LP-284, a small molecule acylfulvene, exerts potent antitumor activity in preclinical non-Hodgkin's lymphoma models and in cells deficient in DNA damage repair
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Jianli Zhou1, Drew Sturtevant1, Cassie Love2, Aditya Kulkarni1, Neha Biyani1, Umesh Kathad1, Elizabeth Thacker3, Sandeep Dave2 and Kishor Bhatia1
1 Lantern Pharma Inc., Plano, TX 75024, USA
2 Department of Medicine, Duke University, Durham, NC 27708, USA
3 Data Driven Bioscience, Durham, NC 27707, USA
|Jianli Zhou,||email:||[email protected]|
Keywords: non-Hodgkin's lymphoma; DNA damage; homologous recombination repair; transcription-coupled nucleotide excision repair; ATM
Received: May 09, 2023 Accepted: June 01, 2023 Published: June 12, 2023
Despite advances in therapies treating non-Hodgkin’s lymphoma (NHL), 20~40% of patients experience relapsed or refractory disease. While solid tumors with homologous recombination deficiencies have been successfully targeted with synthetic lethal agents such as poly-ADP ribose polymerase (PARP) inhibitors, such synthetic lethality strategy has not yet been approved to treat patients with NHL. Here we investigated the mechanism of action (MoA) and therapeutic potential of a new-generation acylfulvene compound, LP-284, in both in vitro and in vivo NHL models. One of LP-284’s MoA includes inducing the repair of double-strand DNA break (DSB). We found that LP-284 exerts nanomolar potency in a panel of hematological cancer cell lines including fifteen NHL cell lines. In vivo, LP-284 treatment prolongs the survival of mantle cell lymphoma (MCL) cell line JeKo-1 derived xenograft mice by two-fold and shows increased efficacy over bortezomib and ibrutinib. In addition, LP-284 is capable of inhibiting tumor growth of JeKo-1 xenografts that are refractory to bortezomib or ibrutinib. We further showed that LP-284 is particularly lethal in cells with deficient DNA damage response and repair, a targetable vulnerability in NHL.
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