Molecular Mechanisms Underlying the Prevention of BCC Resistance

NARRATIVE Clinical resistance, tumor recurrence and an unacceptable side-effect profile are the major limitations of currently available targeted therapies for patients with basal cell nevus syndrome (BCNS) (also known as Gorlin-Goltz syndrome) as well as in patients with sporadic BCCs that are surgically inoperable or have metastasized. We will test the hypothesis that dysregulation of the epigenetic regulators BRD7 and BRD9 are drivers of BCC resistance by investigating the mechanisms responsible for these effects and test the preclinical utility of pharmacological BRD9 blockade in overcoming vismodegib resistance, potentially reducing the side-effect profile and improving the therapeutic index of pharmacologic inhibitors of Sonic Hedgehog signaling in these tumors.