Drug resistance is a major obstacle of most of anticancer therapeutics. Several clinical studies have described reduced response to antiangiogenic therapy targeting VEGF pathway over time followed by regrowth of treated tumors. As tumor angiogenesis is governed by multiple pathways, one difficulty in antiangiogenic therapy is the selective up-regulation of other pro-angiogenic factors, including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF), which bypasses VEGF and renders tumors refractory to anti-VEGF therapy. Although targeting VEGF pathway carries an enormous therapeutic potential, it is very likely that resistance to inhibition of these pathways will emerge as a potential obstacle to be overcome in clinical practice. The main goal of this study is to elucidate potential cellular and molecular mechanisms mediating tumor resistance to anti-VEGF therapy. The main hypothesis is that induction of other proangiogenic signaling, independent of VEGF, is the leading mechanism of development of tumor resistance and is associated with hypoxia in tumor microenvironment. Application of the innovative approaches to study this significant relationship could greatly expand our limited understanding of bypass mechanisms of tumors to anti-VEGF agents and provide rationale to select multi-targeting agents that counteract such mechanisms of resistance mediated by alternative proangiogenic signaling. This goal will be accomplished through the following Specific Aims: 1) Identify the pathways involved in crosstalk between VEGF and VEGF-independent proangiogenic signaling transduction in stroma-tumor co-cultures;2) Evaluate the roles of stromal cells rescuing tumors from the anti-VEGF therapy-induced hypoxia;and 3) Identify in vivo resistance signatures to anti-VEGF treatments using xenograft model. From these experiments, we will identify potential pathways of resistance to be targeted, and to validate in vitro and in vivo pre-clinical models for identifying resistance to targeted agents, thereby proving insight into the design of future therapeutic strategies for tumors refractory to anti-VEGF therapy.

Public Health Relevance

Prostate cancer remains as a major public health issue, with limited treatment options for the advanced disease setting. Angiogenesis inhibition is a newly emerging modality for prosate cancer. Identifying molecular mechanisms by which tumor microenvironment plays a role in mediating angiogenesis-resistance, which this application strives for, will benefit to exploit the full therapeutic potential ofthe angiangiogenic therapy for the prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103639-03
Application #
8723256
Study Section
Special Emphasis Panel (ZRR1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Jaiprasart, Pharavee; Yeung, Bertrand Z; Lu, Ze et al. (2018) Quantitative contributions of processes by which polyanion drugs reduce intracellular bioavailability and transfection efficiency of cationic siRNA lipoplex. J Control Release 270:101-113
Buechel, Megan; Dey, Anindya; Dwivedi, Shailendra Kumar Dhar et al. (2018) Inhibition of BMI1, a Therapeutic Approach in Endometrial Cancer. Mol Cancer Ther 17:2136-2143
Ha, Ji Hee; Radhakrishnan, Rangasudhagar; Jayaraman, Muralidharan et al. (2018) LPA Induces Metabolic Reprogramming in Ovarian Cancer via a Pseudohypoxic Response. Cancer Res 78:1923-1934
Dey, Anindya; Xiong, Xunhao; Crim, Aleia et al. (2018) Evaluating the Mechanism and Therapeutic Potential of PTC-028, a Novel Inhibitor of BMI-1 Function in Ovarian Cancer. Mol Cancer Ther 17:39-49
Boswell-Casteel, Rebba C; Johnson, Jennifer M; Roe-Žurž, Zygy et al. (2018) Expression and purification of human and Saccharomyces cerevisiae equilibrative nucleoside transporters. Protein Expr Purif 142:68-74
Jiao, Yang; Watts, Tanya; Xue, Jing et al. (2018) Sorafenib and docosahexaenoic acid act in synergy to suppress cancer cell viability: a role of heme oxygenase 1. BMC Cancer 18:1042
Sun, X; Ren, Y; Gunawan, S et al. (2018) Selective inhibition of leukemia-associated SHP2E69K mutant by the allosteric SHP2 inhibitor SHP099. Leukemia 32:1246-1249
Amreddy, Narsireddy; Babu, Anish; Panneerselvam, Janani et al. (2018) Chemo-biologic combinatorial drug delivery using folate receptor-targeted dendrimer nanoparticles for lung cancer treatment. Nanomedicine 14:373-384
Liu, Xuan; Shen, Tao; Mooers, Blaine H M et al. (2018) Drug resistance profiles of mutations in the RET kinase domain. Br J Pharmacol 175:3504-3515
Boswell-Casteel, Rebba C; Johnson, Jennifer M; Hays, Franklin A (2018) Functional Characterization of the Saccharomyces cerevisiae Equilibrative Nucleoside Transporter 1 (ScENT1). Molecules 23:

Showing the most recent 10 out of 68 publications