Pancreatic cancer is responsible for the third most cancer-related deaths in the United States, and >60,000
Americans will be diagnosed in 2022. Further, patients with pancreatic ductal adenocarcinoma (PDAC) face a
5-year survival rate of less than 5%. Although the genetic drivers of PDAC have been well established, these
cancers remain largely refractory to treatment. To survive, PDACs depend on autophagy, an intracellular nutrient
recycling process. Autophagy provides an internal nutrient pool for tumor cell survival, and pancreatic stellate
cells also use autophagy to support their metabolic demands. Further, autophagy contributes to immune evasion,
a well-known therapeutic challenge in PDAC. Consistent with these roles, genetic autophagy inhibition has been
shown to reduce PDAC tumor growth; however, the translation of these discoveries is limited by a lack of
pharmacologic autophagy inhibitors available for preclinical use.
To address this problem, our lab developed a potent and selective small molecule inhibitor of ULK1 (ULK-101),
a protein kinase that controls autophagy induction. Importantly, we have shown that starved cancer cells are
highly sensitive to ULK1 inhibition, consistent with autophagy-dependent survival during stress. While several
ULK1 inhibitors exist, we have demonstrated that ULK-101 is the most potent and selective to date and the ideal
candidate for preclinical investigations. Therefore, we propose to evaluate the effects of ULK-101 in mouse
models of pancreatic cancer. We hypothesize that ULK-101 will suppress autophagy through ULK1 inhibition
and thereby reduce pancreatic tumor growth and improve therapeutic efficacy.
Aim 1 will use an orthotopic tumor model using human pancreatic cancer cell lines (MIA PaCa-2 and PANC-1)
to test whether ULK-101 treatment reduces tumor progression in vivo. We will then use these orthotopic models
to assess target engagement and ULK-101 selectivity by measuring ULK1 inhibition using chemoproteomics.
These orthotopic models will also be used to evaluate the effect of ULK-101 on tumor progression, which we will
benchmark against hydroxychloroquine, an approved lysosomal inhibitor. For Aim 2, we will use a syngeneic
orthotopic tumor model with 7940b murine cells and the established pancreatic KPC mouse (LSL-KrasG12D/+,
LSL-Trp53R172H/+, Pdx1-cre model) to test whether ULK-101 will decrease tumor burden. Because autophagy
inhibition sensitizes PDACs to immunotherapy, we will also evaluate ULK-101 in combination with dual immune
checkpoint blockade (anti-CTL4 and anti-PD-1). The genetically engineered mouse model in Aim 2 features a
functional immune system, tumors at the appropriate site, and disease progression that parallels human
Through these thorough in vivo studies, we will examine ULK1 inhibition as a strategy for treating pancreatic
cancer and may provide evidence for further development of ULK-101 and novel autophagy inhibitors.