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
Sica, Vincent P; Rees, Evan R; Raja, Huzefa A et al. (2017) In situ mass spectrometry monitoring of fungal cultures led to the identification of four peptaibols with a rare threonine residue. Phytochemistry 143:45-53
Henkin, Joshua M; Sydara, Kongmany; Xayvue, Mouachanh et al. (2017) Revisiting the linkage between ethnomedical use and development of new medicines: A novel plant collection strategy towards the discovery of anticancer agents. Journal of medicinal plant research 11:621-634
Paguigan, Noemi D; Al-Huniti, Mohammed H; Raja, Huzefa A et al. (2017) Chemoselective fluorination and chemoinformatic analysis of griseofulvin: Natural vs fluorinated fungal metabolites. Bioorg Med Chem 25:5238-5246
Wang, Jiang; Zhu, Xiaohua; Kolli, Shamala et al. (2017) Plasma pharmacokinetics and bioavailability of verticillin A following different routes of administration in mice using liquid chromatography tandem mass spectrometry. J Pharm Biomed Anal 139:187-192
Chen, Wei-Lun; Ren, Yulin; Ren, Jinhong et al. (2017) (+)-Strebloside-Induced Cytotoxicity in Ovarian Cancer Cells Is Mediated through Cardiac Glycoside Signaling Networks. J Nat Prod 80:659-669
Paguigan, Noemi D; El-Elimat, Tamam; Kao, Diana et al. (2017) Enhanced dereplication of fungal cultures via use of mass defect filtering. J Antibiot (Tokyo) 70:553-561
Ren, Yulin; Chen, Wei-Lun; Lantvit, Daniel D et al. (2017) Cardiac Glycoside Constituents of Streblus asper with Potential Antineoplastic Activity. J Nat Prod 80:648-658
Acuña, Ulyana Munoz; Curley Jr, Robert W; Fatima, Nighat et al. (2017) Differential Effect of Wortmannolone Derivatives on MDA-MB-231 Breast Cancer Cells. Anticancer Res 37:1617-1623
Ren, Yulin; Gallucci, Judith C; Kinghorn, A Douglas (2017) An Intramolecular CAr-H•••O=C Hydrogen Bond and the Configuration of Rotenoids. Planta Med 83:1194-1199
Brooks, Wilson C; Paguigan, Noemi D; Raja, Huzefa A et al. (2017) qNMR for profiling the production of fungal secondary metabolites. Magn Reson Chem 55:670-676

Showing the most recent 10 out of 126 publications