A two-pronged “senolytic” approach to treatment of oral cavity cancer

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ABSTRACT Standard therapies (surgery, radiation, and cisplatin) for oral cavity squamous cell carcinoma (OCSCC) have not changed for decades, and no molecularly targeted agents have an established role as first-line treatment. Unlike HPV-positive oropharynx cancer, which has an excellent prognosis, advanced OCSCC (which is predominantly HPV-negative) carries a high recurrence rate (~20-30%) and poor overall survival (~50% at 5 years). The biology of OCSCC is well described. Loss of p16INK4A (p16) function is the driving defect in cell cycle regulation. p16 inhibits cyclin-dependent kinases 4 and 6 (CDK4/6), which leads to cell cycle arrest in G1. The FDA-approved cancer therapeutic, palbociclib, is a small molecule inhibitor that targets CDK4/6. Our preliminary work shows that palbociclib consistently induces senescence in OCSCC cells. We have also shown that these cells consistently upregulate the pro-survival molecule, BCL-xL, in response to palbociclib. There has been growing interest in targeting senescent cells in cancer. Though senescent cells do not proliferate, they have been shown to produce inflammatory signals that promote and support neighboring cancer cells in the tumor micorenvironment. There has been growing interest in agents that specifically target senescent cells (‘senolytics’). Perhaps the most well- studied senolytic, ABT-263 (navitoclax), targets BCL2 family pro-survival anti-apoptotic signaling molecules, BCL2, BCL-xL, and BCL-w. Our preliminary work has shown that combining palbociclib (inducing senescence) with navitoclax (senolytic) results in profound apoptosis in OCSCC cells. In this proposal, we aim to study the palbociclib/navitoclax combination extensively in OCSCC. In Specific Aim #1, we will study the response to palbociclib in a panel of OCSCC cell lines, and concurrently in a ‘cell reprogramming’ model, which allows perpetual culture of primary OCSCC tumor cells derived from patients treated at our own institution. We will specifically measure the senescence response (Specific Aim#1a) and apoptosis signaling using a high throughput method called ‘BH3’ profiling (Specific Aim1b). In Specific Aim#2 we will measure synergy between palbociclib and ABT-263 (navitoclax) using cell viability assays, and evaluate in vivo efficacy using an orthotopic tongue xenograft model of OCSCC.