The Diversity Research Supplement Program to Promote Diversity in Health-Related Research from the National Institutes of Health (NIH) Center to Reduce Cancer Health Disparities (CRCHD) provides a great career development opportunity to Dr. Antonio Bartholomew Ward, an African-American cancer researcher holding a full-time faculty position as a Postdoctoral Research Fellow at the University of South Alabama Mitchell Cancer Institute (USA-MCI) to continue his academic career and develop his pathway as an independent investigator. He is applying for this supplement based on the parent grant entitled ?Phosphodiesterase 10A, a Novel Target for Lung Cancer Chemoprevention (1R01CA197147)?, awarded to Dr. Gary Piazza, Professor of Oncologic Sciences and Chief of the Drug Discovery Research Center at MCI. The parent grant proposes studies to chemically modify sulindac to block cyclooxygenase (COX) binding to eliminate related gastrointestinal, renal and cardiovascular side-effects, while increasing potency and selectivity to inhibit lung tumor cell growth by inhibiting cyclic guanosine monophosphate phosphodiesterases (cGMP PDEs) enzymes. Specifically, the PDE 10 isozyme was found to be elevated in lung tumor cells and essential for lung tumor cell growth and survival. His team has also explored the molecular mechanism driving the apoptosis of lung tumor cells induced by sulindac derivatives that involves the activation of cGMP-dependent protein kinase G signaling and suppression of oncogenic ?-catenin/Tcf- mediated transcriptional activity to inhibit cell cycle regulatory proteins, such as cyclin D1, c-myc, and survivin. For this supplement application Dr. Ward proposes a recently discovered mechanism responsible for the anti-cancer activity of sulindac derivatives, specifically with compound MCI-062, based on his preliminary data showing compound selectivity for inhibiting the growth of colon and lung cancer cells harboring the oncogenic mutant form of the rat sarcoma viral oncogene (RAS), specifically KRAS, and on recent literature linking mutant KRAS to an increased expression of the immune checkpoint inhibitor protein programmed death ligand-1 (PD-L1) on the surface of cancer cells thereby promoting increased cancer cell immunity. He hypothesizes that by inhibiting RAS-RAS effector binding and RAS cell signaling, PD-L1 protein levels will also be decreased, thereby increasing anti-cancer immunity. Dr. Ward will investigate if MCI-062 effects are mediated by RAS inhibition and a decrease in PD-L1 protein levels, leading to an increase in T-lymphocyte (T- cell) tumor infiltration, proliferation, and activation, and determine the mechanism of action responsible for anti- cancer immunity effects using 2D and 3D RAS-driven non-small cell lung cancer (NSCLC) models. In conclusion, this research will validate a novel RAS inhibitor, MCI-062, for targeted therapeutic use in NSCLC by its effect on RAS regulated cancer cell immunity and increase the need for small molecule targeted immunotherapeutic approaches for difficult to treat RAS-driven cancers.
This research proposal for a supplement application to the parent grant, 1R01CA197147 (P.I. Gary Piazza, Ph.D.) will study a novel molecular mechanism for non-cyclooxygenase inhibitory derivatives of sulindac to exert their anti-tumor and anti-cancer cell immunity activity by inhibiting RAS and decreasing PD-L1 protein levels thereby increasing T-cell proliferation, activation, and infiltration to tumor sites in lung tumor cells harboring oncogenic mutations in the KRAS gene. NSCLCs that harbor RAS mutations are associated with poor prognosis and survival in humans, therefore applying small molecule targeted therapy against cancer oncogenes such as RAS in order to weaken cancer cell immunity and enhance the body?s own natural immune response to combat cancer is indeed a novel approach worth investigating. This supplement will expand Dr. Ward?s career development in cancer research and will establish his path to become an independent investigator towards a tenure-track faculty position.
| Keeton, Adam B; Salter, E Alan; Piazza, Gary A (2017) The RAS-Effector Interaction as a Drug Target. Cancer Res 77:221-226 |
| Zhu, Bing; Lindsey, Ashley; Li, Nan et al. (2017) Phosphodiesterase 10A is overexpressed in lung tumor cells and inhibitors selectively suppress growth by blocking ?-catenin and MAPK signaling. Oncotarget 8:69264-69280 |
| Piazza, Gary A (2017) Validation of PDE5 as a Chemoprevention Target. Cancer Prev Res (Phila) 10:373-376 |
| Lee, Kevin; Lindsey, Ashley S; Li, Nan et al. (2016) ?-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG. Oncotarget 7:5353-65 |
| Li, Nan; Chen, Xi; Zhu, Bing et al. (2015) Suppression of ?-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10. Oncotarget 6:27403-15 |
