Five-year survival rate of pancreatic cancer patients has remained at 3-6% for over past three decades. Such a poor prognosis is largely due to the resistance of pancreatic cancer to currently available therapeutic modalities. Hence, there is clearly a pressing need to develop a novel, mechanism-based refined therapeutic approach against pancreatic cancer. Emerging data suggest a major role of tumor-stromal interaction in pancreatic cancer pathobiology and chemoresistance. In this regard, we have recently shown that the chemokine CXCL12, mostly derived from the stromal cells, confers drug-resistance to pancreatic cancer cells through potentiation of CXCR4-mediated survival mechanisms. In additional novel findings, we demonstrate a role of CXCL12/CXCR4 signaling axis in upregulation of hedgehog ligand (sonic hedgehog, SHH) in pancreatic cancer cells. Furthermore, we show that conditioned media (CM) from stimulated pancreatic cancer cells enhances CXCL12 production by pancreatic stellate cells (PSCs), in part, through hedgehog-dependent mechanism. More importantly, we demonstrate that PSCs-induced chemoresistance of pancreatic cancer cells in a co-culture assay involves supportive roles of CXCL12/CXCR4 and hedgehog signaling mechanisms. Based on these novel findings, we hypothesize that CXCL12/CXCR4 and hedgehog pathways engage in a vicious loop to cooperatively promote pancreatic cancer growth and chemoresistance, and combined targeting of these signaling nodes will produce superior therapeutic outcome. To test these hypotheses, we have proposed three specific aims.
In aim 1, we will characterize the mechanisms underlying CXCL12/CXCR4 and hedgehog cross-talk in pancreatic cancer. We will also investigate if these pathways promote growth and chemoresistance of pancreatic cancer cells by essentially acting in paracrine mechanisms or they also involve intracellular signaling overlap and/or cooperation.
In aim 2, we will determine the clinical relevance of CXCL12/CXCR4 and hedgehog interaction in pancreatic cancer. We will assess the incidence, intensity and correlative expression of CXCL12, CXCR4 and SHH in pancreatic cancer, and examine their joint clinical association with tumor -grade, -stage, and patient's survival.
In aim 3, we will evaluate the efficacy of a combination therapy targeting CXCL12/CXCR4 and hedgehog pathways in two complementary models (orthotopic xenograft and genetically-engineered mouse) of pancreatic cancer. Treatment response will be evaluated by non-invasive imaging, tumor measurements and analyses of molecular markers. Completion of these proposed studies will provide us important data on collective (mechanistic, clinical and therapeutic) relevance of CXCL12/CXCR4 and hedgehog pathways in pancreatic cancer. In the long term, the resulting information may lead to a novel and effective treatment for lethal pancreatic cancer.

Public Health Relevance

Pancreatic cancer remains a therapeutic challenge for clinicians and translational researchers with a rising incidence and unabated mortality. We have identified signaling pathways that operate through tumor-stromal interaction and mutually promote chemoresistance of pancreatic cancer. The proposed research will systematically investigate the significance of these signaling nodes as novel combination therapy targets and thus, in due course, open up new avenues for effective therapeutic care of pancreatic cancer patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of South Alabama
Organized Research Units
United States
Zip Code
Azim, Shafquat; Zubair, Haseeb; Srivastava, Sanjeev K et al. (2016) Deep sequencing and in silico analyses identify MYB-regulated gene networks and signaling pathways in pancreatic cancer. Sci Rep 6:28446
Zubair, Haseeb; Azim, Shafquat; Khan, Husain Yar et al. (2016) Mobilization of Intracellular Copper by Gossypol and Apogossypolone Leads to Reactive Oxygen Species-Mediated Cell Death: Putative Anticancer Mechanism. Int J Mol Sci 17:
Zubair, Haseeb; Azim, Shafquat; Srivastava, Sanjeev Kumar et al. (2016) Glucose Metabolism Reprogrammed by Overexpression of IKKε Promotes Pancreatic Tumor Growth. Cancer Res 76:7254-7264
Bhardwaj, Arun; Srivastava, Sanjeev K; Singh, Seema et al. (2016) MYB Promotes Desmoplasia in Pancreatic Cancer through Direct Transcriptional Up-regulation and Cooperative Action of Sonic Hedgehog and Adrenomedullin. J Biol Chem 291:16263-70
Tyagi, Nikhil; Arora, Sumit; Deshmukh, Sachin K et al. (2016) Exploiting Nanotechnology for the Development of MicroRNA-Based Cancer Therapeutics. J Biomed Nanotechnol 12:28-42
Patel, Girijesh Kumar; Patton, Mary C; Singh, Seema et al. (2016) Pancreatic Cancer Exosomes: Shedding Off for a Meaningful Journey. Pancreat Disord Ther 6:e148
Tyagi, Nikhil; Marimuthu, Saravanakumar; Bhardwaj, Arun et al. (2016) p-21 activated kinase 4 (PAK4) maintains stem cell-like phenotypes in pancreatic cancer cells through activation of STAT3 signaling. Cancer Lett 370:260-7
Khan, Mohammad Aslam; Zubair, Haseeb; Srivastava, Sanjeev Kumar et al. (2015) Insights into the Role of microRNAs in Pancreatic Cancer Pathogenesis: Potential for Diagnosis, Prognosis, and Therapy. Adv Exp Med Biol 889:71-87
Srivastava, Sanjeev K; Bhardwaj, Arun; Arora, Sumit et al. (2015) MYB is a novel regulator of pancreatic tumour growth and metastasis. Br J Cancer 113:1694-703
Srivastava, Sanjeev K; Bhardwaj, Arun; Arora, Sumit et al. (2015) MicroRNA-345 induces apoptosis in pancreatic cancer cells through potentiation of caspase-dependent and -independent pathways. Br J Cancer 113:660-8

Showing the most recent 10 out of 21 publications