Limited clinical data are available regarding the utility of multikinase inhibition in neuroblastoma. Repotrectinib (TPX-0005) is a multikinase inhibitor that targets ALK, TRK, JAK2/STAT, and Src/ FAK, which have all been implicated in the pathogenesis of neuroblastoma. We evaluated the preclinical activity of repotrectinib monotherapy and in combination with chemotherapy as a potential therapeutic approach for relapsed/refractory neuroblastoma.In vitro sensitivity to repotrectinib, ensartinib, and cytotoxic chemotherapy was evaluated in neuroblastoma cell lines. In vivo antitumor effect of repotrectinib monotherapy, and in combination with chemotherapy, was evaluated using a genotypically diverse cohort of patient-derived xenograft (PDX) models of neuroblasto-ma. Repotrectinib had comparable cytotoxic activity across cell lines irrespective of ALK mutational status. Combination with chemotherapy demonstrated increased antiproliferative activity across several cell lines. Repotrectinib monotherapy had notable antitumor activity and prolonged event-free survival compared with vehicle and ensartinib in PDX models (P < 0.05). Repotrectinib plus chemotherapy was superior to chemotherapy alone in ALKmutant and ALK wild-type PDX models. These results demonstrate that repotrectinib has antitumor activity in genotypically diverse neuroblastoma models, and that combination of a multikinase inhibitor with chemotherapy may be a promising treatment paradigm for translation to the clinic.

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<p>Supplementary figures and tables</p>

<p>Supplementary figures and tables</p>

Introduction: Malignant rhabdoid (MRT) and Wilms tumor (WT) comprise more than 5% of all pediatric cancers. Despite intensive multimodality therapy, outcomes remain dismal for a subset of patients with aggressive or high-risk molecular features. Characteristic of most pediatric cancers, MRT and WT demonstrate relatively low frequencies of somatic mutations compared to adult tumors and generally lack therapeutically targetable genetic alterations. Hence, we applied a systems biology approach to identify and evaluate non-genetically encoded vulnerabilities in MRT and WT. Methods: MetaVIPER analysis was performed to computationally infer protein activity from MRT and WT whole transcriptomic data available in the TARGET database. Expanded metaVIPER analysis of TARGET and TCGA cohorts demonstrated XPO1 as having consistently high inferred activity in MRT and WT. Functional in vitro studies using a selective inhibitor of XPO1, selinexor, were performed on a panel of MRT and WT cell lines to evaluate the effects of XPO1 inhibition on proliferation, cell cycle transition and apoptosis induction. In vivo validation of anti-tumor activity following XPO1 inhibition were performed in cell line-derived (CDX) and patient-derived xenograft (PDX) models of MRT and WT. Results: MetaVIPER analysis identified consistent high inferred activity of XPO1 in MRT and WT compared to other tumor types. MRT and WT cell lines demonstrated in vitro sensitivity to selinexor treatment resulting in cell cycle arrest and apoptosis induction. Furthermore, protein expression analysis showed increased nuclear sequestration of tumor suppressors proteins following treatment with selinexor. In vivo treatment of panel of MRT and WT CDX and PDX models with selinexor and a next-generation XPO1 inhibitor, eltanexor, resulted in significant abrogation of tumor growth with associated decreases in inferred XPO1 activity. Pharmacodynamic analysis of treated PDX tumors show decreased levels of XPO1, RB1-pSer780, and increased p53, p27 and p21 protein levels. Based on promising preclinical data, we describe a case report of a child with relapsed and progressive Wilms tumor who experienced a sustained complete remission on maintenance selinexor therapy. Conclusion: XPO1 represents a non-genetically encoded vulnerability in MRT and WT. Promising preclinical activity in MRT and WT models has provided the preclinical rationale for evaluation of XPO1 inhibition in an investigator-initiated clinical trial of Selinexor in pediatric MRT and WT. Citation Format: Diego F. Coutinho, Chelsey Burke, Prabhjot Mundi, Michael V. Ortiz, Kelly L. Vallance, Matthew Long, Nestor Rosales, Glorymar Ibanez, Lianna J. Marks, Daniel Diolaiti, Andoyo Ndengu, Daoqi You, Armaan Siddiquee, Ervin S. Gaviria, Allison R. Rainey, Andrea Califano, Andrew L. Kung, Filemon S. Dela Cruz. Targeting of the nuclear export protein XPO1 represents a non-genetically encoded vulnerability in malignant rhabdoid and Wilms tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1810.