Abstract 2903: Evaluation of SMP-3124, a novel liposome-encapsulated CHK1 inhibitor, in patient-derived preclinical models of treatment-resistant ovarian cancer

Abstract Purpose: Checkpoint kinase 1 (CHK1) plays a critical role in DNA damage repair by responding to and managing DNA replication stress. CHK1 activation results in cell cycle arrest and the induction of DNA damage repair pathways. Targeting CHK1 is a promising therapeutic strategy due to high levels of replication stress in cancer cells. CHK1 inhibition causes replication catastrophe and inhibits cell growth in a wide range of cancers (Toledo L, 2017). In the past decade, multiple drugs targeting this pathway have been tested in clinical trials (de Costa AABA, 2023). Although some of the CHK1 inhibitors showed promising clinical responses as monotherapies or in combination therapies in patients with gynecological cancers, efficacies were limited due to toxicities. To maximize the potential for efficacy and limited toxicities, we utilized a CHK1 inhibitor formulated as a liposomal nanomedicine since liposomal drugs are reported to alter drug distribution to achieve longer drug retention in plasma and higher accumulation in tumors in preclinical and clinical settings (J Vaage, 1997, Barenholz Y, 2012, Northfelt DW, 1996). Methods: SMP-3124 is an investigational selective CHK1 inhibitor encapsulated within a liposome. SMP-3124 showed a durable pharmacodynamic response due to the liposomal accumulation in the tumor in an ES-2 ovarian cancer xenograft model. Results: We confirmed potent anti-tumor activities of SMP-3124 in multiple preclinical subcutaneous xenograft models without weight loss. To further evaluate the potential of SMP-3124, especially in recurrent ovarian cancer, we established a novel preclinical model from the ascites of a patient with multiple treatment-resistant ovarian cancers. The preclinical study using this model revealed resistance to the standard treatment drugs in ovarian cancer, while showing sensitivity to SMP-3124. Furthermore, we investigated the therapeutic potential of SMP-3124 in patient-derived xenograft models of ovarian cancer, including platinum-resistant models generated at Kyoto University. SMP-3124 showed more than 40% tumor regression relative to baseline in seven out of fourteen of the preclinical patient-derived xenograft models and achieved complete remission in three cases. These results support the investigation of SMP-3124 in ovarian cancer patients and the ongoing phase 1/2 study of SMP-3124 in adults with advanced solid tumors overall. Citation Format: Yuka Kumagai, Junzo Hamanishi, Ryusuke Murakami, Kana Shimizu, Yosuke Ota, Yusuke Sawayama, Naoaki Shimada, Kento Hayashi, Yoshiko Fukuoka, Steven L. Warner, Jason M. Foulks, Masaki Mandai, Makoto Matsuoka, Seiji Kamioka, Hitoshi Ban, Hiroki Umehara. Evaluation of SMP-3124, a novel liposome-encapsulated CHK1 inhibitor, in patient-derived preclinical models of treatment-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2903.