TPS5602 Background: Metnase is a recently characterized DNA repair component present in anthropoid primates. Metnase, the fusion of a SET histone methylase domain and a Transposase nuclease (Tn) domain, enhances DNA double-stranded break (DSB) repair. The Tn domain trims free DNA ends for optimal end-joining, and is required to re-start stalled replication forks. The SET domain di-methylates H3K36 at the DSB, recruiting non-homologous end-joining repair components. Cisplatin (CDDP), the central chemotherapy in HNSCC, covalently binds DNA leading to intra- and interstrand crosslinks (ICL). In addition to blocking strand transcription and segregation, the ICL stalls DNA replication fork progression leading to collapse and DSB. The role of Metnase in DNA repair, including overcoming the stalled replication fork, makes it a potential therapeutic target. We hypothesize that Metnase inhibition may be a useful adjunct to CDDP. 3D modeling of the Metnase Tn domain identified significant homology with human immunodeficiency virus 1 (HIV-1) integrase. A virtual screen of the Chem Div library identified the HIV-1 integrase inhibitor, raltegravir, as a lead compound for inhibiting the Metnase Tn domain. We designed a pilot study in HNSCC to evaluate potentiation of CDDP DNA damage by raltegravir. Methods: The primary objective of this window-of-opportunity study is to analyze biomarkers of DNA damage, fork arrest, and apoptosis in serial tumor biopsies from patients (pts) with HNSCC undergoing CDDP, with and without raltegravir. Eligible pts: 1) have HNSCC with tumor site amenable to repeat, awake biopsy; 2) are appropriate candidates for CDDP. Pts are treated with 2 doses of CDDP 30 mg/m2. One CDDP dose is administered with raltegravir 400 mg bid for 5 days, starting the day before CDDP. Pts undergo 3 research biopsies, at baseline and 48-72 hours after each CDDP. Serial biopsies will be evaluated for expression changes in γH2AX, Annexin V, pChk1, pChk2, and p53BP1 by immunohistochemistry. Numerical increase in biomarker expression in tumors exposed to CDDP-raltegravir vs. CDDP will justify development of a phase I/II study. Four of 12 pts have enrolled and completed all biopsies. Supported by a grant from the American Cancer Society.