Harshil Dhruv

Harshil Dhruv Ph.D.

Assistant Professor
Cancer and Cell Biology Division

Harshil Dhruv Ph.D.

TGen has proven a fertile environment for Dr. Dhruv’s background in bioengineering to gain a translational thrust through development and characterization of patient derived models of cancer for utilization in precision medicine. Malignant tumors when present in the brain present the highest challenge with most dismal prognosis and very limited treatment options. This sets the stage for his major research initiatives: 

1. The most common and most aggressive primary brain tumor, glioblastoma (GB), defies management by surgery, radiation, and conventional chemotherapy. One of the major foci of Dr. Dhruv’s lab is to develop and deploy preclinical models of GB to practice precision medicine.  Dr. Dhruv uses comprehensive molecular characterization (including DNA and RNA Sequencing) combined with targeted therapeutics to discover relationships predictive of in vivo tumor response.  As Assistant Professor in the Brain Tumor Unit (BTU) he oversees the use of 75 patient derived xenograft (PDX) models of GB. Multiple vibrant collaborations with academic and pharmaceutical partners access these models for testing targeted therapeutics and understanding how best to match drug to vulnerable tumor. In addition, these models provide a rich platform for testing novel bioinformatic tools to improve precision medicine algorithms.    

2. Establish clinical partnerships to move novel therapeutics into clinical trials for treatment of GB.  We are currently collaborating with Barrow Neurological Institute (BNI) for a very novel Phase 0 clinical trial to investigate BBB permeability of the Wee1 inhibitor AZD1775. Additionally, we carried out correlative studies using PDX resources developed by BTU to identify molecular markers of response for AZD1775. 

3. Establish clinical partners to access retrospective clinical trial specimens to discover a genomic context of vulnerability for targeted therapeutics and validate the identified signature using PDX resources developed by BTU. We are currently collaborating with Northwestern University and Baylor Scott & White Research Institute to validate the genomic context of vulnerability to Arsenic Trioxide in GB.

4. Among the more encouraging advances in the field of cancer research over the last decade is the emergence of “local control” of cancer using frontline therapies. Such advances, while celebrated, underscore the aggressive regrowth of cancer cells in distant organs, accounting for 95% of all cancer deaths. A diagnosis of central nervous system (CNS) recurrence is not uncommon in patients with breast cancer and an estimated 10% to 30% of all breast cancer patients will eventually develop brain metastases. The diagnosis of breast cancer brain metastases is associated with the shortest survival time compared with other sites of metastatic spread and with progressive neurologic deficits that result in a reduced quality of life. Dr. Dhruv’s lab develops preclinical models of breast tumor metastasis to the brain for use in evidence-based precision medicine.

Dr. Dhruv joined TGen as a post-doctoral fellow in 2009 under the mentoring of Dr. Michael Berens. Dr. Dhruv did his first post-doctoral fellowship at ASU developing a novel drug delivery system for treatment of GB. He obtained his MS and PhD degrees in Bioengineering from Utah State University.


PUBLICATIONS

MAPK-interacting kinase 1 (MNK1) and mRNA translation regulate differential responses to arsenic trioxide in glioma stem cells. Jonathan B. Bell, Frank Eckerdt, Harshil D. Dhruv, Darren Finlay, Sen Peng, Seungchan Kim, Barbara Kroczynska, Elspeth M. Beauchamp, Kristen Alley, Jessica Clymer, Stewart Goldman, Shi-Yuan Cheng, C. David James, Ichiro Nakan, Craig Horbinsk, Andrew P. Mazar, Kristiina Vuori, Priya Kumthekar, Jeffrey Raizer, Michael E. Berens, and Leonidas C. Platanias. Molecular Cancer Research, 2017. (Accepted).

Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Matthew J. Hangauer, Vasanthi S. Viswanathan, Matthew J. Ryan, Dhruv Bole, John K. Eaton, Alexandre Matov, Jacqueline Galeas, Harshil D. Dhruv, Michael E. Berens, Stuart L. Schreiber, Frank McCormick and Michael T. McManus. Nature, 2017. (Accepted)

Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma. Robert S. McNeill, Demitra A. Canoutas, Timothy J. Stuhlmiller, Harshil D. Dhruv, David M. Irvin, Ryan E. Bash, Jeremy M. Simon, Ralf S. Schmid, Marni B. Siegel, Amanda E.D. Van Swearingen, Michael J. Hadler, Erik P. Sulman, Carey K. Anders, Michael E. Berens, Gary L. Johnson, and C. Ryan Miller. Neuro-Oncology, 2017. (E-pub Ahead of Print).

