Abstract LB360: Targeted degradation of p300 and CBP via antibody-drug conjugate in prostate cancer cells
Abstract
p300 and CBP contribute to Androgen Receptor (AR) driven transcriptional programs that support castration-resistant prostate cancer, and their elevated expression has been associated with aggressive disease. p300 and CBP, paralog histone acetyltransferases (HATs), function as co-activators to transcription factors including AR and c-Myc. These enzymes play an essential role in regulating cell growth by acetylating substrates such as AR and histone residues including Histone-3-Lysine 27 (H3K27). Targeting p300 and CBP is an emerging therapeutic strategy in prostate cancer, particularly in disease settings where AR transcriptional activity mediates resistance to current standard of care. Preclinical studies have shown p300 and CBP inhibitor efficacy in metastatic castration-resistant prostate cancer (mCRPC) models. Unfortunately, clinical evaluation of p300 and CBP inhibitors has identified hematologic toxicities including neutropenia, thrombocytopenia, and anemia. These effects are thought to result from disruption of chromatin remodeling and transcriptional programs that are essential for platelet production, red blood cell (RBC) formation and immune cell development. Intermittent dosing schedules, designed to circumvent thrombocytopenia, demonstrate sub-optimal anti-tumor activity due to reduced drug exposure in plasma. In our studies, we demonstrate the use of ADCs to target antigens expressed on prostate cancer cell lines, facilitating the delivery of payloads that…
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