Raushan Kurmasheva Received the CURE Childhood Cancer Award

Abstract

Atypical teratoid/rhabdoid tumors (AT/RT) of the brain and malignant rhabdoid tumors of the kidney (RTK) compose a group of highly malignant pediatric cancers known as malignant rhabdoid tumors (MRT). Both subtypes are characterized by the biallelic loss of the SMARCB1 gene (member of the human SWI/SNF complex), which is thought to function as a tumor suppressor gene, and by the complete absence of its product expression INI1 protein. The occurrence of MRT is limited to patients younger than 5 years, with more than 80% of children being under 2 years old. Further, survival at age 4 for children diagnosed before 6 months of age is less than 10% making the prognosis for infants extremely poor despite the current treatment that includes resection, chemotherapy, and radiation therapy. The rareness and aggressiveness of this tumor as well as the lack of randomized trials resulted in no defined standard of care for children with MRT. These limitations warrant urgent identification of new effective molecularly targetable therapies. In our earlier xenograft studies in the Pediatric Preclinical Testing Program (PPTP), the combination of PARP1 inhibitor talazoparib (TLZ) with the DNA alkylating agent temozolomide (TMZ) demonstrated high activity in the Ewing sarcoma panel. However, in mice and humans (Phase I/II COG clinical trial, NCT 02116777), the combination was toxic and necessitated the reduction of temozolomide dose to ~13% of the maximum tolerated dose. Our recently published in vivo testing results for the combination of PEGylated TLZ (PEG~TLZ) and TMZ in Ewing sarcoma and glioblastoma reported that PEG allows for talazoparib to be delivered to tumor cells without systemic exposure, thus allowing a reduction in overall toxicity of the combination. In the PPTP study, the MRT xenografts were not available for testing, however, we significantly extended the panel of MRTxenograft models and cell lines, and most of them have been molecularly characterized or being analyzed. Furthermore, we conducted a pilot single mouse testing of PEG~TLZ combined with TMZ in 30 pediatric tumor xenograft models, revealing the anti-tumor activity of this drug combination in the MRT panel. PEG~TLZ+TMZ combination was not previously studied in MRT, subsequently and based on our preliminary data we will investigate whether MRT response to PEG~TLZ+TMZ therapy demonstrates dependence on SMARCB1 expression by using a single mouse testing approach and utilizing orthoptic RTK and AT/RT models. We anticipate our work will generate comprehensive preclinical data and this drug combination can be moved to clinical avenue within the next several years.

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