Recent studies of the applicants support the role of the endogenous gaseous biological mediator hydrogen sulfide (H2S) in colorectal cancer: selective upregulation of cystathionine-b-synthase (CBS) and the subsequent production of H2S in colonic cancer cells serves as a pro-survival factor by stimulating tumor cell bioenergetics, growth, proliferation, migration and invasion. This work identifies CBS as a novel antitumor target. In order to advance the clinical translation of this concept, we will pursue the following two Aims:
Aim #1. To conduct screening a composite library of clinical drugs, drug-like compounds and pharmacologically active molecules (>5,000 compounds) to identify novel pharmacological inhibitors of CBS, with the aim of drug repurposing for cancer therapy.
In Aim #2, Inhibitors identified in the cell-based screen will subsequently enter specificity and selectivty screening, followed by bioenergetics studies and studies of tumor cell proliferation in vitro. Successful completion of the current project will be evidenced by the identification of at least one clinically used drug (already used for non-oncological indications), which exerts CBS inhibitory and anti-proliferative effects, at concentrations that are therapeutically achievable in patients. Successful identification of such compound will trigger a Phase II STTR project, aimed at in vivo PK/PD studies and preclinical IND-enabling studies, culminating in the clinical repurposing of the lead compound. The applicant team (the PI at CBS Therapeutics and the head of the subcontract at the University of Texas Galveston) has all necessary theoretical and practical expertise to conduct the proposed work.
Hydrogen sulfide (H2S) is commonly known as swamp gas or sewer gas, an eggy- smelling subject of nuisance of various communities. Although H2S seems like a very unlikely candidate for any role in human biology, recent data shows that animal cells and human cells produce H2S, and use it for their own biological functions. The applicants have discovered that tumor cells contain a specific protein, CBS, which produces large amounts of H2S gas. Subsequent work by the applicants showed that H2S supports the growth and expansion of cancer cells within the cancer patients'body via several mechanisms. First: tumor-produced H2S serves as a hormone that stimulates the growth and expansion of the tumor. Second: tumor-produced H2S serves as a fuel to feed the metabolism of the tumor cells, in order to keep them energized. Third: H2S stimulates the growth of new blood vessels around the tumor tissue, so that the tumor can suck away fresh blood and nutrients from the host. Fourth: the tumor hijacks the blood vessels, and forces it to produce even more H2S. In summary, the tumor produces a H2S-rich local environment, in order to thrive. The therapeutic implication of these processes is that by blocking the tumor from overproducing H2S, the tumor will lose its fuel supply, and will stop growing: it will shrink and will be eliminated by the hot's immunological defenses. In the current project, the applicants propose to conduct a systematic screening of all existing clinical-stage drugs and drug-like compounds, in order to identify those compounds that have inhibitory effects on CBS. Such compounds would be ideal candidates for 'therapeutic repurposing'for the experimental therapy of colorectal cancer. The project will lay the foundation of a radically new concept for cancer therapy.
|Druzhyna, Nadiya; Szczesny, Bartosz; Olah, Gabor et al. (2016) Screening of a composite library of clinically used drugs and well-characterized pharmacological compounds for cystathionine ?-synthase inhibition identifies benserazide as a drug potentially suitable for repurposing for the experimental therapy of colon Pharmacol Res 113:18-37|