Dual Blockade of IGF1R and MEK synergistically inhibits pediatric cancers

Division Of Basic Sciences - Nci

Investigators

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Abstract

In collaboration with LASP, we conducted an in vivo study of trametinib and ganitumab in mouse xenograft models of Ras-mutated rhabdomyosarcoma. We have found that the combination of trametinib and ganitumab provided a survival advantage compared to either agent alone, and also compared to a standard of care chemotherapeutic, vincristine. We also identified that this combination provided the expected pharmacodynamic effects within the tumors, i.e. ERK phosphorylation and IGF1R expression was decreased in tumors that were treated with the combination of trametinib and ganitumab as compared to controls. We also identified that the human Ras-mutated rhabdomyosarcoma cell line, SMS-CTR, is an exceptional responder to the combination of trametinib and ganitumab. In an effort to identify the reason why SMS-CTR responds so well to this combination, we showed that of the Ras-mutated rhabdomyosarcoma cell lines, SMS-CTR has the highest expression of IGF1R. We aimed to identify mechanisms of co-targeting the RAS-RAF-MEK-ERK pathways and the IGF1R-IRS1/2-PI3K-AKT-mTOR pathways that would be effective in cell lines that do not have high IGF1R expression, including monoclonal antibodies specific for the ligand of IGF1R, IGF1/2, and an inhibitor of IRS1/2. This work is currently ongoing. Importantly, we have also tested the combination of trametinib and ganitumab in several PDX models of RAS-mutated RMS. We show efficacy of the combination in cell line xenograft and PDX models driven by both NRAS and HRAS. The models with relative intrinsic resistance to the combination are models that also have an alteration in genes of the PI3 kinase pathway, either PIK3CA mutation or loss of expression of PTEN. Importantly, knockdown of PTEN expression in SMS-CTR cells confers resistance to trametinib. Current work is aimed at better understanding the effectors downstream of PI3 kinase that might mediate this resistance. We were in discussions with CTEP and the Children's oncology group regarding the initiation of a phase I/II clinical trial of trametinib and ganitumab in pediatric patients. We were also in discussions with ImmunityBio regarding an investigator-initiated single institution trial. Unfortunately, ganitumab is no longer available for new clinical trials. We are now in discussions with BI regarding xentuzumab, a monoclonal antibody specific for IGF1/2. We will perform preclinical studies of xentuzumab in combination with trametinib prior to clinically translating this combination. In order to facilitate the clinical translation of this combination, we are evaluating the efficacy of trametinib/ganitumab in other disease histologies. We have shown efficacy of trametinib/ganitumab in two cell line xenografts of RAS-mutated neuroblastoma, and are continuing to evaluate the combination in neuroblastoma models driven by alterations in the MAPK pathway that are not RAS itself, as well as in MPNST, driven by alterations in NF1 or BRAF. In the course of the animal study of the trametinib and ganitumab combination, we created an SMS-CTR cell line that is resistant to trametinib. We are currently in the process of identifying the mechanism of resistance to trametinib in this cell line. Whole exome sequencing and whole transcriptome sequencing did not reveal a new SNV or fusion responsible for the resistance. However. gene expression and phosphoproteomic analysis has revealed that these cells upregulate RTKs to activate the PI3K/AKT pathway. This is a novel finding, as most RAS-mutated cells upregulate RTKs to re-activate the MAPK pathway in a SHP2/SOS1 dependent manner, and could explain the lack of efficacy of SHP2 inhibitors in FN-RMS. Our current work is aimed at vaildating these results.