The presence and clinical implication of intraductal carcinoma of prostate in metastatic castration resistant prostate cancer.

BACKGROUND: Intraductal carcinoma of prostate (IDC-P) is always underestimated pathological pattern in prostate cancer and its role is still unclear in castration resistant prostate cancer (CRPC). This study was conducted to investigate the presence and the roles of IDC-P in patients with metastatic CRPC. METHODS: 45 patients with initially diagnosed metastatic prostate cancer and then progressed to CRPC, were included. All of them were received twice transperineal biopsies at the time of initial diagnosis and the time of CRPC. All samples were retrieved to detect the presence of IDC-P. PSA doubling time (PSADT) was considered as a parameter presenting the progression of CRPC. The relationships between IDC-P and other clinicopathological variables were analyzed. RESULTS: IDC-P was found only in 20% (9/45) cases at initial diagnosis, whereas, it increased to 62.5% (28/45) at the time of CRPC (χ(2) = 16.568, P = 0.000). Compared to acinar adenocarcinoma components in tumor tissues, IDC-P components, especially solid subtype, had obviously poor/no response to androgen deprivation therapy (ADT). In addition, among patients treated with docetaxel-based chemotherapy (n = 24), patients with IDC-P also showed more unfavorable response than those without IDC-P (20% vs. 66.7%, P = 0.022). The presence of IDC-P and serum testosterone at the time of CRPC, were significantly associated with rapid disease progression. 13/28 (46.4%) CRPC with IDC-P had PSADT less than 30 days, while, only 1/17 (5.9%) patient without IDC-P had a less than 30 days PSADT (χ(2) = 8.114, P = 0.004). Limitations included the relative short follow-up time and a relative small cohort. CONCLUSIONS: The presence of IDC-P was significantly associated with rapid progression of CRPC. And its presence could suggest the poor response to initial ADT and sequential docetaxel-based chemotherapy. Detection of IDC-P should be of importance in CRPC, and re-biopsy at the time of CRPC might be one of practical solutions. The mechanism of the ADT and docetaxel resistance to IDC-P needed to be further investigated.

PIM protein kinases regulate the level of the long noncoding RNA H19 to control stem cell gene transcription and modulate tumor growth.

The proviral integration site for Moloney murine leukemia virus (PIM) serine/threonine kinases have an oncogenic and prosurvival role in hematological and solid cancers. However, the mechanism by which these kinases drive tumor growth has not been completely elucidated. To determine the genes controlled by these protein kinases, we carried out a microarray analysis in T-cell acute lymphoblastic leukemia (T-ALL) comparing early progenitor (ETP-ALL) cell lines whose growth is driven by PIM kinases to more mature T-ALL cells that have low PIM levels. This analysis demonstrated that the long noncoding RNA (lncRNA) H19 was associated with increased PIM levels in ETP-ALL. Overexpression or knockdown of PIM in these T-ALL cell lines controlled the level of H19 and regulated the methylation of the H19 promoter, suggesting a mechanism by which PIM controls H19 transcription. In these T-ALL cells, the expression of PIM1 induced stem cell gene expression (SOX2, OCT-4, and NANOG) through H19. Identical results were found in prostate cancer (PCa) cell lines where PIM kinases drive cancer growth, and both H19 and stem cell gene levels. Small molecule pan-PIM inhibitors (PIM-i) currently in clinical trials reduced H19 expression in both of these tumor types. Importantly, the knockdown of H19 blocked the ability of PIM to induce stem cell genes in T-ALL cells, suggesting a novel signal transduction cascade. In PCa, increases in SOX2 levels have been shown to cause both resistance to the androgen deprivation therapy (ADT) and the induction of neuroendocrine PCa, a highly metastatic form of this disease. Treatment of PCa cells with a small molecule pan-PIM-i reduced stem cell gene transcription and enhanced ADT, while overexpression of H19 suppressed the ability of pan-PIM-i to regulate hormone blockade. Together, these results demonstrate that the PIM kinases control the level of lncRNA H19, which in turn modifies stem cell gene transcription regulating tumor growth.

Precision medicine applications in prostate cancer.

Aided by developments in diagnostics and therapeutics, healthcare is increasingly moving toward precision medicine, in which treatment is customized to each individual. We discuss the relevance of precision medicine in prostate cancer, including gene targets, therapeutics and resistance mechanisms. We foresee precision medicine becoming an integral component of prostate cancer management to increase response to therapy and prolong survival.