Utilizing nucleic acid scavengers to elucidate how DNA/RNA-containing DAMPs promote pancreatic cancer metastasis and to mitigate such processes

Abstract public domain (NIH RePORTER)

Statement of Work – Sullenger and White MPIs The overall objective of this project is to develop nucleic acid binding polymers that can scavenge extracellular nucleic acid-containing Damage Associated Molecular Patterns (DAMPs) in the setting of pancreatic cancer therapy to mitigate activation of cancer cell migration and metastasis safely and effectively. Our translational hypothesis is that treatment of pancreatic cancer patients with chemotherapy or surgery induces the release of such nucleic acid-containing DAMPs and that administration of a second-generation nucleic acid-containing DAMP scavenger during such therapy will be particularly impactful as it will safely limit the ability of cancer cells to respond to and mobilize as a result of such proinflammatory treatments. The White and Sullenger labs started to collaboratively explore the ability of NASs to neutralize the downstream TLR mediated and pro-invasive effects of extracellular nucleic acids and nucleic acid-containing (NA) DAMPs to improve PC therapy. As we jointly reported, administration of the NAS PAMAM-G3 dramatically reduced metastases of syngeneic KPC pancreatic cancer cells to the liver of mice while also reducing circulating cfDNA levels. Our published data suggest that: 1] inflammation and the presence of activated inflammatory cells and platelets in the tumor and periphery promote cancer invasion and metastasis and 2] modulating inflammation with a NAS controls cancer invasion and metastasis. Though our initial analyses is quite encouraging, it has a major limitation that needs to be addressed to facilitate translation of this NAS strategy to the clinic. Specifically, the NAS PAMAM-G3 we have used has well known dose limiting toxicities. For this reason, the Sullenger lab has developed a new generation NAS, called PAMAM-G3 50:50, that retains the ability to scavenge nucleic acid DAMPs in vitro and in vivo while greatly reducing NAS- associated toxicity. Moreover, the Sullenger laboratory has recently started to evaluate a cationic cyclodextrin polymer (CDP), that has already been translated into the clinic for siRNA delivery in melanoma cancer patients, for its ability to scavenge DAMPs and limit metastasis in the setting of pancreatic cancer. We believe that both of these agents should have wider therapeutic windows than the first generation NAS, PAMAM-G3. The Sullenger and White labs propose to evaluate the potential of these two second generation NASs and the DAMP scavenging therapeutic approach to set the stage for IND-enabling studies for translation of this innovative strategy into the clinic to attempt to improve the outcomes of pancreatic cancer patients. The Sullenger lab will be responsible for all in vitro NAS biochemistry and nucleic acid DAMP analyses as well as all animal models not involving patient derived xenografts. The White lab will be responsible for all studies involving human samples including animal models that utilize patient derived tumor xenografts. Dr. Sullenger and Dr. White will share all findings and meet via Zoom at least twice per month.

Public health relevance public domain (NIH RePORTER)

Project Narrative Nucleic Acid Scavengers for Combating Pancreatic Cancer Dead and dying cancer cells release nucleic acids. These extracellular RNAs and DNAs can be recognized as Damage Associated Molecular Patterns (DAMPs) and taken up by inflammatory and/or cancer cells and activate them. In this study we will determine how DAMP-induced inflammation impacts cancer progression and metastasis and investigate if blocking nucleic acid debris-induced inflammation using compounds that scavenge tumor debris will augment antitumor responses, thereby providing rationale for inclusion of such inflammation blocking agents in therapeutic strategies for treating patients with pancreatic cancer. We have preformed preliminary studies indicating that such “nucleic acid scavengers” can limit metastasis in animal models of cancer. Herein we propose to perform detail preclinical studies with such novel therapeutic agents to facilitate the translation of this approach to the clinic. Successful completion of these studies will yield a novel strategy as well as lead therapeutic agents to treat pancreatic cancer as well as potentially other solid tumors. Thus these studies are greatly needed and highly clinically significant.