Genomic profiles of low-grade murine gliomas evolve during progression to glioblastoma. Mark Vitucci*, David M. Irvin*, Robert S. McNeill, Ralf S. Schmid, Harshil D. Dhruv, Andrea M. Werneke, Ryan E. Bash, Seungchan Kim, Michael E. Berens, and C. Ryan Miller. Neuro-Oncology, 2017. (E-pub Ahead of Print).

Dependency of high mesenchymal state cancer cells on a lipid hydroperoxide-dissipation pathway. Vasanthi S Viswanathan, Matthew J Ryan, Harshil D Dhruv, Shubhroz Gill, Ossia M Eichhoff, Brinton Seashore-Ludlow, Samuel D Kaffenberger, John K Eaton, Kenichi Shimada, Andrew J Aguirre, Srinivas R Viswanathan, Shrikanta Chattopadhyay, Pablo Tamayo, Wan Seok Yang, Matthew G Rees, Sixun Chen, Zarko V Boskovic, Sarah Javaid, Cherrie Huang, Xiaoyun Wu, Yuen-Yi Tseng, Elisabeth M Roider, Dong Gao, James M Cleary, Brian M Wolpin, Jill P Mesirov, Daniel A Haber, Jeffrey A Engelman, Jesse S Boehm, Joanne D Kotz, Cindy S Hon, Yu Chen, William C Hahn, Mitchell P Levesque, John G Doench, Michael E Berens, Alykhan F Shamji, Paul A Clemons, Brent R Stockwell, Stuart L Schreiber. Nature. 547(7664): 453 – 457, 2017.

Integrated Genomic Analysis of Survival Outliers in Glioblastoma. Sen Peng*, Harshil Dhurv*, Brock Armstrong, Bodour Salhia, Christophe Legendre, Jeffrey Kiefer, Julianna Parks, Selene Virk, Andrew E. Sloan, Quinn T. Ostrom, Jill S. Barnholtz-Sloan, Nhan L. Tran, and Michael E. Berens. Neuro-Oncology, 19(6):833 – 844, 2017. (*These authors contributed equally to the work).

Identification of Aurintricarboxylic Acid as a selective inhibitor of the TWEAK-Fn14 signaling pathway in Glioblastoma Cells. Alison Roos*, Harshil D. Dhruv*, Ian T. Mathews, Lauren Hartman, Donald Chow, Nghia Millard, Holly H. Yin, Jean Kloss, Joseph C. Loftus, Jeffrey A. Winkles, Michael E. Berens, and Nhan L. Tran. Oncotarget, 8(7):12234, 2017. (*These authors contributed equally to the work).

Differential Pathway Dependency Discovery Associated with Drug Response across Cancer Cell Lines. Gil Speyer, Divya mahendra, Jeff Kieffer, Stuart Schreiber, Paul Clemons, Harshil Dhruv, Michael Berens, and Seungchan Kim, Pacific Symposium on Biocomputing, 22:497, 2016.

SGEF expression is regulated via TWEAK-Fn14 signaling through NF-kB and promotes cells survival in glioblastoma by modulation of the DNA repair response to temozolomide. Shannon P. Fortin Ensign, Ian T. Mathews, Harshil D. Dhruv, Jann N. Sarkaria, March H. Symons, Joseph C. Loftus, Michael E. Berens, and Nhan L. Tran. Molecular Cancer Research, 14(3): 302 – 312, 2016.

Knowledge-Assisted Approach to Identify Pathways with Differential Dependencies. Gil Speyer, Jeff Kieffer, Harshil Dhruv, Michael Berens, and Seungchan Kim. Pacific Symposium on Biocomputing, 21: 33 – 44, 2016.

Propentofylline inhibits glioblastoma cell invasion and survival by targeting the TROY signaling pathway. Harshil D. Dhruv, Alison Roos, Patrick J. Tomboc, Serdar Tuncali, Ashley Chavez, Ian Mathews, Michael E. Berens, Joseph C. Loftus, and Nhan L. Tran. Journal of Neuro-Oncology, 126(3): 397 – 404, 2016.

Intravenous delivery of camptothecin-loaded PLGA nanoparticles for the treatment of intracranial glioma. Kyle T. Householder, Danielle M. DiPerna, Eugene P. Chung, Gregory M. Wohlleb, Harshil D. Dhruv, Michael E. Berens, and Rachael W Sirianni.   International Journal of Pharmaceutics, 479(2): 374-380, 2015.

