Oncology Abstracts

NEPC is a lethal subtype of PCa frequently arising from adenocarcinoma via NE transdifferentiation following ADT. In AACR-PCF West Dream Team series of sequential biopsies of over 300 CRPC biopsies, NEPC was discovered in 17% of cases, making neuroendocrine transdifferentiation one of the most common mechanisms underlying ADT resistance. However, a mechanistic understanding of both NEPC development and its aggressiveness remain elusive. Research in this field has been hampered by a lack of relevant preclinical cancer models. We have developed a panel of unique, clinically-relevant PCa PDX models, including the first-in-field PDX model of complete transdifferentiation of prostatic adenocarcinoma (LTL331) to NEPC (LTL331R). Using transcriptomic analyses in these models, we have identified a heterochromatin gene signature in NEPC. Longitudinal analysis of the LTL331/331R model revealed that among those heterochromatin-related genes, HP1α expression is increased early, rises steadily during NEPC development, and remains elevated in fully developed NEPC. Its elevated expression is further confirmed in clinical NEPC samples. HP1α knockdown dramatically inhibits NEPC cell proliferation, completely ablates colony formation, and induces apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promotes NE transdifferentiation in adenocarcinoma cells. Mechanistically, HP1α reduces expression of AR and REST, two crucial transcription factors silenced in NEPC, by enriching the repressive histone mark H3K9me3 on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a novel therapeutic target in NEPC. Subsequently, we have developed small molecule inhibitors (SMIs) of HP1α using an in silico drug discovery pipeline. This SMI series is actively under preclinical development. Significance: Heterochromatin proteins play a fundamental role in NEPC, illuminating new therapeutic targets for this aggressive disease, accordingly new SMIs are on the way to come.