Despite being a staple therapy for pancreatic cancer (PC), Radiation Therapy (RT) provides limited objective clinical response due to inherently high radioresistance (RR) of PC. As the risk of radiation-induced toxicity for PC patients far outweighs the therapeutic benefits attained, effective methods to improve the radiosensitivity of PC are urgently needed. The overall objective of this project is to identify and characterize pathway(s) contributing to RR in PC that can be explored as novel targets for radiosensitization (RS). Preliminary global gene expression analysis suggested novel involvement of cholesterol biosynthesis pathway in the RR in PC cells. Inhibition of cholesterol biosynthesis (CBS) by Zoledronic acid (Zometa) resulted in RS of panel of RR murine and human PC cells. Further, this RS was recapitulated by the inhibition of the small GTPase Rac1, whose activity is controlled by the CBS pathway. Therefore, we seek to delineate mechanisms of RR mediated by cholesterol biosynthesis pathway, and evaluate the potential of Zometa as a radiosensitizer (RST) in preclinical and clinical studies. We propose to exploit the strength of stereotactic radiation therapy and genetically engineered mouse models to comprehensively test the hypothesis that ?cholesterol biosynthesis pathway contributes to radioresistance in PC and Zometa inhibits specific pathways consistently implicated in RR and its use will radiosensitize PC both in vitro and in vivo?. To achieve our goal, three specific aims are proposed.
Aim 1 will elucidate the mechanisms of radioresistance in PC and validation of FDPS/Rac1 inhibitors (Zometa and NSC23766) as RSTs. The functional role of critical genes identified will be determined by knockdown and overexpression studies, use of specific inhibitors, and immunohistochemistry on clinical samples.
Aim 2 will determine the efficacy of Zometa as RST in mouse models (xenograft and autochthonous). A novel strategy of stereotactic irradiation for murine models will be developed.
In Aim 3, a Phase-I/II study will be undertaken to assess the radiosensitizing potential of Zometa in human subjects and determine if Zometa is well tolerated in PC patients undergoing RT.
Radiation therapy is the cornerstone of the management of pancreatic cancer (PC) patients;yet its efficienty is limited due to inharent radioresistance of the disease. Undertanding of the underlying mechanisms and translating the emerging knowledge to augment radiosensitivity can significantly improve the outcome of PC patients. Zometa, a clinically aproved agent can work as a novel radiosensitizer for PC and improve the efficacy of radiation therapy.
|Attri, Kuldeep S; Murthy, Divya; Singh, Pankaj K (2017) Racial disparity in metabolic regulation of cancer. Front Biosci (Landmark Ed) 22:1221-1246|
|Wu, Guangyin; Verma, Vivek; Haefner, Matthias F et al. (2017) Feasibility and reproducibility of substituting oral contrast with water for duodenal volume delineation in patients undergoing pancreatic stereotactic body radiotherapy. J Gastrointest Oncol 8:705-709|
|Verma, Vivek; Lazenby, Audrey J; Zheng, Dandan et al. (2017) Dosimetric parameters correlate with duodenal histopathologic damage after stereotactic body radiotherapy for pancreatic cancer: Secondary analysis of a prospective clinical trial. Radiother Oncol 122:464-469|
|Karmakar, Saswati; Seshacharyulu, Parthasarathy; Lakshmanan, Imayavaramban et al. (2017) hPaf1/PD2 interacts with OCT3/4 to promote self-renewal of ovarian cancer stem cells. Oncotarget 8:14806-14820|
|Shukla, Surendra K; Purohit, Vinee; Mehla, Kamiya et al. (2017) MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer. Cancer Cell 32:71-87.e7|
|King, Ryan J; Yu, Fang; Singh, Pankaj K (2017) Genomic alterations in mucins across cancers. Oncotarget :|
|Krishn, Shiv Ram; Kaur, Sukhwinder; Sheinin, Yuri M et al. (2017) Mucins and associated O-glycans based immunoprofile for stratification of colorectal polyps: clinical implication for improved colon surveillance. Oncotarget 8:7025-7038|
|Gautam, Shailendra K; Kumar, Sushil; Cannon, Andrew et al. (2017) MUC4 mucin- a therapeutic target for pancreatic ductal adenocarcinoma. Expert Opin Ther Targets 21:657-669|
|Abrego, Jaime; Gunda, Venugopal; Vernucci, Enza et al. (2017) GOT1-mediated anaplerotic glutamine metabolism regulates chronic acidosis stress in pancreatic cancer cells. Cancer Lett 400:37-46|
|Souchek, Joshua J; Davis, Amanda L; Hill, Tanner K et al. (2017) Combination Treatment with Orlistat-Containing Nanoparticles and Taxanes Is Synergistic and Enhances Microtubule Stability in Taxane-Resistant Prostate Cancer Cells. Mol Cancer Ther 16:1819-1830|
Showing the most recent 10 out of 163 publications