Abstract B033: LP-184, a tumor site activated small molecule therapeutic, is synthetically lethal in pancreatic cancers with DNA damage repair defects
Authors: Kulkarni Aditya , Restifo Diana , Santos Troy Dos , Cvetkovic Dusica , McDermott Joseph , Bhatia Kishor , Sharma Panna , Ma Charlie , Astsaturov Igor 
Published: November 2022

Biomarker-based therapeutic strategies associated with increased efficacy, manageable toxicity and extended disease-free survival are urgently needed in pancreatic cancer (PaCa). 15-20% of PaCa carry mutations in DNA repair pathways (BRCA1/BRCA2/PALB2/RAD51/ATR/ATM/FANCD2). Additionally, mutations in nucleotide excision repair (NER) genes (ERCC2/3/4/5/6) have been reported in ~5% of PaCa. LP-184 is an acylfulvene analog that is converted to an active alkylating agent in the strict dependency on the oxidoreductase, prostaglandin reductase 1 (PTGR1). LP-184 induced tumor cell kill is enhanced in the presence of DNA damage repair (DDR) defects. Mutation or expression driven TC-NER and/or HR deficiency is expected to predispose PaCa cells to increased sensitivity to LP-184. To test the idea of LP-184 activity in DNA repair-deficient tumors, we evaluated the anti-tumor effects of LP-184 in mouse subcutaneous PDX models harboring pathogenic frameshift mutations in ATR (CTG-1522 model) or BRCA1 (CTG-1643 model) representing HR deficiency in PaCa. Two cycles of LP-184 treatment in CTG-1522 resulted in 140% tumor growth inhibition (TGI), relative to 80% TGI with gemcitabine in this FOLFIRONOX non-responder. Similarly, complete and durable tumor regression with 112% TGI was observed in CTG-1643 with single agent LP-184. There was &lt;5% body weight loss and no significant hematological toxicity in both these models during or after LP-184 treatment. In selected PaCa models, we determined LP-184 efficacy to be synergistic in combination with multiple treatment modalities including standard of care agent gemcitabine, and ERCC3 degrader spironolactone in vitro, and with radiation therapy (RT) in vivo. Overall Bliss synergy scores (score &gt; 10 indicates synergy) of 12.37 for LP-184 + gemcitabine in Capan-1, and 14.08, 16.47 and 15.52 for LP-184 + spironolactone in Capan-1 (BRCA2 loss), Hs766t (ATR mutant) and Panc03.27 cell lines respectively were achieved. Taking advantage of the transcriptional regulation underlying the NRF2 mediated anti-oxidant response pathway, we reasoned that induction of PTGR1 expression, a downstream NRF2 target gene, in irradiated PaCa tumors would thereafter poise them for LP-184 treatment. Indeed, we found that Panc03.27 xenograft tumors treated with 3 mg/kg i.p. LP-184 + 4 Gy RT once weekly for 3 weeks were significantly smaller than those receiving LP-184 alone or RT alone, thus capitalizing on the opportunity to increase PTGR1 expression (and linked LP-184 anti-tumor cytotoxicity) selectively in irradiated tumors. Increased PTGR1 expression has emerged as a promising biomarker for LP-184 cytotoxicity. Moreover, LP-184 can become synthetically lethal in multiple contexts when combined with genetic or pharmacologic DDR pathway aberrations, or with RT. Based on these properties, we anticipate that LP-184 will extend therapeutic opportunities to a large subset of PaCa patients.

Citation Format: Aditya Kulkarni, Diana Restifo, Troy Dos Santos, Dusica Cvetkovic, Joseph McDermott, Kishor Bhatia, Panna Sharma, Charlie Ma, Igor Astsaturov. LP-184, a tumor site activated small molecule therapeutic, is synthetically lethal in pancreatic cancers with DNA damage repair defects [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B033.