This proposal brings together a unique interdisciplinary team with complementary expertise in high-LET radiobiology, pancreatic cancer research, and high-LET physics. It leverages the engineered PDA (pancreatic ductal adenocarcinoma) mouse models and imaging capabilities at our ?PDA Mouse Hospital? together with the high-LET charged particle beams generated at Brookhaven?s NSRL and our Radiological Research Accelerator Facility (RARAF) at Columbia to address the central hypothesis that heavy ion radiotherapy (HIRT) effects in PDA are LET dependent and can be enhanced by pharmacological induction of ferroptosis. HIRT represents a promising therapeutic opportunity for improving (PDA) survival, with very encouraging survival results reported after combined carbon-ion and gemcitabine therapy for locally advanced PDA. Compared with other radiotherapy modalities the high-LET radiations deposit energy far more densely resulting in complex DNA damage, clustered reactive oxygen species (ROS) formation, and altered damage signaling. The generation of clustered ROS by HIRT is clearly linked to cell killing, however, PDA upregulates ROS detoxification pathways, potentially leading to mitigation of tumor cell killing by radiation. Our labs have recently shown that pharmacological inhibition of cystine import counters PDA resistance to endogenous ROS, triggering ferroptotic death in PDA cell lines and tumors, and resulting in significantly improved survival of autochthonous PDA tumor bearing mice. The efficiency of lipid peroxidation, upon which ferroptosis depends, varies with LET, suggesting that overcoming ferroptosis resistance in combination with optimized HIRT may prove a powerful approach for PDA treatment. Thus our central hypothesis is that HIRT effects in PDA are LET dependent and can be enhanced by pharmaceutical induction of ferroptosis. The goal is to understand and quantify PDA-HIRT relevant endpoints using state-of-the art PDA mouse models in extended heavy-ion beams customized for mouse tumor exposure, with and without pharmacological induction of ferroptosis. Our second goal is understanding the LET dependencies of PDA-HIRT relevant endpoints: First to find the optimal dose-averaged LET (LETD) corresponding to these endpoints, and second to assess whether clinical helium ion beams may induce similar yields of these endpoints ? a conclusion that would potentially revolutionize heavy ion radiotherapy. Our mouse irradiations will use custom extended heavy-ion beams at Brookhaven?s NSRL facility. However, the LETD distributions within the irradiated mouse tumors cover a much smaller LET range than in typical human tumors treated with HIRT. We will assess whether the conclusions drawn from these studies are still valid at the higher LETs and lower LETs respectively of relevance for clinical carbon-ion and helium-ion HIRT, by recapitulating relevant endpoints at RARAF, our preclinical heavy-ion irradiation facility where mono- LET beams for cellular irradiations are available from 10 to 200 keV/?m.
Despite decades of research, pancreatic ductal adenocarcinoma remains one of the deadliest of cancers, but recent advances in heavy-ion radiotherapy and in ferroptosis-inducing drugs may begin to change this. This proposal will investigate the relationship of linear energy transfer with tumor killing and associated endpoints, as well as how these interact with the induction of ferroptosis. The knowledge gained will help to develop optimized approaches to heavy ion radiotherapy, potentially making it both more clinically effective and more cost effective to improve outcomes for pancreatic cancer and other hard-to-treat tumors.