Projects
A summarization of our current research projects are detailed.
Novel Small Molecule Alternol for Prostate Cancer Therapy
Ideally, any cancer therapy should be able to selectively kill cancer cells without harming benign tissues. With this idea in mind, after several years of hard work, we identified a novel small molecule, Alternol, that preferentially kills malignant prostate cancer cells over benign prostate-derived epithelial cells. Alternol is produced by mutant fungi isolated from the bark of a yew tree, similar to the source of Paclitaxel. We demonstrated that Alternol triggers apoptotic cell death depending on reactive oxygen species (ROS)-mediated activation of pro-apoptotic Bax protein preferentially in malignant cells but not in benign cells. We also defined the purine metabolic enzyme XDH/XO as the responding source for ROS accumulation. With a Mass-Spec approach, we identified 14 cellular proteins that are Alternol targets, including five metabolic enzymes (GAPDH, DLAT, DLST, FH & MDH2), leading to disturbance of TCA cycle and ATP production in vitro and in vivo in prostate cancer. We are now working on the mechanisms of Alternol action on GAPDH related to cellular glycolysis.
Small Peptide Technology for AR Protein Degradation
Current therapies for CRPC focus on blocking androgen-stimulated AR activation or reducing androgen production in prostate cancer tissues. Unfortunately, these therapies fail to deliver a clinically meaningful benefit in patients due to AR gene mutation or splice variation. We invented a small peptide-based therapeutic approach that will overcome treatment resistance in CRPC through a novel mechanism for peptide-mediated client protein-specific degradation of AR protein. The small peptides with 8mers eliminate the highly-activated AR protein in prostate cancer cells, leading to cancer cell death (U.S. patent application #62-886104). Large-scale preclinical animal experiments are planned to evaluate its anti-tumor effect in vivo.
PI3K/p110β-Specific Inhibitor for Metastatic Prostate Cancer
TGX-221 is a novel, isoform-specific and potent small molecule inhibitor of PI3K-p100β. While TGX-221, therefore, has considerable potential as a novel chemotherapy agent for prostate cancer, its poor solubility and lack of selectivity for prostate cancer cells limit its clinical application. We have recently synthesized TGX-221 derivatives, TGX-D1 and BL140, which have a greatly enhanced water solubility but exhibit similar activity and isoform-specificity as TGX-221. We are evaluating their therapeutic effectiveness in combination with other anti-prostate cancer agents, including immune checkpoint inhibitors.