Combined bromodomain and CDK4/6 inhibition in NUT Carcinoma and other solid tumors

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Project Summary NUT Carcinoma (NC) is an undifferentiated or poorly differentiated squamous cell carcinoma that typically affects the midline structures, including the head, neck, and thoracic areas. NC occurs predominantly in adolescents and young adults of both sexes, a vulnerable and under-recognized cancer population. It is among the most aggressive of all solid malignancies, with most patients having locally advanced or metastatic disease at diagnosis. NC is characterized by the presence of a NUT fusion oncogene (also known as NUTM1), the most common of which is BRD4-NUT. The chimeric genes encode BRD-NUT fusion proteins which retain BRD- encoded bromodomains that bind acetylated histones and recruit chromatin-remodeling complexes. Mechanistically, BRD-NUT fusion proteins appear to exert their pro-tumorigenic effect by blocking differentiation, possibly through sequestering histone acetyltransferase activity. MYC, an oncogene that encodes a transcription factor that plays a central role in tumor initiation and maintenance, has been identified as a key downstream target of BRD4-NUT. BRD4-NUT has been associated with the MYC promoter and is required to maintain MYC expression in NC cell lines. There is no FDA approved therapy or established treatment regimen for NC. Cytotoxic chemotherapy regimens are used for first-line systemic therapy, and subsequent-line treatment remains an area of high unmet need. Several BET inhibitors have been in development as monotherapies for the treatment of both hematologic and solid tumors, and have shown limited clinical activity in NUT carcinoma. More effective strategies are needed and combinations of BET inhibitors with other therapies represent an intuitive next step. Recently, combined BET and CDK4/6 inhibition demonstrated strong synergism in preclinical models of NUT Carcinoma. We are conducting a combination treatment strategy using the BET inhibitor ZEN003694 with the CDK4/6 inhibitor abemaciclib in patients with NC and other solid tumors through the NCI Cancer Therapy Evaluation Program (CTEP) (Protocol #10509). Tumor tissue research biopsies will be obtained, if safely accessible, at baseline, on-treatment, and at progression to characterize changes in cell cycle and proliferation markers, and to explore potential biomarkers of response and resistance to treatment. These include but are not limited to Ki-67, MYC expression, annexin V (apoptosis detection), whole exome sequencing (WES), chromatin analysis (ATAC sequencing) and histone marks profiling (H3K27ac CHIP-seq). Peripheral blood samples will be collected at baseline, during treatment, and at progression to assess thymidine kinase 1 (TK1) activity. Decrease in serum TK activity has been previously described with CDK4/6 inhibition in breast cancer and may correlate with a change in tumor Ki67. If clinical benefit is observed with ZEN003694 and abemaciclib, this will support exploring the combination further in a phase 2 trial.