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)
Type
Exploratory Grants (P20)
Project #
5P20GM103639-03
Application #
8723256
Study Section
Special Emphasis Panel (ZRR1)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Boswell-Casteel, Rebba C; Johnson, Jennifer M; Duggan, Kelli D et al. (2014) FUN26 (function unknown now 26) protein from saccharomyces cerevisiae is a broad selectivity, high affinity, nucleoside and nucleobase transporter. J Biol Chem 289:24440-51
Aravindan, Natarajan; Aravindan, Sheeja; Pandian, Vijayabaskar et al. (2014) Acquired tumor cell radiation resistance at the treatment site is mediated through radiation-orchestrated intercellular communication. Int J Radiat Oncol Biol Phys 88:677-85
Bio, Moses; Rajaputra, Pallavi; Nkepang, Gregory et al. (2014) Far-red light activatable, multifunctional prodrug for fluorescence optical imaging and combinational treatment. J Med Chem 57:3401-9
Janakiram, Naveena B; Mohammed, Altaf; Brewer, Misty et al. (2014) Raloxifene and antiestrogenic gonadorelin inhibits intestinal tumorigenesis by modulating immune cells and decreasing stem-like cells. Cancer Prev Res (Phila) 7:300-9
Babu, Anish; Wang, Qi; Muralidharan, Ranganayaki et al. (2014) Chitosan coated polylactic acid nanoparticle-mediated combinatorial delivery of cisplatin and siRNA/Plasmid DNA chemosensitizes cisplatin-resistant human ovarian cancer cells. Mol Pharm 11:2720-33
Xiong, Xunhao; Arvizo, Rochelle R; Saha, Sounik et al. (2014) Sensitization of ovarian cancer cells to cisplatin by gold nanoparticles. Oncotarget 5:6453-65
Aravindan, S; Natarajan, M; Ramraj, S K et al. (2014) Abscopal effect of low-LET ýý-radiation mediated through Rel protein signal transduction in a mouse model of nontargeted radiation response. Cancer Gene Ther 21:54-9
VandenHeuvel, Katherine A; Carpentieri, David F; Chen, Jie et al. (2014) Ectomesenchymoma with embryonal rhabdomyosarcoma and ganglioneuroma, arising in association with benign triton tumor of the tongue. Pediatr Dev Pathol 17:226-30
Aravindan, Sheeja; Natarajan, Mohan; Herman, Terence S et al. (2013) Radiation-induced TNF* cross signaling-dependent nuclear import of NF*B favors metastasis in neuroblastoma. Clin Exp Metastasis 30:807-17
Chang, Theodore S; Lin, Hsueh-Kung; Rogers, Kyle A et al. (2013) Expression of aldo-keto reductase family 1 member C3 (AKR1C3) in neuroendocrine tumors & adenocarcinomas of pancreas, gastrointestinal tract, and lung. Int J Clin Exp Pathol 6:2419-29

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