Linear energy transfer (LET) dependencies for understanding pancreatic tumor control and relevant molecular endpoints in support of RBE-based heavy-ion radiotherapy

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.

Grant Number: 5R01CA256840-05
NIH Institute/Center: NIH
Principal Investigator: Sally Amundson