Grants - V Scholar Grants - Pennsylvania - 2017

Donita Brady, Ph.D.

Funded by the Stuart Scott Memorial Cancer Research Fund

Pancreatic ductal adenocarcinoma (PDAC) is a uniformly lethal cancer with a five-year patient survival rate of fewer than eight percent. This dismal statistic is caused in part by the inability to detect PDAC early enough for surgical resection and PDAC tumors do not respond to standard chemotherapies. Ninety-five percent of PDAC tumors have an activating mutation in the gene KRAS. Despite 30 years of research invested in anti-RAS therapies, it is still not possible to directly inhibit RAS clinically. Hence, research has focused on identifying cellular processes that help KRAS mutant cancers grow, survive, and resist treatment with chemotherapies. One cellular process that mutant KRAS turns on in PDAC is autophagy, which is a process of ‘self-eating’ in which cells digest themselves in order to recycle building blocks needed as fuel sources for aggressive growth. Chloroquine, a drug that blocks autophagy, reduces PDAC tumor growth in preclinical models and clinical trials. In addition, the tumor-inhibiting effects of gemcitabine, a frontline chemotherapeutic for advanced PDAC, are enhanced when autophagy is decreased with chloroquine. However, chloroquine blocks autophagy non-selectively, requires high doses, and turns on autophagy when treatment is prolonged. Therefore, alternative autophagy inhibitors are needed. Recent studies in our lab discovered that limiting the availability of the transition metal copper to KRAS mutant cells reduces autophagy and in turn tumorigenic properties. Thus, the proposed studies will address whether copper-reducing drugs used to lower copper levels in humans can be repurposed for the treatment of KRAS mutation-positive PDAC by blocking autophagy.