Ovarian cancer (OC) is the second leading cause of deaths related to gynecologic cancers in US women. Advances in surgery and chemotherapy have not significantly changed the overall survival rate of OC patients for the last few decades, which highlights the need for new therapeutics. Even though most patients initially respond to platinum drugs based chemotherapy, about 80% of the cases relapse, develop platinum resistance and die with the advanced disease. Therefore, it is vital to understand the molecular mechanisms contributing to platinum resistance and disease recurrence in OC. In a paradigm-shift, our studies discovered Rad6 protein upregulation and poor survival of OC patients. Rad6 r...

Read More

Ovarian cancer (OC) is the second leading cause of deaths related to gynecologic cancers in US women. Advances in surgery and chemotherapy have not significantly changed the overall survival rate of OC patients for the last few decades, which highlights the need for new therapeutics. Even though most patients initially respond to platinum drugs based chemotherapy, about 80% of the cases relapse, develop platinum resistance and die with the advanced disease. Therefore, it is vital to understand the molecular mechanisms contributing to platinum resistance and disease recurrence in OC. In a paradigm-shift, our studies discovered Rad6 protein upregulation and poor survival of OC patients. Rad6 regulates multiple DNA repair networks to protect cells from platinum drugs induced DNA damage. Thus, we hypothesize that inhibition of Rad6 can compromise DNA repair networks, stem cell signaling and sensitizes chemoresistant OC cells to platinum drugs and prevent tumor recurrence. Towards this goal, we have designed and synthesized novel chemical series of Rad6 inhibitors using virtual screening approaches and evaluated their Rad6 inhibitory activity. We propose to further study their activity against OC cells alone and in combination with platinum drugs using in vitro and in vivo model systems. In the following two aims we will evaluate thirty newly discovered small molecule inhibitors of Rad6 in a panel of OC cell lines (Aim 1) and the efficacy of Rad6 inhibitors selected for high potency and selectivity for OC cells in an in vivo mouse orthotopic model of OC (Aim 2). The significance of these developmental stage high-impact studies is their potential to accelerate the development of Rad6 inhibitors for OC and will validate Rad6 as a novel drug target to prevent platinum resistance. If successful, this research could significantly improve therapeutic outcomes in OC patients by accelerating the development of Rad6 inhibitors.

Read Less