Grants and Contracts Details


Metastatic colorectal cancer (CRC) is difficult to treat and patients have few long term effective therapeutic options. The aggressiveness of this disease is in part driven by the aberrant expression of oncoproteins. At the molecular level, translation of the precursor oncogenic mRNAs is frequently activated. Our recent work have demonstrated that deregulation of cap-dependent translation downstream of mTOR at the level of 4E-BP1/eIF4E plays a critical role in tumor formation and metastatic progression as well as in altering the therapeutic response to mTOR inhibitors in CRC. As an extension of our published studies, using polysome-bound mRNA analysis, we unexpectedly found in CRC cells that inhibition of cap-dependent translation by dephosphorylated 4E-BP1 using mTOR kinase inhibitors induced active translation and protein expression of PD-L1, an immune checkpoint protein known to inhibit the function of T cells through binding to their PD-1 receptors. Luciferase reporter-based analysis of 5’-untranslated region of PD-L1 mRNA identified PD-L1 containing an internal ribosome entry site (IRES) element to drive its translation in a cap-independent manner. Inhibition of eIF4A, a translation apparatus required for both cap-dependent and -independent translation, profoundly downregulated PD-L1 protein expression. Our overarching hypothesis is that the deregulated IRES-mediated PD-L1 translation reduces the efficacy of mTOR inhibitors by restriction of T cell anti-CRC immunity. In this application, we aim to elucidate the molecular mechanisms underlying translational activation of PD-L1 by mTOR inhibition, and explore a therapeutic strategy by co-targeting PD-1 and mTOR for enhancing CRC therapy. Specifically, in Aim 1, we will identify and characterize key molecular regulators of IRES-dependent translation and protein synthesis of PDL1 upon mTOR inhibition. In Aim 2, we will determine the effectiveness of PD-1 and mTOR inhibitors alone and in combination to suppress tumor growth and metastasis using both immunocompetent syngeneic mouse orhotopic CRC model and humanized mouse patient-derived xenograft (PDX) CRC model. Cumulatively, the proposed studies will provide novel insights into the biology and clinical relevance of PD-L1 in translational control of CRC progression, and help guide the deployment of new translatable treatment regimens to enhance benefit for patients with advanced CRC and potentially other major cancers.
Effective start/end date7/9/184/8/19


  • National Cancer Institute


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