We hypothesize that there is a convergence of prosurvival, angiogenesis and motility signals at common pathways in the local tumor microenvironment for therapeutic targeting and monitoring. Our findings suggest that molecular therapeutics targeted against the tumor microenvironment may to be more active when administered to inhibit pathways in series rather than in parallel and also when they affect both the tumor and the local interactive cells. The novel statistically based predictive drug modeling project was successful in identification of unanticipated targets affected by clinical agents. Further studies are ongoing by Dr. Hays with initial support via cell lines and drugs from the MSS. Confirmation of success of this pilot project will lead to a more comprehensive examination of agents and shRNA against their primary and potential key targets such that the biochemical cause of activity is identified and will be done by Dr. Hays as part of his translational laboratory objectives at OSU. 2) Our findings of the interactive role of PARP inhibition with angiogenesis inhibition was initiated based upon findings that gH2AX was required for overcoming endothelial cell hypoxic drive. We observed an interaction of a pan-VEGFR inhibitor, cediranib, with a PARP inhibitor and demonstrated a sequence specificity to administration. Further examination of the mechanisms underlying this are on hold due to resource limitations, although the clinical trial is in progress with our group responsible for translational endpoints.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC009374-22
Application #
8763695
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2013
Total Cost
$244,636
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Mineo, Marco; Garfield, Susan H; Taverna, Simona et al. (2012) Exosomes released by K562 chronic myeloid leukemia cells promote angiogenesis in a Src-dependent fashion. Angiogenesis 15:33-45
Yu, Minshu; Henning, Ryan; Walker, Amanda et al. (2012) L-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer. J Cell Mol Med 16:2369-78
Taverna, Simona; Flugy, Anna; Saieva, Laura et al. (2012) Role of exosomes released by chronic myelogenous leukemia cells in angiogenesis. Int J Cancer 130:2033-43
Corrado, Chiara; Raimondo, Stefania; Flugy, Anna Maria et al. (2011) Carboxyamidotriazole inhibits cell growth of imatinib-resistant chronic myeloid leukaemia cells including T315I Bcr-Abl mutant by a redox-mediated mechanism. Cancer Lett 300:205-14
Hoskins, Ebony; Rodriguez-Canales, Jaime; Hewitt, Stephen M et al. (2011) Paracrine SLPI secretion upregulates MMP-9 transcription and secretion in ovarian cancer cells. Gynecol Oncol 122:656-62
Hernandez, Lidia; Hsu, Sarah C; Davidson, Ben et al. (2010) Activation of NF-kappaB signaling by inhibitor of NF-kappaB kinase beta increases aggressiveness of ovarian cancer. Cancer Res 70:4005-14
Annunziata, Christina M; Walker, Amanda J; Minasian, Lori et al. (2010) Vandetanib, designed to inhibit VEGFR2 and EGFR signaling, had no clinical activity as monotherapy for recurrent ovarian cancer and no detectable modulation of VEGFR2. Clin Cancer Res 16:664-72
Lee, J-M; Sarosy, G A; Annunziata, C M et al. (2010) Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity. Br J Cancer 102:495-9
Devoogdt, Nick; Rasool, Nabila; Hoskins, Ebony et al. (2009) Overexpression of protease inhibitor-dead secretory leukocyte protease inhibitor causes more aggressive ovarian cancer in vitro and in vivo. Cancer Sci 100:434-40
Simpkins, Fiona A; Devoogdt, Nick M; Rasool, Nabila et al. (2008) The alarm anti-protease, secretory leukocyte protease inhibitor, is a proliferation and survival factor for ovarian cancer cells. Carcinogenesis 29:466-72

Showing the most recent 10 out of 13 publications