mln-8237 and Prostatic-Neoplasms--Castration-Resistant

Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may develop. Sixty men were treated with alisertib 50 mg twice daily for 7 days every 21 days. Eligibility included metastatic prostate cancer and at least one: small-cell neuroendocrine morphology; ≥50% neuroendocrine marker expression; new liver metastases without PSA progression; or elevated serum neuroendocrine markers. The primary endpoint was 6-month radiographic progression-free survival (rPFS). Pretreatment biopsies were evaluated by whole exome and RNA-seq and patient-derived organoids were developed.. Median PSA was 1.13 ng/mL (0.01-514.2), number of prior therapies was 3, and 68% had visceral metastases. Genomic alterations involved. Although the study did not meet its primary endpoint, a subset of patients with advanced prostate cancer and molecular features supporting Aurora-A and N-myc activation achieved significant clinical benefit from single-agent alisertib.

Topics: Aged; Aged, 80 and over; Aurora Kinase A; Azepines; Carcinoma, Neuroendocrine; Disease Progression; Humans; Male; Middle Aged; N-Myc Proto-Oncogene Protein; Orchiectomy; Prostate; Prostatic Neoplasms, Castration-Resistant; Pyrimidines; Receptors, Androgen; Signal Transduction

Patients with metastatic castration-resistant prostate cancer did not tolerate the combination of alisertib with abiraterone and prednisone.There was no clear signal indicating that adding alisertib might be beneficial for those patients progressing on abiraterone.. We hypothesized that Aurora A kinase (AK) contributes to castrate resistance in prostate cancer (PCa) and that inhibiting AK with alisertib can resensitize PCa cells to androgen receptor (AR) inhibitor abiraterone.. This was a phase I/II trial to determine the safety and efficacy of alisertib when given in combination with abiraterone plus prednisone (AP). Metastatic castration-resistant prostate cancer (mCRPC) patients were treated with dose escalation (alisertib at 30, 40, and 50 mg orally b.i.d., days 1-7 every 21 days) per standard 3+3 design.. Nine of 43 planned subjects were enrolled. The maximum tolerated dose (MTD) was not reached, and the dose-limiting toxicities (DLTs) included neutropenic fever (1 of 9), neutropenia (1 of 9), fatigue with memory impairment (1 of 9), and diarrhea/mucositis (1 of 9). No prostate-specific antigen (PSA) decrease or circulating tumor cell (CTC) changes were observed during the study. Pharmacodynamically, adding alisertib did not affect total testosterone or dehydroepiandrosterone (DHEA) levels. There was some change in neuroendocrine markers after therapy. Mean duration on study was 2.5 months. The trial was terminated early.. A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone.

Topics: Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Aurora Kinase A; Azepines; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Pyrimidines; Testosterone

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