Targeting the PH/DH Domain of Tiam1 for the Treatment and/or Prevention of Bone Metastases
Prostate Cancer (PCA) is a heterogeneous disease and the 5-year survival rate for men whose cancer has metastasized at the time of diagnosis being 34%, however, if the cancer is detected prior to metastasis the 5-year survival rate increases to nearly 100%. Although most patients respond to androgen suppression by entering into clinical remission, they eventually develop more aggressive tumors that are castration-resistant PCA (CRPCA). While there are currently numerous drugs designed to inhibit metastatic cells and bone, there are currently none which target CRPCA. Invention: Tiam1 is a highly conserved exchange factor that is over-expressed in many cancers, including prostate cancer (CRPCA). Increase in Tiam1 expression is associated with increased metastases and correlates with poor PCA patient survival prognosis. This technology has identified a novel compound which exhibits the ability to reduce prostate cancer bone metastasis by binding to the cPH domain of Tiam1 and inhibiting its cellular functions. Application: This product could one day be developed to be given to any patient with prostate cancer, to target tiam1 in order to impede tumor invasion and metastasis. Advantages: This invention has been demonstrated to be superior to the state-of-the-art in (a) theory, (b) simulations, and (c) using real data. Our simulation results show orders of magnitude in improvement, as compared to traditional methods. Real results from data closely replicate the performance of our simulations. • In vitro assays revealed that compound TPH-9 significantly reduced the number of fillipodia;• At a concentration of 10 mM, TPH-9 prevented wound closure of PC-3 cells and invasion by 72.1±9.6%;• TPH-9 induced a tumor growth delay in a PC-3 mouse xenograft study;• Only compound which specifically targets CRPCA. Lead Inventor: Dr. Emmanuelle Meuillet
美國
