Our long-term objective is to discover and develop leads for new anticancer agents. This research utilizes a collaboration between the Marine Bioorganic Chemistry group at U. of California Santa Cruz (UCSC) led by Prof. P. Crews and the Developmental Therapeutics Program at the Josephine Ford Cancer Center (JFCC) led by Dr. F. A. Valeriote. The hypothesis is that small molecule natural products (<2000 amu), can be identified and used, to selectively inhibit the growth of solid cancer tumors.
The aims outlined below will provide a foundation to discover and explore new biomolecules that will be of broad interest while also addressing general hypotheses guiding this research. Our focus is on tumors with relative insensitivity to most of the standard anticancer drugs. Thus, the overall aim is to obtain new compounds with effective activity against solid tumors, especially pancreatic, colo-rectal, breast, prostrate, brain, ovarian, and lung cancers. The general aims for the next grant period are: 1. To mine our repository of unstudied sponges either to continue or to begin new studies on both known and new bioactive, small biomolecules. 2. To use marine-derived fungi cultured in various media as a source for new active small biomolecules. 3. To use and refine our sponge-inspired hypothesis as the rationale for pursuing culture of Gram-positive and Gram-negative bacteria as a source of new active small biomolecules. 4. To utilize the in vitro cytotoxicity disk diffusion assay network to identify extracts obtained from Aims 1, 2, and 3 with solid tumor selectivity for follow-up fractionation and SAR expansion in Aim 6. 5. To make use of promising analytical methodologies, especially DART MS and DANS NMR, to guide further work on marine extracts, fractions, and library pure compounds obtained from Aims 1, 2, and 3. 6. To efficiently isolate, characterize and/or dereplicate compounds by focusing on the priority hits identified in Aims 4 and 5. 7. To continue capstone studies of solid tumor selective compounds through pharmacology evaluations and therapeutic assessment.

Public Health Relevance

The aim of this application is to discover and develop leads for new anticancer agents with a focus on tumors with relative insensitivity to most of the known anticancer drugs. The overall aim is to obtain new compounds from sponges and associated microorganisms with effective activity against solid tumors, especially pancreatic, colo-rectal, breast, prostrate, brain, ovarian, and lung cancers. This research utilizes a long-term collaboration between the Marine Bioorganic Chemistry group at U. of California Santa Cruz (UCSC) led by Prof. P. Crews and the Developmental Therapeutics Program at the Henry Ford Cancer Center (HFCC) led by Dr. F. Valeriote.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA047135-23A1S1
Application #
8719529
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Ogunbiyi, Peter
Project Start
1989-04-01
Project End
2018-01-31
Budget Start
2013-08-01
Budget End
2014-01-31
Support Year
23
Fiscal Year
2013
Total Cost
$47,173
Indirect Cost
$16,240
Name
University of California Santa Cruz
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
Mejia, Eric J; Loveridge, Steven T; Stepan, George et al. (2014) Study of marine natural products including resorcyclic acid lactones from Humicola fuscoatra that reactivate latent HIV-1 expression in an in vitro model of central memory CD4+ T cells. J Nat Prod 77:618-24
Rodriguez, Jaime; Nieto, Rosa M; Blanco, Maria et al. (2014) Thelepamide: an unprecedented ketide-amino acid from Thelepus crispus, a marine annelid worm. Org Lett 16:464-7
Still, Patrick C; Johnson, Tyler A; Theodore, Christine M et al. (2014) Scrutinizing the scaffolds of marine biosynthetics from different source organisms: Gram-negative cultured bacterial products enter center stage. J Nat Prod 77:690-702
La Clair, James J; Loveridge, Steven T; Tenney, Karen et al. (2014) In situ natural product discovery via an artificial marine sponge. PLoS One 9:e100474
Johnson, Tyler A; Sohn, Johann; Inman, Wayne D et al. (2013) Lipophilic stinging nettle extracts possess potent anti-inflammatory activity, are not cytotoxic and may be superior to traditional tinctures for treating inflammatory disorders. Phytomedicine 20:143-7
Rohena, Cristina C; Peng, Jiangnan; Johnson, Tyler A et al. (2013) Chemically diverse microtubule stabilizing agents initiate distinct mitotic defects and dysregulated expression of key mitotic kinases. Biochem Pharmacol 85:1104-14
Mejia, Eric J; Magranet, Lindsay B; De Voogd, Nicole J et al. (2013) Structures and cytotoxic evaluation of new and known acyclic Ene-Ynes from an American Samoa Petrosia sp. Sponge. J Nat Prod 76:425-32
Wu, Q X; Jin, X J; Draskovic, M et al. (2012) Unraveling the Numerous Biosynthetic Products of the Marine Sediment-Derived Fungus, Aspergillus insulicola. Phytochem Lett 5:114-117
Garcia, Jessica M; Curzon, Stephanie S; Watts, Katharine R et al. (2012) Total synthesis of nominal (11S)- and (11R)-cyclocinamide A. Org Lett 14:2054-7
Watts, Katharine R; Morinaka, Brandon I; Amagata, Taro et al. (2011) Biostructural features of additional jasplakinolide (jaspamide) analogues. J Nat Prod 74:341-51

Showing the most recent 10 out of 90 publications