Project 3 comprises a collaborative effort between the University of North Carolina at Greensboro (chemistry via the Nicholas Oberlies Lab), Mycosynthetix, Inc. (mycology), and Columbia University (biological evaluation via the Brent Stockwell Lab). It is hypothesized that anticancer drug leads with novel structures will be obtained from filamentous fungi. Hence, the goal of Project 3 is the discovery of structurally diverse and biologically active compounds on a scale that facilitates drug development. To do so, the three specific aims can be summarized as:
Specific Aim 1 : Select and culture fungi from the Mycosynthetix library, focusing on unusual cultures and those likely to produce promising leads.
Specific Aim 2. Dereplication, Isolation and structure elucidation of bioactive lead compounds.
Specific Aim 3. Test samples for oncogenic-Ras selective lethality and novel cell death mechanisms using engineered tumor cells. Project 3 has been revised per the helpful suggestions of the reviewers of the initial application. The three aims for Project 3 work in an iterative manner toward anticancer leads, with unique skills in mycology (Aim 1) providing samples for natural products chemistry (Aim 2) that are evaluated for biological activity (Aim 3). Importantly, this latter aim will focus on compounds that are synthetic lethal with oncogenic Ras. The Ras oncoproteins (K-Ras, H-Ras, N-Ras) are of paramount importance in cancer biology. They were discovered over 30 years ago, but have been resistant to direct targeting with small molecules. Thus, despite the fact that the KRAS gene is mutated in ~20% of all tumors, and >95% of pancreatic cancers, there is no therapy for treating mutant KRAS tumors. Compounds that show increased potency and lethality in tumor cells with oncogenic Ras are likely to exhibit an increased therapeutic index, and to reveal mechanisms for targeting tumors harboring mutations in the three Ras genes (HRAS, NRAS and KRAS). The resources of the Program will be utilized for pushing the best leads towards preclinical development. Besides the skills of the other Projects and Cores, this will include close interaction with our corporate partner, Eisai Inc (Andover, MA), who has a successful track record of developing anticancer natural products. The primary purpose of this part of the program project is to discover new cancer chemotherapeutic agents from cultures of filamentous fungi. In order to do this, our group will perform chemical and biological studies in a coordinated manner with the other components of this project.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA125066-06A1
Application #
8608729
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (O1))
Project Start
2006-12-01
Project End
2019-04-30
Budget Start
2014-06-06
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
$363,048
Indirect Cost
$68,573
Name
Ohio State University
Department
Type
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
El-Elimat, Tamam; Raja, Huzefa A; Figueroa, Mario et al. (2015) Sorbicillinoid analogs with cytotoxic and selective anti-Aspergillus activities from Scytalidium album. J Antibiot (Tokyo) 68:191-6
Yong, Yeonjoong; Pan, Li; Ren, Yulin et al. (2014) Assay development for the discovery of semaphorin 3B inducing agents from natural product sources. Fitoterapia 98:184-91
Ren, Yulin; Yuan, Chunhua; Qian, Yanrong et al. (2014) Constituents of an extract of Cryptocarya rubra housed in a repository with cytotoxic and glucose transport inhibitory effects. J Nat Prod 77:550-6
Pan, Li; Woodard, John L; Lucas, David M et al. (2014) Rocaglamide, silvestrol and structurally related bioactive compounds from Aglaia species. Nat Prod Rep 31:924-39
Deng, Youcai; Chu, Jianhong; Ren, Yulin et al. (2014) The natural product phyllanthusmin C enhances IFN-? production by human NK cells through upregulation of TLR-mediated NF-?B signaling. J Immunol 193:2994-3002
El-Elimat, Tamam; Raja, Huzefa A; Day, Cynthia S et al. (2014) Greensporones: resorcylic acid lactones from an aquatic Halenospora sp. J Nat Prod 77:2088-98
Pérez, Lynette Bueno; Still, Patrick C; Naman, C Benjamin et al. (2014) Investigation of Vietnamese plants for potential anticancer agents. Phytochem Rev 13:727-739
Ren, Yulin; Lantvit, Daniel D; Deng, Youcai et al. (2014) Potent cytotoxic arylnaphthalene lignan lactones from Phyllanthus poilanei. J Nat Prod 77:1494-504
Luo, Shangwen; Kang, Hahk-Soo; Krunic, Aleksej et al. (2014) Carbamidocyclophanes F and G with Anti-Mycobacterium tuberculosis Activity from the Cultured Freshwater Cyanobacterium Nostoc sp. Tetrahedron Lett 55:686-689
Bueno Pérez, Lynette; Pan, Li; Muñoz Acuña, Ulyana et al. (2014) Caeruleanone A, a rotenoid with a new arrangement of the D-ring from the fruits of Millettia caerulea. Org Lett 16:1462-5

Showing the most recent 10 out of 65 publications