Abstract 4487: Effective anti-tumor effect in a rare metastatic Wilms tumor xenograft by inhibition of RAS/PI3K hyperactivation

Wilms Tumor (WT) is an embryonal renal tumor that accounts for more than 90% of kidney tumors in children. Significant advances in multidisciplinary therapeutic approaches have increased survival rates up to 90%. However, approximately 15% of patients with favorable histology and 50% of patients with anaplastic WT experience recurrence of disease. Thus, there is still a critical need to develop therapies that are effective and safe for these patients with progressive disease. To address this, we have developed a pipeline of patient derived xenograft (PDX) models from single academic institution patients with metastatic and aggressive cancers. Among these we have developed 3 xenograft models derived from patients with WT. To gain a detailed understanding of the complex array of mutations and identify therapeutic targets, molecular signatures were obtained at the DNA and protein levels via whole genome sequencing and reverse phase protein array analyses respectively. While PDX derived from encapsulated WT specimens exhibited basal levels of PI3K and MAPK pathway activation, which are well-known for promoting tumor survival, growth, and metastasis, no mutations that drive hyperactivation of these pathways were identified in these PDX. In contrast, a rare WT xenograft (PDX120) was established from a female patient with recurrent disease and metastatic cancer in the liver. -OMICS data indicated hyperactivation of PI3K (PIK3CA p.H1047R) and MAPK (KRAS p.G12_G10ins) which was validated by qPCR and immunoblotting in original tumor sample and serially passaged PDX120 xenografts. -OMICS data also confirmed the fidelity of the molecular signature between the original tumor sample and the serially passaged PDX120. The metastatic WT model was screened with two FDA approved drugs as single agents: Trametinib (MAPK pathway inhibitor; BID M-F 1mg/kg PO Day 1-35) or Alpelisib (PI3K pathway inhibitor; QD M-F 50mg/kg PO: Mice were dosed Day 1-29, followed by a gap period, and then dosing re-initiated, Day 86-103). Trametinib therapy did not effectively attenuate PDX120 tumor growth. In contrast, the PI3K inhibitor Alpelisib was well tolerated and significantly decreased PDX120 growth and prolonged survival compared to the vehicle control (Two-way ANOVA, Holm-Sidak, p<0.05). At the end of the study, histological analyses indicated a complete lack of Ki67+ and tumorigenic cells in the Alpelisb-treated tumors compared to vehicle controls, indicating a dominant growth dependency on PI3K pathway activation. While efficacy data generated in PDX derived from patients is not used to guide clinical decisions at this time, it can validate therapeutic approaches and provide rationale for future clinical trials. In conclusion, these studies provide critical feasibility data that has high translational value and great potential to improve survival and quality of life for children suffering with progressive WT. Citation Format: Mohammad Reza Saadatzadeh, Khadijeh Bijangi Vishehsaraei, Erika A. Dobrota, Barbara J. Bailey, Lauren E. Hein, Kathryn L. Coy, Melissa A. Trowbridge, Anthony L. Sinn, Troy A. Markel, Michael J. Ferguson, Pankita H. Pandya, Karen E. Pollok. Effective anti-tumor effect in a rare metastatic Wilms tumor xenograft by inhibition of RAS/PI3K hyperactivation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4487.