Identification of Causal Genetic Drivers of Human Disease through Systems-Level Analysis of Regulatory Networks. James C. Chen, Mariano J. Alvarez, Flaminia Talos, Harshil Dhruv, Gabrielle E. Rieckhof, Archana Iyer, Kristin L. Diefes, Kenneth Aldape, Michael Berens, Michael M. Shen, and Andrea Califano. Cell, 159: 402-414, 2014.

FN14 expression correlates with MET in NSCLC and promotes MET-driven cell invasion. Timothy G. Whitsett, Shannon P. Fortin Ensign, Harshil D. Dhruv, Landon J. Inge, Paul Kurywchak, Kerri K. Wolf, Janine LoBello, Christopher B. Kingsley, Jeffrey W. Allen, Glen J. Weiss, and Nhan L. Tran. Clinical & Experimental Metastasis, 31(6): 613-623 2014.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) promotes glioblastoma cell chemotaxis via Lyn activationHarshil D. Dhruv, Timothy G. Whitsett, Nathan M. Jameson, Falak Patel, Jeffery Winkles, Michael Berens, and Nhan Tran. Carcinogenesis, 35(1): 218 – 226, 2013

Structural Basis and Targeting of the Interaction between Fibroblast Growth Factor-Inducible 14 and Tumor Necrosis Factor-like Weak Inducer of Apoptosis. Harshil D. Dhruv*, Joseph C Loftus*, Pooja Narang*, Joachim L Petit, Maureen Fameree, Julien Burton, Giresse Tchegho, Donald Chow, Holly Yin, Yousef Al-Abed, Michael E. Berens, Nhan L. Tran, Nathalie Meurice. Journal of Biological Chemistry, 288(45): 32261 – 32276, 2013 (*These authors contributed equally to the work).

A Novel Interaction Between Pyk2 and MAP4K4 is Integrated with Glioma Cell Migration. Joseph C. Loftus, Zhongbo Yang, Jean Kloss, Harshil Dhruv, Nhan L. Tran, and Daniel L. Riggs. Journal of Signal Transduction, vol. 2013, Article ID 956580, 12 pages, 2013. 

Reciprocal Activation of Transcription Factors Underlies the Dichotomy between Proliferation and Invasion of Glioma Cells. Harshil D. Dhruv, Wendy S. McDonough Winslow, Brock Armstrong, Serdar Tuncali, Jenny Eschbacher, Kerri Kislin, Joseph C. Loftus, Nhan L. Tran, Michael E. Berens. PLoS One, 8(8): e72134, 2013.

TROY (TNFRSF19) Promotes Glioblastoma Cell Survival Signaling and Therapeutic Resistance. Joseph C. Loftus, Harshil D. Dhruv, Serdar Tuncali, Jean M. Kloss, Zhongbo Yang, Cassie A. Schumacher, Brian B. Cao, Bart O. Williams, Jennifer M. Eschbacher, Julianna T. Ross, Nhan L. Tran. Molecular Cancer Research, 11(8): 865-74, 2013.

Molecular Determinants of Lung cancer Metastasis to the Central Nervous System. Timothy G. Whitsett, Landon J. Inge, Harshil D. Dhruv, Philip Y. Cheung, Glen J. Weiss, Ross M. Bremner, Jeffrey A. Winkles, Nhan L. Tran. Translational Lung Cancer Research, 2(4): 273-283, 2013.

MicroRNA-328 is associated with Non-small Cell Lung Cancer (NSCLC) Brain Metastasis and mediates NSCLC migration. Shilpi Arora, Aarati R. Ranade, Nhan L. Tran, Sara Nasser, Shravan Sridhar, Ronald L. Korn, Julianna T.D Ross, Harshil D. Dhruv, Kristen Nelson, Zita Sibenaller, Timothy Ryken, Michael B. Gotway, Seungchan Kim, Glen J. Weiss. International Journal of Cancer, 129(11): 2621-31, 2011.

Bioresponsive Copolymers of Poly(N-isopropylacrylamide) with Enzyme-Dependent Lower Critical Solution Temperatures. Derek J. Overstreet, Harshil D. Dhruv, and Brent L. Vernon. Biomacromolecules, 11(5): 1154 – 1159, 2010.

Protein Insertion and Patterning of PEG Bearing Langmuir Monolayers. Harshil D. Dhruv, Revathi Pepalla, Mundeta Taveras, and David W. Britt. Biotechnology Progress, 22(1): 150 -155, 2006.

Role of Lactose in Modifying Gel Transition Temperature and Morphology of Self-assembled Hydrogels. Harshil D. Dhruv, Matthew A. Draper, and David W. Britt. Chemistry of Materials, 17(25): 6239 -6245, 2005.
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