Rational design of combination therapies and block of acquired targeted drug resistance

H Reuveni, L Kuperschmidt, S Carmi, N Moskovitz, S Stemmer, I Haviv

Research output: Chapter in Book/Report/Conference proceedingConference contributionpeer-review


ecent successes of targeted drugs on end stage cancer patients highlight the value of mutation-based biomarkers with high positive predictive value for drug response predictions. However, the impact of these drugs is often temporary, and the patients progress to acquired resistance. A common mechanism of drug evasion involves feedback mechanisms that increase expression or phosphorylation-driven activation of an alternative oncogenic pathway. The objective of this work was to set up a streamlined methodology for pre-clinical assessment of the novel drug for refractory cancer targeting, with specific focus of personalized medicine, mediated by sequencing, and seek combination therapies that would block the spontaneous drug evasion. We explored the efficacy of the combination approach on a panel of cancer patient derived xenografts in mice, using tumor size, or metabolic imaging as an end point. Each cancer case was subject to target somatic mutation screening, which resulted in a targeted drug recommendation, and then, mouse groups were treated either with sequeincing-based therapy, or with combination of these therapies with blockers of the suspected evasion mechanisms. As a blocker of the evasion mechanism and epithelial to mesenchymal transition, we characterized the utility of a molecule that leads to the destruction of IRS1/2 of the IGF1R pathway. IRS1/2 are altered during EMT and drug resistance, thus blocking them could block drug resistance, and found multiple scenarios, where the combination of this blockage with currently used targeted drugs, such as Erlotinib, Zelboraf, and Gleevec, all increase the attenuation of the cancer growth and progression. Addition of the IRS1/2 destruction to Erlotinib and Zelboraf resistant H&N and melanoma cancers, respectively, lead to regression of the recurrent tumor mass. This combination therapy was further characterized by shRNA-negative screens, and kinome activity profiling, to assess further drug treatments that could be added, and in search for biomarkers that would identify patients likely to respond to the therapeutic combinations, We believe blocking the IGF1R in combination with drugs that inhibit the MAPK and tyrosine kinase receptor pathways may increase the progression free survival and expand the responding population within an array of cancer types, many of which are currently refractory to chemotherapy.
Original languageAmerican English
Title of host publicationAACR 106th Annual Meeting
StatePublished - 2015

Bibliographical note

Place of conference:USA


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