Pancreatic ductal adenocarcinoma or PDAC is a lethal disease with a 5 year mortality rate of ~93% and little improvement has been made despite the emergence of several targeted, selective agents. Therefore, a new approach is needed. We will pursue transcriptomic-guided combination therapy as well as targets that are upstream of several signaling pathways, thereby affecting multiple downstream cellular processes and potential resistance mechanisms. Redox factor-1 (Ref-1) is one such protein, as Ref-1 regulates multiple transcriptional factors (TFs) that are critical to pancreatic cancer survival and drug resistance. In the previous funding period, we have advanced APX3330, a Ref-1 inhibitor and the first drug targeting Ref-1 to cancer clinical trials (IND 125360) as a novel, oral, first-in-class drug in humans. We have shown that APX3330 reduces tumor growth in several models of PDAC as a single agent and potentiates gemcitabine-mediated inhibition of cell growth. The mechanism of action of APX3330 has been extensively investigated and characterized by our team. Through inhibition of Ref-1, the activity of STAT3, AP-1, NFkB, and HIF-1? can be blocked leading to a decrease in survival protein expression and response to hypoxia. Recognizing that combination therapy will be necessary in PDAC, we propose to utilize transcriptomic data to identify FDA-approved agents that are likely to synergize with APX3330. Drug synthetic lethality is defined as combination therapy of molecular targets whose dual inhibition leads to potentiation of cell death much more dramatically than when administered as single agents. Single cell RNA-seq data identified HIF-1 signaling pathways as significantly down-regulated following Ref-1 knockdown (p=0.0008). Therefore, we tested the combination of Ref-1 inhibition and HIF-1 target, carbonic anhydrase (CA9) in our 3-Dimensional (3D) tumor co-culture model. Dramatic enhancement of Ref-1-induced cell killing is observed upon dual-targeting of Ref-1 and CA9. Our hypothesis is that in order to extend the survival of PDAC patients multi-targeted, combination therapy is essential; therefore we will use original, pathway-driven screening approaches to discover appropriate FDA approved agents to partner with our Ref-1 inhibitor.
AIM 1 - Evaluate the mechanism and efficacy of simultaneous inhibition of the Ref-1 and HIF-1? pathways using in vivo models of PDAC.
AIM 2 - Investigate the role of Ref-1 in sensitizing PDAC to chemotherapy currently used in PDAC treatment. Gemcitabine (Gem), one of the agents that single cell RNA-seq expression profiling predicted should work with APX3330, will be used in combination with APX3330 in the phase 1B trial.
AIM 3 - Screen for drug synthetic lethal hits following Ref-1 inhibition in a validated 3D model system utilizing computational and transcriptomics pathway analysis. Selective disruption of individual molecular effectors has clear limitations; our approach focuses on multi-targeted combination treatments. Thus, this project has the potential to extend pancreatic cancer survival by using appropriate disease-relevant models such as 3D co-culture spheroids, orthotopic, and GEM models.
This project has high clinical / translational value as it seeks to discover an effective combination therapy based on transcriptomics, a computational pipeline that will predict which agents will induce synthetic lethality, and sophisticated in vitro and in vivo model systems. We will also study the mechanism behind the synergy using state-of-the-art disease-relevant models including 3-dimensional tumor spheroids in co-culture with cancer- associated fibroblasts (CAFs), orthotopic, and genetic GEM models.
|Sardar Pasha, Sheik Pran Babu; Sishtla, Kamakshi; Sulaiman, Rania S et al. (2018) Ref-1/APE1 Inhibition with Novel Small Molecules Blocks Ocular Neovascularization. J Pharmacol Exp Ther 367:108-118|
|Ding, Jixin; Fishel, Melissa L; Reed, April M et al. (2017) Ref-1/APE1 as a Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia. Mol Cancer Ther 16:1401-1411|
|Zeleniak, Ann E; Huang, Wei; Brinkman, Mary K et al. (2017) Loss of MTSS1 results in increased metastatic potential in pancreatic cancer. Oncotarget 8:16473-16487|
|Richards, K E; Zeleniak, A E; Fishel, M L et al. (2017) Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene 36:1770-1778|
|Shah, Fenil; Logsdon, Derek; Messmann, Richard A et al. (2017) Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic. NPJ Precis Oncol 1:|
|Kelley, Mark R; Wikel, James H; Guo, Chunlu et al. (2016) Identification and Characterization of New Chemical Entities Targeting Apurinic/Apyrimidinic Endonuclease 1 for the Prevention of Chemotherapy-Induced Peripheral Neuropathy. J Pharmacol Exp Ther 359:300-309|
|Arpin, Carolyn C; Mac, Stephen; Jiang, Yanlin et al. (2016) Applying Small Molecule Signal Transducer and Activator of Transcription-3 (STAT3) Protein Inhibitors as Pancreatic Cancer Therapeutics. Mol Cancer Ther 15:794-805|
|Logsdon, Derek P; Grimard, Michelle; Luo, Meihua et al. (2016) Regulation of HIF1? under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models. Mol Cancer Ther 15:2722-2732|
|Zimmers, Teresa A; Fishel, Melissa L; Bonetto, Andrea (2016) STAT3 in the systemic inflammation of cancer cachexia. Semin Cell Dev Biol 54:28-41|
|Georgiadis, Millie M; Chen, Qiujia; Meng, Jingwei et al. (2016) Small molecule activation of apurinic/apyrimidinic endonuclease 1 reduces DNA damage induced by cisplatin in cultured sensory neurons. DNA Repair (Amst) 41:32-41|
Showing the most recent 10 out of 21 publications