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LP-184, a novel acylfulvene molecule, exhibits anti-cancer activity against diverse solid tumors with homologous recombination deficiency.

Cancer Res Commun 2024 April 18
Homologous recombination (HR) related gene alterations are present in a significant subset of prostate, breast, ovarian, pancreatic, lung and colon cancers rendering these tumors as potential responders to specific DNA damaging agents. A small molecule acylfulvene prodrug, LP-184, metabolizes to an active compound by the oxidoreductase activity of enzyme Prostaglandin Reductase 1 (PTGR1), which is frequently elevated in multiple solid tumor types. Prior work demonstrated that cancer cell lines deficient in a spectrum of (DNA damage repair) DDR pathway genes show increased susceptibility to LP-184. Here, we investigated the potential of LP-184 in targeting multiple tumors with impaired HR function and its mechanism of action as a DNA damaging agent. LP-184 induced elevated DNA double-strand breaks (DSB) in HR deficient (HRD) cancer cells. Depletion of key HR components BRCA2 or ATM in cancer cells conferred up to 12-fold increased sensitivity to the LP-184. LP-184 showed nanomolar potency in a diverse range of HRD cancer models, including prostate cancer organoids, leiomyosarcoma cell lines and patient-derived tumor graft models of lung, pancreatic, and prostate cancers. LP-184 demonstrated complete, durable tumor regression in 10 PDX models of HRD triple-negative breast cancer (TNBC) including those resistant to Poly-ADP ribose polymerase inhibitors (PARPi). LP-184 further displayed strong synergy with PARPi in ovarian and prostate cancer cell lines as well as in TNBC PDX models. These preclinical findings illustrate the potential of LP-184 as a pan-HRD cancer therapeutic. Taken together, our results support continued clinical evaluation of LP-184 in a large subset of HRD solid tumors.

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