sirolimus and Prostatic-Hyperplasia

Benign prostatic hyperplasia (BPH) is a condition that becomes more common with age and manifests itself primarily as the expansion of the prostate and surrounding tissues. However, to date, the etiology of BPH remains unclear. In this respect, we performed single-cell RNA sequencing of prostate transition zone tissues from elderly individuals with different prostate volumes to reveal their distinct tissue microenvironment. Ultimately, we demonstrated that a reduced Treg/CD4+ T-cell ratio in the large-volume prostate and a relatively activated immune microenvironment were present, characterized partially by increased expression levels of granzymes, which may promote vascular growth and profibrotic processes and further exacerbate BPH progression. Consistently, we observed that the prostate gland of patients taking immunosuppressive drugs usually remained at a smaller volume. Furthermore, in mouse models, we confirmed that both suppression of the immune system with rapamycin and induction of Treg proliferation with low doses of IL-2 therapy indeed prevented the progression of BPH. Taken together, our findings suggest that an activated immune microenvironment is necessary for prostate volume growth and that Tregs can reverse this immune activation state, thereby inhibiting the progression of BPH.

Topics: Animals; Disease Models, Animal; Humans; Interleukin-2; Male; Mice; Prostate; Prostatic Hyperplasia; Sirolimus

Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is among the most common diseases affecting aging men, but the underlying molecular features remain poorly understood, and therapeutic options are limited. Here we employ a comprehensive molecular investigation of BPH, including genomic, transcriptomic and epigenetic profiling. We find no evidence of neoplastic features in BPH: no evidence of driver genomic alterations, including low coding mutation rates, mutational signatures consistent with aging tissues, minimal copy number alterations, and no genomic rearrangements. At the epigenetic level, global hypermethylation is the dominant process. Integrating transcriptional and methylation signatures identifies two BPH subgroups with distinct clinical features and signaling pathways, validated in two independent cohorts. Finally, mTOR inhibitors emerge as a potential subtype-specific therapeutic option, and men exposed to mTOR inhibitors show a significant decrease in prostate size. We conclude that BPH consists of distinct molecular subgroups, with potential for subtype-specific precision therapy.

Topics: Adult; Aged; Aged, 80 and over; Aging; Biomarkers; DNA Methylation; Epigenesis, Genetic; Epigenomics; Genomics; Humans; Male; Middle Aged; Mutation Rate; Organ Size; Precision Medicine; Prospective Studies; Prostate; Prostatic Hyperplasia; RNA-Seq; Signal Transduction; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Treatment Outcome; Urological Agents; Whole Genome Sequencing

Benign prostatic hyperplasia (BPH) is the most common age-related disease in men. Here we tested the efficacy of Rapatar, a micellar nanoformulation of rapamycin, in two rat models of BPH: testosterone-induced and sulpiride-induced hyperplasia in ventral lobes and lateral/dorsal lobes, respectively. We found that Rapatar prevented hypertrophic and hyperplastic abnormalities and degenerative alterations in both BPH models. Rapatar normalized weight of the lateral lobes in sulpiride-induced BPH, the most relevant animal model of human BPH. Unlike Finasteride, a standard therapy of BPH, Rapatar reduced inflammation caused by sulpiride. No obvious side effects of Rapatar were detected. Our data provide a rationale for clinical trials of Rapatar in patients suffering from BPH.

Topics: Aging; Animals; Antibiotics, Antineoplastic; Disease Models, Animal; Drug Administration Schedule; Finasteride; Male; Nanomedicine; Prostate; Prostatic Hyperplasia; Rats; Rats, Wistar; Sirolimus; Sulpiride; Testosterone; TOR Serine-Threonine Kinases

To evaluate the activation level of the mammalian target of rapamycin (mTOR) signalling pathway in Chinese patients with prostate cancer, as this pathway is over-activated in many human cancers and is an attractive target for cancer therapy.. We used immunohistochemistry to investigate the activation level of five important markers of the mTOR pathway, including PTEN, p-Akt, p-mTOR, p-p70S6K and p-4E-BP1, in tissues from 182 patients with prostate cancer, 20 with benign prostatic hyperplasia (BPH) and 10 with high-grade prostatic intraepithelial neoplasia (HGPIN). The expression levels of these five markers were associated with patient clinical and pathological characteristics.. Expression levels of p-Akt, p-mTOR, p-4E-BP1 and p-p70S6K were significantly higher in prostate cancer tissues than in BPH and HGPIN tissues. In 182 patients with prostate cancer the p-mTOR expression level significantly and positively correlated with its upstream p-Akt and downstream p-4E-BP1 and p-p70S6K expression levels. The cancer Gleason score was significantly correlated with p-Akt and p-mTOR expression level but not with p-4E-BP1 and p-p70S6K expression level. However, the p-4E-BP1 and p-p70S6K expression levels in primary cancer lesions were statistically significantly correlated with patient T stage and distant metastases.. Most patients with prostate cancer have at least one component of the mTOR signalling pathway activated. The activation of the mTOR pathway might be involved in prostate cancer development and progression. The association between activation of mTOR pathway and patient clinicopathological variables suggested that not all patients are equally amenable to treatment strategies targeting the mTOR pathway.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Disease Progression; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Phosphorylation; Prostatic Hyperplasia; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

In a previous report, we showed that increased activation of Akt, a downstream effector of phosphoinositide 3-kinase (PI3K) together with decreased activation of extracellular-signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase (MAPK) family, predicted poor clinical outcome in prostate cancer (Kreisberg et al. 2004 Cancer Research 64 5232-5236). We now show that Akt activation, but not ERK activation, is correlated with proliferation in human prostate tumors as estimated by the expression of the cell proliferation antigen Ki67. We verified these results in vitro, using the androgen-dependent prostate cancer cell line LNCaP and its androgen-independent clone C4-2 as models of prostate cancer of good and poor clinical outcome, respectively. C4-2 cells expressed higher Akt activation, lower ERK activation and increased proliferation compared with LNCaP cells, similar to cases of poor clinical outcome. The PI3K inhibitor LY294002, but not the MAPK/ERK kinase inhibitor PD98059, induced growth arrest in both cell lines. Transient transfection with constitutively active Akt increased proliferation while dominant negative Akt decreased it, thus showing that Akt plays an important role in prostate cancer proliferation. Akt regulates the expression and activation of the androgen receptor. Androgen receptor inhibition with Casodex induced growth arrest in LNCaP cells, but not in C4-2 cells. Another PI3K downstream effector, p70 S6 kinase, requires prior phosphorylation by mammalian target of rapamycin (mTOR) for complete activation. Activation of p70 S6 kinase was higher in C4-2 compared with LNCaP cells. Rapamycin, an mTOR inhibitor, had a growth-inhibitory effect in C4-2 cells, but not in LNCaP cells. Our data suggest a shift from a Casodex-sensitive proliferation pathway in LNCaP cells to a rapamycin-sensitive pathway in C4-2 cells.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Androgens; Anilides; Antibiotics, Antineoplastic; Cell Proliferation; Enzyme Inhibitors; Humans; Ki-67 Antigen; Male; Mitogen-Activated Protein Kinases; Neoplasms, Hormone-Dependent; Nitriles; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Prostatic Hyperplasia; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Protein Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Receptors, Androgen; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tosyl Compounds; Tumor Cells, Cultured