mTOR inhibition has anti-metastatic effects in osteosarcoma

mTOR inhibition has anti-metastatic effects in osteosarcoma:

Purpose: To successfully metastasize, tumor cells must respond appropriately to biological stressors encountered during metastatic progression. We sought to test the hypothesis that enhanced efficiency of mRNA translation during periods of metastatic stress is required for metastatic competence of osteosarcoma and that this metastasis-specific adaptation is amenable to therapeutic intervention. Experimental Design: We employ novel reporter and proteomic systems that enable tracking of mRNA translation efficiency and output in metastatic osteosarcoma cells as they colonize the lungs. We test the potential to target mRNA translation as an anti-metastatic therapeutic strategy through pharmacokinetic studies and pre-clinical assessment of the prototypic mTOR inhibitor, rapamycin, across multiple models of metastasis. Results: Metastatic osteosarcoma cells translate mRNA more efficiently than non-metastatic cells during critical stressful periods of metastatic colonization of the lung. Rapamycin inhibits translational output during periods of metastatic stress, mitigates lung colonization, and prolongs survival. mTOR-inhibiting exposures of rapamycin are achievable in mice using treatment schedules that correspond to human doses well below the maximum tolerated doses defined in human patients, and as such are very likely to be tolerated over long exposures alone and in combination with other agents. Conclusions: Metastatic competence of osteosarcoma cells is dependent on efficient mRNA translation during stressful periods of metastatic progression and the mTOR inhibitor, rapamycin, can mitigate this translation and inhibit metastasis in vivo. Our data suggest that mTOR pathway inhibitors should be reconsidered in the clinic using rationally designed dosing schedules and clinical metrics related to metastatic progression.



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