Childhood Cancer

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IND-Enabling Studies for WNTinib, a Novel Selective Therapeutic for CTNNB1 Mutant Hepatoblastomas

Icahn School of Medicine at Mount Sinai
Ernesto Guccione, PhD & Josep Llovet, MD & Arvin Dar, PhD
Grant Type: 
Reach Grants
Year Awarded: 
Type of Childhood Cancer: 
Medulloblastoma, Wilms Tumor, Hepatoblastoma
Project Description: 

Hepatoblastoma (HB) is the most frequent pediatric form of liver cancer, generally arising in young children (<3yo). Despite being a rare tumor (1.8 in 1,000,000 children/year), HB rates are on the rise and therapeutic options are limited to chemotherapy. Chemotherapy (i.e. cisplatin) is given to patients without any consideration to a specific mutation within tumors and toxicity is significant. Here we seek to advance a novel therapeutic candidate for HB that has been optimized to selectively kill cancer cells with specific mutations, while sparing normal hepatocites. In this proposal, we plan to advance through to clinical trials, a new small molecule, that we named WNTinib. This compound has demonstrated strong activity in hepatoblastomas with a specific mutation in the CTNNB1 gene, which occurs in 70% of HB cases, suggesting potentially broad utility of this compound as a precision medicine for HB. The major goal of the grant is to test WNTinib alone or in combination with current standard of care therapies, such as cisplatin, for CTNNB1 mutant HB patients. In particular we will assess the efficacy and safety of WNTinib using preclinical models and patient derived samples. Based on the proposed preclinical experiments, we will be able to suggest stratification strategies and identify more effective tailored therapeutics for HB.


Project Goal:

The goal of this proposal is to complete preclinical studies testing a novel compound that we call WNTinib in the subset of hepatoblastoma (HB) cases harboring CTNNB1-mutations. WNTinib has been discovered by our groups as a highly promising lead compound for adult hepatocellular carcinoma (HCC), and we believe the compound could be beneficial for HB as well based on our preliminary experiments. In order to advance towards a clinical trial, we seek to conduct additional safety and efficacy studies in various models of HB. Our long-term goals are to devise a strategy to select the subset of children with HB that would most benefit from WNTinib treatment. We believe that these cases, and possibly other CTNNB1-mutant child tumors such as Medulloblastoma and Wilms tumor, would benefit from targeted therapies matched to the genetics of tumors. Pending the results of our proposed studies, we plan to start a clinical trial with WNTinib for children with CTNNB1-mutant tumors.