Cyanobacteria are among the most ancient organisms on Earth and have evolved chemical weapons for defensive purposes, which we are exploiting for anticancer drug discovery. Our past research has exemplified that marine cyanobacteria contain compounds with exceptionally potent activity and/or possess unusual or first-in-class inhibitors with novel mechanisms of action. However, cyanobacteria are also notorious for producing toxins detrimental to human health and other general cytotoxins. Our proposal addresses main issues in natural products drug discovery, including appropriate sample selection and prioritization for those compounds with promising therapeutic potential and cancer selectivity through innovative dereplication strategies and unique complementary in vitro cellular and in vivo organismal assay sets directed towards key cancer-related pathways. Targeted pathways are related to growth factor receptor activity and angiogenesis, resistance and metastasis, all of which are major areas of concern in cancer research. We have developed new chemical, biochemical and genetic tools to specifically probe novel mechanisms of action that we recently discovered and to identify modulators of these pathways. First, we will carry out field collections of marine cyanobacteria and will subject their extracts to taxonomy- and LC-MS/MS based dereplication strategies in combination with cytotoxicity assays. Prioritized cyanobacteria will be cultured and fraction libraries generated. Second, we will implement a rational screening strategy for selective cytotoxins by assessing differential cytotoxicity of fraction libraries using various suitable human cell-based models. Specifically, we will screen for agents with selective activity against colon cancer cells over the corresponding normal cells, in a mechanistically-unbiased approach. More targeted, we will screen for antiangiogenic agents that exert their activity through a mechanism we recently validated, involving simultaneous downregulation of receptors and growth factors. Through the use of our newly created unique isogenic screening system we then aim to discover novel dual inhibitors of the transcription factors HIF-1 and HIF-2, which have promise for combination therapy with anti-angiogenic agents. Prioritized fractions will be subjected to bioassay-guided isolation and structures will be determined. Third, we have discovered and characterized a novel mechanism to prevent metastasis and developed suitable zebrafish in vivo models to screen for anti-invasive agents that modulate tumor suppressor E-cadherin expression and localization to the cell membrane when applied as single agents or in combination with a synergizing cyanobacterial compound we already discovered. Anti-invasive properties of compounds will be assessed in a new zebrafish tumor model at the single-cell level by monitoring cell dissemination, invasion and metastasis. Fourth, we will mechanistically characterize the identified selective agents to pinpoint the molecular changes induced in the cancer cell and to determine potential direct targets.

Public Health Relevance

Marine cyanobacteria produce selective anticancer agents with specific molecular targets. This research will lead to the discovery of new compounds that could become new drug leads for the treatment of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA172310-04S1
Application #
9330322
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Ogunbiyi, Peter
Project Start
2013-03-06
Project End
2018-02-28
Budget Start
2016-08-01
Budget End
2017-02-28
Support Year
4
Fiscal Year
2016
Total Cost
$43,814
Indirect Cost
$10,378
Name
University of Florida
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Cai, Weijing; Ratnayake, Ranjala; Gerber, Michael H et al. (2018) Development of apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent and its preliminary evaluation in an orthotopic patient-derived xenograft (PDX) model. Invest New Drugs :
Cai, Weijing; Salvador-Reyes, Lilibeth A; Zhang, Wei et al. (2018) Apratyramide, a Marine-Derived Peptidic Stimulator of VEGF-A and Other Growth Factors with Potential Application in Wound Healing. ACS Chem Biol 13:91-99
Cai, Weijing; Matthew, Susan; Chen, Qi-Yin et al. (2018) Discovery of new A- and B-type laxaphycins with synergistic anticancer activity. Bioorg Med Chem 26:2310-2319
Al-Awadhi, Fatma H; Law, Brian K; Paul, Valerie J et al. (2017) Grassystatins D-F, Potent Aspartic Protease Inhibitors from Marine Cyanobacteria as Potential Antimetastatic Agents Targeting Invasive Breast Cancer. J Nat Prod 80:2969-2986
Agarwal, Vinayak; Blanton, Jessica M; Podell, Sheila et al. (2017) Metagenomic discovery of polybrominated diphenyl ether biosynthesis by marine sponges. Nat Chem Biol 13:537-543
Paciaroni, Nicholas G; Ratnayake, Ranjala; Matthews, James H et al. (2017) A Tryptoline Ring-Distortion Strategy Leads to Complex and Diverse Biologically Active Molecules from the Indole Alkaloid Yohimbine. Chemistry 23:4327-4335
Alfurhood, Jawaher A; Sun, Hao; Kabb, Christopher P et al. (2017) Poly(N-(2-Hydroxypropyl) Methacrylamide)-Valproic Acid Conjugates as Block Copolymer Nanocarriers. Polym Chem 8:4983-4987
Kim, Bumki; Ratnayake, Ranjala; Lee, Hyunji et al. (2017) Synthesis and biological evaluation of largazole zinc-binding group analogs. Bioorg Med Chem 25:3077-3086
Al-Awadhi, Fatma H; Salvador, Lilibeth A; Law, Brian K et al. (2017) Kempopeptin C, a Novel Marine-Derived Serine Protease Inhibitor Targeting Invasive Breast Cancer. Mar Drugs 15:
Wu, Ping; Cai, Weijing; Chen, Qi-Yin et al. (2016) Total Synthesis and Biological Evaluation of Apratoxin E and Its C30 Epimer: Configurational Reassignment of the Natural Product. Org Lett :

Showing the most recent 10 out of 26 publications