Abstract 4802: Combination therapy in PDAC involving blockade of the APE1/Ref-1 signaling pathway: An investigation into drug synthetic lethality and anti-neuropathy therapeutic approach
Authors: Shah Fenil L. , Atallah Nadia , Grimard Michelle , Guo Chunlu , Zhang Chi , Fehrenbacher Jill , Kelley Mark R. , Fishel Melissa 
Published: August 2018

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related mortality in the US. Most patients present with advanced disease and ~93% die within five years, with most surviving less than six months. Combination therapies including Gemcitabine (GemzarTM) and sustained release, nab-paclitaxel (AbraxaneTM) and FOLFIRINOX (5-FU/leucovorin/irinotecan/oxaliplatin) offer modest improvement in survival, albeit at an increase in side effects including chemotherapy-induced peripheral neuropathy. Data is presented on Apurinic/apyrimidinic endonuclease/redox factor-1 (APE1/Ref-1 or APE1) and redox-specific APE1 inhibitor, APX3330 and its effects on tumor cell growth and sensory neuron function.

APE1 is a multifunctional protein involved in repairing DNA damage via endonuclease activity and in redox regulation of transcription factors such as HIF-1α, NFkB and STAT3. High expression levels of APE1 indicate decreased survival in PDAC as well as other cancers. Because APE1 is essential for cell viability, generation of APE1 knockout cell lines and determining a comprehensive list of genes regulated by APE1 has been difficult.

To circumvent this, we performed single cell RNA-Sequencing on PDAC cells following APE1 knockdown under normoxia and hypoxia to identify differentially expressed genes and further explore APE1's effects on HIF-1α and STAT3 signaling under both conditions. Proteomic analysis on PDAC cells following APE1 knockdown in normoxia and hypoxia revealed changes in signaling downstream of APE1, complementing the transcriptomic data and providing a more complete understanding of pathways affected by APE1.

We used the newly identified APE1 targets and pathways along with drug sensitivity data of cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) to generate potential combination therapies of FDA approved drugs and the APE1 redox inhibitor, APX3330 and next generation analogs. These combinations were tested using an ex vivo 3D tumor-stroma model system using patient derived cells from the tumor as well as cancer-associated fibroblasts. We identified synergy with agents such as Napabucasin and Entinostat.

We also tested APX3330 in combination with drugs that are part of PDAC standard of care. In vivo studies combining APX3330 with Gemcitabine showed significantly decreased tumor volume. Combining oxaliplatin (part of FOLFIRINOX) with APX3330 caused a significant reduction in oxaliplatin-induced DNA damage in sensory neurons from a KPC orthotopic graft model, without hindering its anti-cancer activity. With the phase I clinical trial for APX3330 underway (IND 125360), the potential for APE1 targeted therapy enhancing tumor efficacy while providing neuroprotective effects in the sensory neurons provides a win-win scenario.

Citation Format: Fenil L. Shah, Nadia Atallah, Michelle Grimard, Chunlu Guo, Chi Zhang, Jill Fehrenbacher, Mark R. Kelley, Melissa Fishel. Combination therapy in PDAC involving blockade of the APE1/Ref-1 signaling pathway: An investigation into drug synthetic lethality and anti-neuropathy therapeutic approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4802.