Deregulation of the PI3K-Akt-mTOR pathway plays a critical role in the development and progression of many cancers. In prostate cancer, evidence suggests that it is mainly driven by PTEN loss of function. For many years, the development of selective Akt inhibitors has been challenging. In recent phase II and III clinical trials, Ipatasertib and Capivasertib associated with androgen deprivation therapies showed promising outcomes in patients with metastatic castration-resistant prostate cancer and PTEN-loss. Ongoing trials are currently assessing several Akt inhibitors in prostate cancer with different combinations, at different stages of the disease.

Active surveillance (AS) in prostate cancer (PCa) represents a curative alternative for men with localised low-risk PCa. Continuous improvement of AS patient’s selection and surveillance modalities aims at reducing misclassification, simplifying modalities of surveillance and decreasing need for invasive procedures such repeated biopsies. Biomarkers represent interesting tools to evaluate PCa diagnosis and prognosis, of which many are readily available or under evaluation. The aim of this review is to investigate the biomarker performance for AS selection and patient outcome prediction. Blood, urinary and tissue biomarkers were studied and a brief description of use was proposed along with a summary of major findings. Biomarkers represent promising tools which could be part of a more tailored risk AS strategy aiming to offer personalized medicine and to individualize the treatment and monitoring of each patient. The usefulness of biomarkers has mainly been suggested for AS selection, whereas few studies have investigated their role during the monitoring phase. Randomized prospective studies dealing with imaging are needed as well as larger prospective studies with long-term follow-up and strong oncologic endpoints.

Background: Iodine seed implant brachytherapy is indicated for low risk and selected favorable intermediate risk prostate cancers. A percentage of positive biopsies > 50% is usually considered as a contra-indication, and the tumor location could also influence the treatment efficacy. We studied the association of the percentage of positive biopsy cores, and tumor location, with progression-free survival. Methods: Among the 382 patients treated at our center by permanent implant iodine seed brachytherapy for a localized prostate cancer between 2006 and 2013, 282 had accessible detailed pathology reports, a minimum follow-up of 6 months, and were included. Progression was defined as a biochemical, local, nodal, or distant metastatic relapse. We studied cancer location on biopsies (base, midgland or apex of the prostate) and percentage of positive biopsy cores, as well as potential confounders (pre-treatment PSA, tumor stage, Gleason score, risk group according to D’Amico’s classification modified by Zumsteg, adjunction of androgen deprivation therapy, and dosimetric data). Results: Most patients (197; 69.9%) had a low risk, 67 (23.8%) a favorable intermediate risk, 16 (5.7%) an unfavorable intermediate risk, and 1 (0.3%) a high-risk prostate cancer. An involvement of the apex was found for 131 patients (46,5%), of the midgland for 149 (52,8%), and of the base for 145 (51,4%). The median percentage of positive biopsy cores was 17% [3–75%]. The median follow-up was 64 months [12–140]. Twenty patients (7%) progressed: 4 progressions (20%) were biochemical only, 7 (35%) were prostatic or seminal, 6 (30%) were nodal, and 3 (15%) were metastatic. The median time to failure was 39.5 months [9–108]. There were more Gleason scores ≥7 among patients who progressed (40% vs 19%; p = 0.042). None of the studied covariates (including tumor location, and percentage of positive biopsy cores), were significantly associated with progression-free survival. The risk group showed a trend towards an association (p = 0.055). Conclusions: Brachytherapy is an efficient treatment (5-year control rate of 93%) for patients carefully selected with classical criteria. The percentage and location of positive biopsies were not significantly associated with progression-free survival. A Gleason score ≥ 7 was more frequent in case of progression.

Background: The molecular and cellular mechanisms that drive castration-resistant prostate cancer (CRPC) remain poorly understood. LSC^med cells defines an FACS-enriched population of castration-tolerant luminal progenitor cells that has been proposed to promote tumorigenesis and CRPC in Pten-deficient mice. The goals of this study were to assess the relevance of LSC^med cells through the analysis of their molecular proximity with luminal progenitor-like cell clusters identified by single-cell (sc)RNA-seq analyses of mouse and human prostates, and to investigate their regulation by in silico-predicted growth factors present in the prostatic microenvironment. Methods: Several bioinformatic pipelines were used for pan-transcriptomic analyses. LSC^med cells isolated by cell sorting from healthy and malignant mouse prostates were characterized using RT-qPCR, immunofluorescence and organoid assays. Results: LSC^med cells match (i) mouse luminal progenitor cell clusters identified in scRNA-seq analyses for which we provide a common 15-gene signature including the previously identified LSC^med marker Krt4, and (ii) Club/Hillock cells of the human prostate. This transcriptional overlap was maintained in cancer contexts. EGFR/ERBB4, IGF-1R and MET pathways were identified as autocrine/paracrine regulators of progenitor, proliferation and differentiation properties of LSC^med cells. The functional redundancy of these signaling pathways allows them to bypass the effect of receptor-targeted pharmacological inhibitors. Conclusions: Based on transcriptomic profile and pharmacological resistance to monotherapies that failed in CRPC patients, this study supports LSC^med cells as a relevant model to investigate the role of castration-tolerant progenitor cells in human prostate cancer progression.