This entire project is based on the hypothesis that we can design and develop new synthetic triterpenoids that would eventually be clinically useful for chemoprevention and treatment of cancer. The project is articulated in 3 Specific Aims that cover the entire range of preclinical studies, all the way from design of new drugs;to elucidation of their biological activity, their molecular mechanisms of action, and their molecular targets;and finally, testing of efficacy for prevention of cancer in animal models of carcinogenesis that are considered relevant to actual human disease.
Our Specific Aims are as follows: (1) To continue to synthesize new triterpenoids and tricyclic bis-enones (TBEs) for chemoprevention of cancer. (2) To continue to test new triterpenoids from Specific Aim 1 for biological activity in a series of cell culture assays relevant to chemoprevention and chemotherapy of cancer. Such assays measure anti-proliferative activity, induction of differentiation in tumor cells, induction of apoptosis, and anti-inflammatory activity. We will also use biotinylated triterpenoids to identify proximate molecular targets mediating the anti-proliferative, differentiating, apoptotic, and anti-inflammatory actions of triterpenoids. In conjunction with these studies, we will conduct further investigations of downstream targets and pathways, to define molecular mechanisms of action. Furthermore, new studies on effects of TBEs in gene array experiments will be started. (3) To continue to test promising new triterpenoids or TBEs in appropriate animal models for chemoprevention of cancer, with special emphasis on prevention of pancreatic, lung, and hepatocellular cancer. Particular emphasis will also be placed on testing of new triterpenoids in combination with other chemopreventive agents that are known to be effective in the animal models. In addition to the chemoprevention studies, we will do pancreatic and lung cancer experiments in a chemotherapy mode, by waiting until the animals have developed detectable cancers and then determining if our agents are effective as treatments. Triterpenoids previously synthesized with support from this grant are already in active use in Phase I clinical trials for treatment of leukemia, lymphoma, and solid tumors. Historically, many chemopreventive agents have entered clinical use for cancer prevention by first being shown to be active in treatment protocols, and we intend to continue to pursue this cross-talk between therapeutic and preventive approaches to the cancer problem with the results of the proposed new studies.
Relevance Lung cancer, pancreatic cancer, and liver cancer are three devastating and common forms of malignancy for which current therapies are extremely inadequate. A totally different approach to control of these three diseases would be to find some safe and effective way to prevent their occurrence. This grant application deals with the development and testing of new drugs to prevent lung, pancreatic, and liver cancer, with the eventual goal of using such drugs to prevent disease in men and women at high risk.
|Choi, Sung Hee; Kim, Byung-Gyu; Robinson, Janet et al. (2014) Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis. J Clin Invest 124:2472-82|
|To, Ciric; Kim, Eun-Hee; Royce, Darlene B et al. (2014) The PARP inhibitors, veliparib and olaparib, are effective chemopreventive agents for delaying mammary tumor development in BRCA1-deficient mice. Cancer Prev Res (Phila) 7:698-707|
|Tran, Kim; Risingsong, Renee; Royce, Darlene B et al. (2013) The combination of the histone deacetylase inhibitor vorinostat and synthetic triterpenoids reduces tumorigenesis in mouse models of cancer. Carcinogenesis 34:199-210|
|Tran, Kim; Risingsong, Renee; Royce, Darlene et al. (2012) The synthetic triterpenoid CDDO-methyl ester delays estrogen receptor-negative mammary carcinogenesis in polyoma middle T mice. Cancer Prev Res (Phila) 5:726-34|
|Kim, Eun-Hee; Deng, Chuxia; Sporn, Michael B et al. (2012) CDDO-methyl ester delays breast cancer development in BRCA1-mutated mice. Cancer Prev Res (Phila) 5:89-97|
|Sporn, Michael B; Liby, Karen T; Yore, Mark M et al. (2011) New synthetic triterpenoids: potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress. J Nat Prod 74:537-45|
|Kim, Eun-Hee; Deng, Chu-Xia; Sporn, Michael B et al. (2011) CDDO-imidazolide induces DNA damage, G2/M arrest and apoptosis in BRCA1-mutated breast cancer cells. Cancer Prev Res (Phila) 4:425-34|
|Yore, Mark M; Kettenbach, Arminja N; Sporn, Michael B et al. (2011) Proteomic analysis shows synthetic oleanane triterpenoid binds to mTOR. PLoS One 6:e22862|
|Liby, Karen T; Royce, Darlene B; Risingsong, Renee et al. (2010) Synthetic triterpenoids prolong survival in a transgenic mouse model of pancreatic cancer. Cancer Prev Res (Phila) 3:1427-34|
|Cano, Marisol; Thimmalappula, Rajesh; Fujihara, Masashi et al. (2010) Cigarette smoking, oxidative stress, the anti-oxidant response through Nrf2 signaling, and Age-related Macular Degeneration. Vision Res 50:652-64|
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