Researchers at Stony Brook University have been awarded a five-year, $4.2 million grant from the National Cancer Institute (NCI) to expand work into promising therapeutic agents against metastatic prostate cancer.
The team, led by Iwao Ojima, PhD, director of the Institute of Chemical Biology and Drug Discovery (ICB&DD) at Stony Brook, in collaboration with scientists at Cold Spring Harbor Laboratory and Artelo Biosciences, is examining a group of proteins called fatty acid-binding proteins (FABs) as targets to treat certain cancers, inflammatory conditions, and pain.
This new funding is based on work originally supported by a seed grant called a “Fusion Award” from the Renaissance School of Medicine at Stony Brook University.
Ojima, along with Martin Kaczocha, PhD, an institute professor, and Cold Spring Harbor professor Lloyd Trotman, PhD, developed FAB5 inhibitors that were significantly toxic to treatment-resistant metastatic prostate cancer cells. FABP5 inhibitors also enhanced the anti-tumor effects of current chemotherapies in animal models.
“This grant is a tremendous example of how collaborative research … have pushed forward a bioscience concept initially supported by seed money from our school to a level where the National Cancer Institute sees its potential as a new and better treatment for metastatic prostate cancer,” Kenneth Kaushansky, MD, dean of the Renaissance School of Medicine at Stony Brook, said in a press release.
FABP5 is a protein that carries lipid (fat) molecules, whose production is increased in metastatic prostate cancer cells and leads to cell growth, invasion, and tumor formation. The FABP5 inhibitors alone were toxic to prostate cancer cells but showed limited toxicity in noncancerous cells.
When combined with current taxane chemotherapies docetaxel (brand name Taxotere, generics also available) or cabazitaxel (brand name Jevtana, sold by Sanofi-Aventis), the FABP5 inhibitors produced synergistic toxic effects in cancer cells. Treating mice with these inhibitors reduced tumor growth, and in combination with a suboptimal dose of docetaxel, lowered cancer cell growth even further.
“In our research, neither docetaxel or cabazitaxel alone was able to eradicate prostate cancer cells in vitro (in the lab), while combinations of taxanes with FABP5 inhibitors resulted in complete prostate cell death with synergism at very low concentrations of taxanes,” Ojima said.
Taxanes can be an effective treatment for prostate cancers, but tumors can become resistant to these medicines and patients often report troubling side effects.
“While the FABP5 inhibitors produced limited or no cell cytotoxicity [toxicity to cells] in noncancerous cells, they achieved near-complete cell death in the prostate cancer cell lines used in our study, which suggests the FABP5 inhibitors would have much fewer side-effects compared with the current taxane/steroid-based therapy,” said Kaczocha, a team co-leader and an assistant professor in the school’s department of anesthesiology.
Under the grant, the team will use the 3D structure of FABP5 and a chemical synthesis approach to design potent and selective inhibitors. The efficacy of the best candidates will be tested in mouse disease models alone, and in combination with approved therapies.
The team will be collaborating with scientists at Artelo, which entered into an exclusive license agreement with the Research Foundation for the State University of New York in 2018 for the rights to develop FABP inhibitors for the treatment of pain, inflammation, and cancer.
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