Major Research Interests:
Standard therapy for advanced Prostate Cancer (PCa) consists of anti-androgens, which provide respite from disease progression, but ultimately fail resulting in the incurable phase of the disease: mCRPC. Targeting PCa cells before their progression to mCRPC would greatly improve the outcome. Combination therapy targeting the DNA Damage Response (DDR) has been limited by general toxicity, and a goal of clinical trials is how to target the DDR more specifically. We found that androgen deprivation therapy (ADT) of PCa cells results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DDR that typically results in a temporary cell cycle arrest of androgen responsive PCa cells. Following DNA damage, addition of TLK specific inhibitors, thioridazine (THD) or J54, impairs ATR and Chk1 activation, while its abrogation leads to apoptosis, providing a pathway for preventing mCRPC progression. Moreover, we recently found that TLK1 is also upstream of the NEK1>YAP pathway that leads to reprogramming of androgen-sensitive PCa cells to become ADT refractory (mCRPC). Hence, inhibiting the activity of TLK1 promotes both apoptosis in combination with ADT, as well prevention of mCRPC conversion.
In addition to these projects, we have other key work dealing with the function of TLK1 in Homologous Recombination Repair (the faithful pathway for DSB repair) based on its regulation of Rad54, the key DNA motor of recombinational repair. Finally, very recently we have begun investigation on a new function of TLK1 as crucial upstream activator of MK5, a central kinase involved in cell motility/invasion/ metastasis. This is a departure from the classic view of TLK1 as a kinase mainly involved in chromatin dynamics.
