Columbia University Health Sciences has received a USD 1.83 million NIH R01 grant from the National Cancer Institute to investigate how Histone PARylation Factor 1 (HPF1) governs bone marrow toxicity during radiation therapy and PARP inhibitor treatment — a clinically significant problem that contributed to the FDA withdrawing two PARP inhibitors from maintenance therapy indications in 2022.
The award addresses a poorly understood selectivity problem: why radiation and PARP inhibitors (PARPi) disproportionately damage erythropoiesis compared with other genotoxic agents such as cisplatin or nucleoside analogs. Principal investigator Shan Zha and colleagues have generated preliminary data suggesting HPF1 — a recently characterized regulator of PARP1 and PARP2 — sits at the intersection of normal hematopoietic function and DNA damage response. Critically, while HPF1 deletion alone is dispensable for hematopoiesis in mice, combined loss of HPF1 and PARP2 in the presence of PARP1 expression proved embryonically lethal with severe anemia, pointing to a specific regulatory axis relevant to PARPi-induced hematological toxicity. The research will examine how HPF1 shapes PAR chain structural diversity — including serine versus glutamine versus aspartate ribosylation and chain length — and how this specificity influences which PAR-binding proteins are recruited during DNA damage.
The translational case is direct: if HPF1 activity can be modulated to reduce PARP1 trapping in erythroid progenitors without compromising tumor cell killing, it could offer a path to safer PARPi-radiation combination regimens. Approved PARPi — including olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca) — have all faced hematological toxicity concerns, and the field has lacked a mechanistic framework to decouple on-tumor efficacy from bone marrow damage. This grant funds preclinical work through May 2029 that could inform that framework.