Dhan V. Kalvakolanu, PhD

Over the years we have developed several siRNA and direct plasmid-based gene therapy delivery strategies for suppressing oncogenic transcription factors and promoting tumor suppress expression in vivo. In a collaborative study we have developed a cod-derived glycopeptide as a blocker of Galectin-3 mediated tumor-induced T-cell apoptosis was developed for protecting immune response against the tumors in vivo.

1. Gao, L., Zhang, L., Hu, J., Li, F., Shao, Y., Zhao, D., Kalvakolanu, D. V., Kopecko, D. J., Zhao, X. & Xu, D. Q. (2005) Down-regulation of signal transducer and activator of transcription 3 expression using vector-based small interfering RNAs suppresses growth of human prostate tumor in vivo. Clin Cancer Res 11, 6333-6341.
2. Zhang, L., Gao, L., Zhao, L., Guo, B., Ji, K., Tian, Y., Wang, J., Yu, H., Hu, J., Kalvakolanu, D. V., Kopecko, D. J., Zhao, X. & Xu, D. Q. (2007) Intratumoral delivery and suppression of prostate tumor growth by attenuated Salmonella enterica serovar typhimurium carrying plasmid-based small interfering RNAs. Cancer Res 67, 5859-5864.
3. Guha, P., Kaptan, E., Bandyopadhyaya, G., Kaczanowska, S., Davila, E., Thompson, K., Martin, S. S., Kalvakolanu, D. V., Vasta, G. R. & Ahmed, H. (2013) Cod glycopeptide with picomolar affinity to galectin-3 suppresses T-cell apoptosis and prostate cancer metastasis. Proc. Natl. Acad. Sci. USA 110, 5052-5057.
4. Tian, Y., Guo, B., Jia, H., Ji, K., Sun, Y., Li, Y., Zhao, T., Gao, L., Meng, Y., Kalvakolanu, D. V., Kopecko, D. J., Zhao, X., Zhang, L. & Xu, D. (2012) Targeted therapy via oral administration of attenuated Salmonella expression plasmid-vectored Stat3-shRNA cures orthotopically transplanted mouse HCC. Cancer Gene Ther 19, 393-401.
5. Li, X., Li, Y., Hu, J., Wang, B., Zhao, L., Ji, K., Guo, B., Yin, D., Du, Y., Kopecko, D. J., Kalvakolanu, D. V., Zhao, X., Xu, D. & Zhang, L. (2013) Plasmid-based E6-specific siRNA and co-expression of wild-type p53 suppresses the growth of cervical cancer in vitro and in vivo. Cancer Lett 335, 242-250.

I have obtained my Ph.D. from Indian Institute of Science (some say the MIT of India), a premier academic research institute. I have worked on the biology of oncogenic retroviruses or my Ph.D. Following graduation I have obtained post-doctoral training at the Fred Hutchinson Cancer Research Center, Seattle, WA and then at Lerner Research Institute of the Cleveland Clinic Foundation, Cleveland, OH. I have several years of experience in the areas of Molecular biology, Cancer Biology, Virology, cytokine-induced innate immunity, Signal transduction, autophagy, and transcriptional regulation of gene expression. My seminal contributions include the discovery of GRIMs, a novel group of tumor suppressor genes; novel cytokine inducible gene regulatory elements, their cognate transcription factors and signal transduction pathways that control them. I am also one of the first few investigators who described mechanisms of viral resistance to Interferon actions. I have developed the concept of GRIMs and identified the critical genes involved in this process. My lab was the first to describe GRIM-19, a novel tumor suppressor, monoclonal antibodies against it, its interacting proteins, functionally inactivating somatic mutations, loss of expression in primary human tumors. We have also developed conditional knockout mouse models that allow the study of tumor suppressors and oncogenes. We were also one of first group to apply genome-wide expression knockdown technologies before the description of whole genome sequences and RNAi technology.

Until now tumor suppressors have been thought to control cell growth via a regulation of intracellular processes like division, apoptosis and adhesion. Emerging reports indicate these molecules may also regulate extracellular environment. Immune escape is a major contributor to tumor metastases. We have shown the upregulation of a set of gene products, which include many cytokines, in GRIM-19 deficient tumors. Currently, we are studying how the loss/mutation of GRIM-19 favors the development of immunosuppressive microenvironment. We are also testing if blockade of these upstream regulators blocks such chemokine wave and blunts tumor progression. In this manner, our investigations are a “bed to bench and bench to bed” studies with strong basic and translational impact- for our studies were based on initial clinical observations, defined the candidate genes in the lab, validated their aberration in clinical samples and came back to bench for further understanding of molecular bases for tumor development.  The information gained from these studies will be useful in developing better-targeted therapies for HNSCCs and other cancers.

My other contribution to science is the definition of novel signal transduction pathways employed by cytokines. In particular, we have identified non JAK-STAT pathways that promote antitumor actions of interferons. Earlier we have defined a critical role for MAPK signaling pathways and transcription factor C/EBP-β in driving anti-tumor actions. The expression of a metastasis suppressing kinase DAPK1 is inactivated in a number of human cancers. C/EBP-β collaborates with another factor ATF6 in promoting the expression of a calcium/calmodulin dependent protein serine-threonine kinase- the death-associated protein kinase 1(DAPK1). Recently, we have identified a novel non-canonical NF-κB/HDAC dependent axis in suppressing DAPK1 expression in acute myeloid leukemia. During the last 4 years- we have identified a role of endoplasmic reticulum resident transcription factor ATF6 in driving autophagy, apoptosis and tumor suppression. We have described a role of proteolysis and phosphorylation-dependent proteolytic activation of ATF6 in the Golgi. A novel role for apoptosis-stimulating kinase-1 (ASK1) in inducing ATF6 phosphorylation in the ER has been identified in these studies. Currently, the role of ATF6 and ASK1 in the antitumor autophagy is being investigated in the lung cancer in vivo and in primary human tumors.

Awards:

Visiting Professor, University of Science and Technology, Hefei, PR China, 2006-2009, 2010, 2014

Visiting Professor, Tongji Medical College and Hospital, Wuhan, PR China, 2006-2014

Visiting Professor, Dalian Medical University, Dalian, PR China, 2013-present.

Foreign Member, AP academy of sciences, India

Professional Organization Memberships:

 Member, American Society for the Advancement of Science. 1997-present

Member, Federation of American Societies for Experimental Biology 1996- present

Member. American Society for Microbiology, 1997-present

Member, American Society for Biochemistry and Molecular Biology, 1995-present

Member, International Society for Interferon and Cytokine Research, 1994-2013

Member, International Cytokine and Interferon Society, 2013-present

Chartered Member, CSR-CAMP study section

Member, International Council, International Society for Interferon and Cytokine Research, 2001

Member, Awards committee, International Cytokine and Interferon Society, 2010-2016

Transcriptional assays, Chromatin-Immunoprecipitation, RNA-seq analyses, RNAi with lentiviral vectors, mitochondrial respiration, apoptosis, autophagy and cell growth assays; Knockout mice, tumor xenografts