mln-8237 and Prostatic-Neoplasms

Topics: Aurora Kinase A; Azepines; Biomarkers; Castration; Humans; Male; Prostatic Neoplasms; Pyrimidines

Neuroendocrine (NE) cancers are a diverse group of neoplasms typically diagnosed and treated on the basis of their site of origin. This Perspective focuses on advances in our understanding of the tumorigenesis and treatment of poorly differentiated neuroendocrine tumors. Recent evidence from sequencing indicates that, although neuroendocrine tumors can arise de novo, they can also develop as a result of lineage plasticity in response to pressure from targeted therapies. We discuss the shared genomic alterations of these tumors independently of their site of origin, and we explore potential therapeutic strategies on the basis of recent biological findings.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Azepines; Benzodiazepines; Carcinogenesis; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Cell Differentiation; Cell Lineage; Cell Plasticity; Colonic Neoplasms; Disease Progression; Epigenesis, Genetic; Esophageal Neoplasms; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Molecular Targeted Therapy; Neoplasms, Glandular and Epithelial; Neuroendocrine Tumors; Ovarian Neoplasms; Prostatic Neoplasms; Proto-Oncogene Proteins c-met; Proto-Oncogene Proteins c-myc; Pyrimidines; Retinoblastoma Binding Proteins; Triazoles; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases; Urinary Bladder Neoplasms; Uterine Cervical Neoplasms

MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Aurora Kinase A; Azepines; Cell Line, Tumor; Cell Transformation, Neoplastic; Enzyme Activation; Epithelial Cells; Exome; Gene Expression Regulation, Neoplastic; Genes, myc; Humans; Laser Capture Microdissection; Male; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplastic Stem Cells; Neuroendocrine Tumors; Orchiectomy; Phenylurea Compounds; Prostatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Pyrimidines; Recombinant Fusion Proteins; Transduction, Genetic; Xenograft Model Antitumor Assays

The transition from castration-resistant prostate adenocarcinoma (CRPC) to neuroendocrine prostate cancer (NEPC) has emerged as an important mechanism of treatment resistance. NEPC is associated with overexpression and gene amplification of MYCN (encoding N-Myc). N-Myc is an established oncogene in several rare pediatric tumors, but its role in prostate cancer progression is not well established. Integrating a genetically engineered mouse model and human prostate cancer transcriptome data, we show that N-Myc overexpression leads to the development of poorly differentiated, invasive prostate cancer that is molecularly similar to human NEPC. This includes an abrogation of androgen receptor signaling and induction of Polycomb Repressive Complex 2 signaling. Altogether, our data establishes N-Myc as an oncogenic driver of NEPC.

Topics: Animals; Azepines; Enhancer of Zeste Homolog 2 Protein; Genes, myc; Heterografts; Humans; Male; Mice; Mice, Transgenic; N-Myc Proto-Oncogene Protein; Neuroendocrine Tumors; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Pyrimidines; Signal Transduction; Transcription, Genetic