The objective of the proposed research is to discover and develop new classes of anti-breast cancer agents from higher plants, which have been and still remain a significant source of new drugs. We will identify structurally unique hits from rare sources of plants, particularly rainforest extracts with confirmed cytotoxic activity as screened b the National Cancer Institute, as well as medicinal plants used for cancer-related therapy. Lead compounds, optimized using medicinal chemistry approaches, will be subjected to critical preclinical in vivo assessment, not only with conventional xenograft mouse models, but also with an innovative and unique genetically engineered spontaneous breast cancer mouse model having conditional mutations on tumor suppressor genes Brca1 and p53. Furthermore, we will explore possible mechanism(s) of action based on chemical profiling and effects on responsible pathways, including sex steroid receptors, cell cycle arrest, kinase inhibition, or signal transduction pathways. The overall goals of our program are to identify and develop clinical trial candidates, especially for treating breast cancers. The following specific studies will be carried out to accomplish our goals.
Specific Aim -1: In vitro screening and bioactivity-directed fractionation and isolation to identify breast cancer-selective compounds starting from plant extracts with confirmed activity and counter-screened in-house on the basis of susceptibility to breast cancer cell lines.
Specific Aim -2: New lead optimization using synthetic modifications to improve pharmacological profile. Structural characterization of new active leads (Aim 1) and modified compounds (Aim 2) will be accomplished by chemical, physical, and spectroscopic techniques.
Specific Aim -3: Two-step in vivo evaluations to confirm activity in mouse models, both conventional xenograft mouse models and innovative breast cancer Brca1/p53-Crec mouse model.
Specific Aim -4: Mechanism of action studies to identify druggable targets and compounds for breast cancer treatment. Advantages of our program include 1) an excellent supply of highly active lead compounds and promising cytotoxic plant species, including rainforest species from the NCI Natural Product Repository Program, (2) excellent productivity in isolation and structural modification of new leads with new mechanisms of action as clinical trials candidates, which in turn could lead to innovative methods for cancer chemotherapy, and (3) superior prospects for the successful development of a clinically useful drug, based on promising in vivo results with neo-tanshinlactone analogs against breast cancers. An emphasis of our study will be on finding optimal analogs from these different compound classes to advance to anticancer clinical trials during the next grant period.

Public Health Relevance

New drugs are continually needed to treat various types of cancer, particularly breast cancer, as a woman in the US has about a 12% chance of getting breast cancer in her lifetime, and a woman who has heterozygously inherited the mutant breast cancer susceptibility gene (BRCA1 or BRCA2) can have up to a 60-90% risk of being diagnosed with breast cancer. With the use of an innovative double conditional knockout mouse (Brca1f11/f11p53f5&6/f5&6WAPCrec) that mimics human breast cancer, we will be able to successfully discover new anticancer drug candidates from novel active constituents of medicinal plants, especially from unique rainforest species, which are disappearing rapidly. These lead compounds can be optimized through synthetic modification, as seen with our new neo-tanshinlactone analogs that have already shown promising results in this mouse model and will also be a focus of this research program.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA177584-01
Application #
8550474
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2013-07-01
Project End
2018-04-30
Budget Start
2013-07-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$376,379
Indirect Cost
$127,649
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Tan, Cheng-jian; Zhao, Yu; Goto, Masuo et al. (2016) Alkaloids from Oxytropis ochrocephala and antiproliferative activity of sophoridine derivatives against cancer cell lines. Bioorg Med Chem Lett 26:1495-7
Xiao, Zhiyan; Morris-Natschke, Susan L; Lee, Kuo-Hsiung (2016) Strategies for the Optimization of Natural Leads to Anticancer Drugs or Drug Candidates. Med Res Rev 36:32-91
Song, Zi-Long; Wang, Mei-Juan; Li, Lanlan et al. (2016) Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives. Eur J Med Chem 115:109-20
Wang, Sheng-Biao; Cui, Mu-Tian; Wang, Xiao-Feng et al. (2016) Synthesis, biological evaluation, and physicochemical property assessment of 4-substituted 2-phenylaminoquinazolines as Mer tyrosine kinase inhibitors. Bioorg Med Chem 24:3083-92
Nakagawa-Goto, Kyoko; Chen, Jo-Yu; Cheng, Yu-Ting et al. (2016) Novel sesquiterpene lactone analogues as potent anti-breast cancer agents. Mol Oncol 10:921-37
Miyake, Katsunori; Suzuki, Airi; Morita, Chihiro et al. (2016) Acetophenone Monomers from Acronychia trifoliolata. J Nat Prod 79:2883-2889
Nakagawa-Goto, Kyoko; Taniguchi, Yukako; Watanabe, Yurie et al. (2016) Triethylated chromones with substituted naphthalenes as tubulin inhibitors. Bioorg Med Chem 24:6048-6057
Xin, Guang; Wei, Zeliang; Ji, Chengjie et al. (2016) Metformin Uniquely Prevents Thrombosis by Inhibiting Platelet Activation and mtDNA Release. Sci Rep 6:36222
Lin, Yi-Chien; Chen, Yi-Fong; Tseng, Li-Shin et al. (2016) Synthesis and structure-activity relationship studies of novel 3,9-substituted α-carboline derivatives with high cytotoxic activity against colorectal cancer cells. Eur J Med Chem 110:98-114
Feng, Jia-Hua; Nakagawa-Goto, Kyoko; Lee, Kuo-Hsiung et al. (2016) A Novel Plant Sesquiterpene Lactone Derivative, DETD-35, Suppresses BRAFV600E Mutant Melanoma Growth and Overcomes Acquired Vemurafenib Resistance in Mice. Mol Cancer Ther 15:1163-76

Showing the most recent 10 out of 46 publications