):241-8. PMID: 19427996 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692743/?tool=pubmed
Upreti M., Galitovskaya E., Chu R., Tackett A.J., and Chambers T.C.  Vinblastine-induced Bcl-xL phosphorylation: identification of major site by mass spectrometry and mutational analysis. Journal of Biological Chemistry 283:35517-25. PMID: 18974096. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2602892/?tool=pubmed
Upreti M., Chu R., Galitovskaya E., Smart S.K. and Chambers T.C.  Key role for Bak activation and Bak-Bax interaction in the apoptotic response to vinblastine. Molecular Cancer Therapeutics 7(7):2224-32. PMID: 18645031 http://www.ncbi.nlm.nih.gov/pubmed?term=18645031
Nagarajan R. and Upreti M.  Comment on causality and pathway search in microarray time series experiment. Bioinformatics 24(7): 1029-3. PMID: 18304931 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679500/?tool=pubmed
Kolomeichuk S.N., Bene A., Upreti M., Dennis R.A., Lyle C.S., Rajasekaran M., Chambers T.C.  Induction of apoptosis by vinblastine via c-Jun auto-amplification and p53-independent downregulation of p21WAF1/CIP1. Molecular Pharmacology 73(1):128-36. PMID: 18094076 http://www.ncbi.nlm.nih.gov/pubmed?term=18094076
Nagarajan R. and Upreti M.  Correlation statistics for cDNA microarray image analysis. IEEE/ACM Transactions Computational Biology Bioinformatics 3(3):232-8. PMID: 17048461 http://www.ncbi.nlm.nih.gov/pubmed?term=17048461
Upreti M., Lyle C.S., Skaug B., Du L., Chambers T.C.  Vinblastine-induced apoptosis is mediated by discrete alterations in subcellular location, oligomeric structure, and activation status of specific Bcl-2 family members. Journal of Biological Chemistry 281(23), 15941-50. PMID: 16574665 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1656399/?tool=pubmed
Upreti M., Rath P.C.  Expression and DNA binding activity of the recombinant interferon regulatory factor-1 (IRF-1) of mouse. Molecular Biology Reports 32(2):103-16. PMID: 16022283 http://www.ncbi.nlm.nih.gov/pubmed?term=16022283
Padmavathi B., Upreti M, Singh V., Rao A.R, Singh R.P. and Rath P.C.  Chemoprevention by Hippophae rhamnoides: effects on tumorigenesis phase II-, antioxidant enzymes and IRF-1 transcription factors. Nutrition and Cancer 51(1); 59-67. PMID: 15749631 http://www.ncbi.nlm.nih.gov/pubmed?term=15749631
Upreti M., Kumar S. and Rath, P.C.  Replacement of 198MQMDII203 of mouse IRF-1 by 197IPVEVV202 of human IRF-1 abrogates induction of IFN-b, iNOS and COX-2 Biochemical Biophysical Research Communication 314(3), 737-44. PMID: 14741697 http://www.ncbi.nlm.nih.gov/pubmed?term=14741697
Agrawal A., Choudhry D., Upreti M., Rath P.C. and Kale R.K.  Radiation induced oxidative stress: St- udies in Ehrlich solid tumor in mice Molecular and Cellular Biochemistry Jul; 223(1-2):71-80. PMID: 11681724 http://www.ncbi.nlm.nih.gov/pubmed?term=11681724