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Chandra Kumar Maharjan

Photo of Chranda MaharjanAddress: 2-551 BSB
Phone: (319) 335-7663
Email: chandrakumar-maharjan@uiowa.edu

Mentor: Dawn E. Quelle, PhD

Undergraduate Institution: Wright State University

Graduate Program: Pharmacology

Year Entered Into Program: 2016


Research Description

Role of RABL6A in Pancreatic Neuroendocrine Tumor Development and Progression

Pancreatic neuroendocrine tumors (pNETs) are rare, slow-growing neoplasms that silently grow to aggressive, advanced stages. Although localized pNETs can be completely cured by surgical resection, most pNETs at diagnosis are advanced, unresectable, and lack effective therapies to improve patient survival and quality of life. Greater understanding of mechanisms driving pNET development and progression is urgently required to identify meaningful prognostic biomarkers and more effective therapeutic targets. Our lab studies the oncogenic role of a novel Rab-like GTPase protein, called RABL6A, in pNETs and other tumors. We previously showed that RABL6A promotes pNET cell survival and proliferation in vitro by regulating key pNET associated pathways including inhibition of the Rb1 tumor suppressor and activation of the Akt/mTOR oncogenic signaling. However, from functional studies, it became clear that there are additional, unknown targets of RABL6A that contribute to its oncogenic activity in pNETs. Identification of those currently ‘undefined’ pathways will advance our understanding of the disease and facilitate the development of more efficient therapies. We also seek to obtain direct evidence from in vivo pNET models that RABL6A promotes tumor pathogenesis because that will strengthen the biological relevance of studying RABL6A signaling in this disease.

My first project aims to identify novel RABL6A-regulated drivers or suppressors of pNET pathogenesis by employing a powerful, forward genetic screen called Sleeping Beauty (SB) transposition. The SB system is based on insertional mutagenesis involving random insertion of an exogenous mutagenic piece of DNA (called transposon) into the genomic DNA of the tumor cells via a recombinase enzyme (called transposase). Based on the transposon insertion site, SB-induced genetic mutations can activate an oncogene or silence a tumor suppressor. Our SB screen selects for altered genes that enable pNET cells to grow in the absence of RABL6A. Normally, cells lacking RABL6A die or stop growing. The mutagenized genes are identified by Illumina sequencing and subsequently validated for their RABL6A-effector role in pNETs in molecular and cell biological assays. This project is being done in close collaboration with a SB expert on campus, Dr. Adam Dupuy (Anatomy and Cell Biology), and his team.

My second project explores the in vivo role of RABL6A in pNET development and angiogenesis using a genetically engineered pNET mouse model called RIP-Tag2 (RT2). In RT2 mice, the islet β-cell specific expression of the SV-40 large T-antigen drives rapid and synchronous development of hyperplastic and angiogenic islets that can transform into full blown pNETs (mainly insulinomas). Normally, these animals die by 12-16 weeks of age from their tumors. We crossed the RT2 mice with our RABL6A knockout (KO) mice to determine if loss of RABL6A disrupts pNET development, progression and angiogenesis. Our findings are exciting and provide compelling evidence that RABL6A drives pNET pathogenesis in vivo. Specifically, we have found that RABL6A inactivation reduces the rate of formation and size of pNETs in RT2 mice, which correlates with decreased blood vessel development and improved survival. This project has been greatly facilitated by UI colleagues Dr. Sam Stephens (Internal Medicine), Dr. Ben Darbro (Pediatrics) and Dr. Dave Meyerholz (Pathology).

Awards

  • Selected ‘Early Investigator’ Platform Talk, North American Neuroendocrine Tumor Society (NANETS) Annual Symposium, 2019 and 2020
  • Ranbir K. Bhatnagar Travel Award, 2019
  • Graduate College Post-Comprehensive Research Award, 2018

Publications

  1. Scott A, Weitz TM, Breheny PJ, Ear PH, Darbro B, Brown BJ, Braun TA, Li G, Umesalma S, Kaemmer CA, Maharjan CK, Quelle DE, Bellizzi AM, Chandrasekharan C, Dillon JS, O'Dorisio TM, and Howe JR.: Gene Expression Signatures Identify Novel Therapeutics for Metastatic Pancreatic Neuroendocrine Tumors. Clinical Cancer Research 26(8):2011-2021, 2020. PMID: 31937620
  2. Kohlmeyer JL, Kaemmer CA, Pulliam C, Maharjan CK, Samayoa AM, Major HJ, Cornick KE, Knepper-Adrian V, Khanna R, Sieren JC, Leidinger MR, Meyerholz DK, Zamba KD, Weimer JM, Dodd RD, Darbro BW, Tanas MR, and Quelle DE.: RABL6A Is an Essential Driver of MPNSTs that Negatively Regulates the RB1 Pathway and Sensitizes Tumor Cells to CDK4/6 Inhibitors. Clinical Cancer Research 26(12):2997-3011, 2020. PMID: 32086342

Books / Chapters

  1. Maharjan CK, Gobinda K, Prakash G, Kabin M, Sundar A, Doddayya H.:  Comparative evaluation of ketorolac tromethamine loaded proniosomal and ethosomal gel. Inventi Journals, Pharm Tech, Issue 2 [ISSN 0976-3783].