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 6 Specific Aims that cover the entire range of preclinical studies, all the way from design of new drugs, elucidation of their biological activity and molecular mechanism of action, study of their pharmacokinetics, 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, with our priorities determined by results obtained in the in vitro and in vivo test systems described in the subsequent Specific Aims. These studies will be done in collaboration with the Department of Chemistry at Dartmouth College. (2) To continue to test the new triterpenoids from Specific Aim 1 for their biological activity on a series of cell culture assays that are relevant to chemoprevention of cancer. Such assays will measure anti-proliferative and apoptotic activity, induction of differentiation in tumor cells, and anti-inflammatory activity. (3) To evaluate the molecular mechanism of action, in cell biology and molecular biology assays, of the new triterpenoids from Specific Aim 1. In conjunction with these studies, we will attempt to identify the proximate molecular target(s) that mediates the anti-proliferative, apoptotic, anti-inflammatory, and differentiating actions of the synthetic triterpenoids made at Dartmouth. (4) To evaluate the ability of new triterpenoids to induce apoptosis in cells that are relevant to human carcinogenesis, with special emphasis on induction of apoptosis in immortalized human breast epithelium, both non-neoplastic and neoplastic. (5) To evaluate the pharmacokinetics of promising new triterpenoids, in preclinical studies, to optimize choice of agents that might eventually be used for preventing cancer in men and women. As an adjunct to the pharmacokinetics, we will also undertake some preliminary assays of short-term toxicity in rats and mice. (6) To test promising new triterpenoids in appropriate animal models for chemoprevention of cancer, with special emphasis on prevention of breast and colon cancer. Triterpenoids previously synthesized with support from this grant are already under consideration for clinical use in treatment of leukemia. 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078814-10
Application #
7332268
Study Section
Special Emphasis Panel (ZRG1-CDP (01))
Program Officer
Perloff, Marjorie
Project Start
1999-03-08
Project End
2008-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
10
Fiscal Year
2008
Total Cost
$341,132
Indirect Cost
Name
Dartmouth College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Liby, Karen T (2014) Synthetic triterpenoids can protect against toxicity without reducing the efficacy of treatment with Carboplatin and Paclitaxel in experimental lung cancer. Dose Response 12:136-51
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
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
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
Kaidery, Navneet Ammal; Banerjee, Rebecca; Yang, Lichuan et al. (2013) Targeting Nrf2-mediated gene transcription by extremely potent synthetic triterpenoids attenuate dopaminergic neurotoxicity in the MPTP mouse model of Parkinson's disease. Antioxid Redox Signal 18:139-57
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
Liby, Karen T; Sporn, Michael B (2012) Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol Rev 64:972-1003
Sporn, Michael B; Liby, Karen T (2012) NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer 12:564-71
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

Showing the most recent 10 out of 67 publications