Secondary OSCC Chemoprevention via Multiple Agents

Abstract. Over 1/3 of patients who have undergone oral squamous cell carcinoma (OSCC) surgical resections develop life-threatening and often untreatable recurrences. A variety of drugs, intended for management of recurrent or disseminated cancers, were designed to exploit cancer cells' reliance upon overexpressed receptors and gratuitous signaling. Despite their conceptual promise, clinical trials showed these agents lacked efficacy and were often toxic. These findings are consistent with evasion of pathway-targeted treatments via extensive signaling redundancies and compensatory mechanisms common to cancers. Optimal secondary OSCC chemoprevention requires long term efficacy with multifaceted, nontoxic agents. Accordingly, this study evaluated the abilities of three complementary chemopreventives i.e. the vitamin A derivative fenretinide (4-HPR, induces apoptosis and differentiation, inhibits signaling proteins and invasion), the estrogen metabolite 2-methoxyestradiol (2-ME, apoptosis-inducing, antiangiogenic) and the humanized monoclonal antibody to the IL-6R receptor tocilizumab (TOC, reduces IL-6 signaling) to suppress OSCC gratuitous signaling and tumorigenesis. Modeling studies demonstrated 4-HPR's high affinity binding at STAT3's dimerization site and c-Abl and c-Src ATP-binding kinase sites. Although individual agents suppressed cancer-promoting pathways including STAT3 phosphorylation, STAT3-DNA binding, and production of the trans-signaling enabling sIL-6R, maximal chemopreventive effects were observed with agent combinations. OSCC tumor xenograft studies showed that locally-delivered TOC, TOC+4-HPR and TOC+4-HPR+2-ME treatments all prevented significant tumor growth. Notably, the TOC+4-HPR+2-ME treatment resulted in the smallest overall increase in tumor volume. The selected agents employ diverse mechanisms to disrupt tumorigenesis at multiple venues i.e. intracellular, tumor cell-ECM and tumor microenvironment; beneficial qualities for secondary chemopreventives.

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