Abstract 1201: The PLK4 inhibitor RP-1664 drives centriole modulation and single agent tumor regressions in preclinical neuroblastoma models

Abstract Background: Increased expression of TRIM37, an E3 ligase encoded at chromosome 17q23, causes dysfunction of the pericentriolar material and creates a synthetic lethal vulnerability with PLK4 inhibition in cancer cells (Yeow, Nature 2020 and Meitinger, Nature 2020). High-risk neuroblastoma (HRNB) is a childhood cancer that is typically, widely metastatic at diagnosis and is lethal in over 50% of patients despite intensive multimodal therapy. Copy number gain of 17q is a common somatic aberration across human cancers but is a universal feature of HRNB. Here we tested the hypothesis that 17q gain is a biomarker for TRIM37 overexpression and the resulting mitotic centriole dysfunction can be exploited therapeutically with the first-in-class, selective, highly potent and bioavailable PLK4 inhibitor RP-1664. Methods: Chromosome 17q copy number status and TRIM37 expression were quantified across 46 primary HRNBs obtained at diagnosis and 15 patient-derived and cell-line derived xenograft (PDX/CDX) models (11 with MYCN amplification, 8 with ALK mutation, 2 with TP53 mutation) by next generation sequencing. CB17 SCID mice harboring established xenografts were randomized to receive RP-1664 formulated chow orally at 450 ppm or blank chow (N=3/arm) when tumors reached 150-250 mm3 for six weeks, followed by two 1 week on / 1 week off dosing cycles. Study endpoint was tumor volume of 2 cm3 or day 100 from enrollment. Maintained complete responses (MCRs) were defined as elimination of tumor for six weeks. Results: A total of 42/46 diagnostic HRNBs showed 17q23 copy number gain (range 3-9 copies relative to chromosome 17 centromere) and this was directly associated with TRIM37 mRNA expression (p=0.023). All 15 xenograft models showed 17q23 copy number gain with high median TRIM37 expression levels. RP-1664 was generally well tolerated with no interruption in dosing in 12/15 models for 15% or greater weight loss after 5 weeks of treatment. Body weight was restored rapidly after a brief drug holiday. RP-1664 showed robust single agent anti-tumor activity with complete responses in 7/15 (5 maintained), partial response in 1/15, and significant tumor growth delay with extension of survival in 4/15 PDX/CDX models. Mechanistically, RP-1664 induced established readouts of PLK4 inhibition, including elevated PLK4 levels, modulation of centrosome numbers and activation of the p53 pathway both in vitro and in vivo. In addition to expected dependence of HRNB cellular sensitivity on TRIM37, we uncovered a second, novel mechanism of RP-1664 sensitivity in HRNB cells driven by inability to compensate for excess centrosomes. Conclusion: Chromosome 17q gain and TRIM37 overexpression are pathognomonic features of HRNB. The novel PLK4 inhibitor RP-1664 was broadly efficacious across a wide array of highly resistant HRNB preclinical models and support clinical development of this therapy. Citation Format: Minu Samanta, Daivd Groff, Isabel Soria-Bretones, Joanna Li, Parham Nejad, Elliot Goodfellow, Alvin Farrel, Khushbu Patel, Kateryna Krytska, Steven B. Neuhauser, Timothy M. Stearns, Yael P. Mossé, JD Schonhoft, Marc L. Hyer, Michal Zimmermann, Gary Marshall, John M. Maris. The PLK4 inhibitor RP-1664 drives centriole modulation and single agent tumor regressions in preclinical neuroblastoma models [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 1201.