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Purpose: Targeted therapies that use the signaling path-characterize the function of human FKBP7 and explore its ways involved in prostate cancer are required to overcome role in cancer. We discovered that FKBP7 was upregulated chemoresistance and improve treatment outcomes for men. in human prostate cancers and its expression correlated Molecular chaperones play a key role in the regulation of with the recurrence observed in patients receiving doce-protein homeostasis and are potential targets for overcom-taxel. FKBP7 silencing showed that FKBP7 is required to ing chemoresistance. maintain the growth of chemoresistant cell lines and Experimental Design: We established 4 chemoresistant chemoresistant tumors in mice. Mass spectrometry analysis prostate cancer cell lines and used image-based high-content revealed that FKBP7 interacts with eIF4G, a component of siRNA functional screening, based on gene-expression signa-the eIF4F translation initiation complex, to mediate the ture, to explore mechanisms of chemoresistance and identify survival of chemoresistant cells. Using small-molecule new potential targets with potential roles in taxane resistance. inhibitors of eIF4A, the RNA helicase component of The functional role of a new target was assessed by in vitro and eIF4F, we were able to kill docetaxel- and cabazitaxel-in vivo silencing, and mass spectrometry analysis was used to resistant cells. identify its downstream effectors. Conclusions: Targeting FKBP7 or the eIF4G-containing Results: We identified FKBP7, a prolyl-peptidyl isomer-eIF4F translation initiation complex could be novel thera-ase overexpressed in docetaxel-resistant and in cabazitaxel-peutic strategies to eradicate taxane-resistant prostate cancer resistant prostate cancer cells. This is the first study to cells. Fil: Garrido, Marine F.. Inserm; Francia Fil: Martin, Nicolas J.-P.. Inserm; Francia Fil: Bertrand, Matthieu. Inserm; Francia Fil: Gaudin, Catherine. Institut Anti-cancer Gustave Roussy; Francia Fil: Commo, Fred Eric. Inserm; Francia Fil: Kalaany, Nassif El. Inserm; Francia Fil: Al Nakouzi, Nader. University of British Columbia; Canadá Fil: Fazli, Ladan. University of British Columbia; Canadá Fil: Nery, Elaine Del. Université Pierre et Marie Curie; Francia Fil: Camonis, Jacques. Université Pierre et Marie Curie; Francia Fil: Perez, Franck. Université Pierre et Marie Curie; Francia Fil: Lerondel, Stéphanie. Centre National de la Recherche Scientifique; Francia Fil: Le Pape, Alain. Inserm; Francia Fil: Compagno, Daniel Georges. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Gleave, Martin. University of British Columbia; Canadá Fil: Loriot, Yohann. Inserm; Francia Fil: Desaubry, Laurent. Centre National de la Recherche Scientifique; Francia Fil: Vagner, Stephan. Université Pierre et Marie Curie; Francia Fil: Fizazi, Karim. Institut Anti-cancer Gustave Roussy; Francia Fil: Chauchereau, Anne. Inserm; Francia

// Christophe Massard 1, 2, * , Marianne Oulhen 2, 3, * , Sylvestre Le Moulec 4 , Nathalie Auger 5 , Stephanie Foulon 6 , Aurelie Abou-Lovergne 1 , Fanny Billiot 2, 3 , Alexander Valent 5 , Virginie Marty 7 , Yohann Loriot 1, 2 , Karim Fizazi 1, 2 , Philippe Vielh 2, 3, 5, # , Francoise Farace 2, 3, # 1 Gustave Roussy, Universite Paris-Saclay, Department of Medicine, F-94805, Villejuif, France 2 INSERM, U981 “Identification of Molecular Predictors and New Targets for Cancer Treatment”, F-94805, Villejuif, France 3 Gustave Roussy, Universite Paris-Saclay, “Circulating Tumor Cells” Translational Platform, AMMICA CNRS UMS3655 – INSERM US23, F-94805, Villejuif, France 4 Hopital d’Instruction des Armees du Val de Grâce, Department of Oncology, F-75005, Paris, France 5 Gustave Roussy, Universite Paris-Saclay, Department of Biopathology, F-94805, Villejuif, France 6 Gustave Roussy, Universite Paris-Saclay, Department of Biostatistics and Epidemiology, F-94805, Villejuif, France 7 Gustave Roussy, Universite Paris-Saclay, “Histo Cytopathology” Translational Platform, AMMICA CNRS UMS3655 – INSERM US23, F-94805, Villejuif, France * These authors contributed equally to the study # These authors contributed equally to the study Correspondence to: Francoise Farace, email: francoise.farace@gustaveroussy.fr Keywords: prostate cancer, biopsy, circulating tumor cells, androgen receptor, TMPRSS2-ERG translocation Received: March 24, 2016 Accepted: June 17, 2016 Published: July 04, 2016 ABSTRACT Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR -amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR -amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG -rearrangement was observed between metastatic biopsies and CTCs even if additional ERG -alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs. Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients.

Background Our prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies. Methods Overall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed. Results We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53–0.71], Doc (HR = 0.77, 95% CI 0.68–0.87), ZA + Cel (HR = 0.78, 95% CI 0.62–0.97), ZA + Doc (HR = 0.79, 95% CI 0.66–0.94), Cel (HR = 0.94 95% CI 0.75–1.17) and ZA (HR = 0.90 95% CI 0.79–1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability). Conclusions Uniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.

The goal of treatment of metastatic prostate cancer remains palliation. The oligometastatic state could be the right time to intensify therapy by introducing metastases directed treatments. The aim of this trial was to evaluate the benefit of radiotherapy to all macroscopic metastatic sites and to the primary disease in patients with hormone sensitive oligometastatic prostate cancer.

Background Evidence suggests that ATB and gut microbiota composition are associated to anti-PD-1 outcomes in RCC patients. Network analysis of the gut microbiota represents a novel tool to determine “guilds” of bacterial communities. Methods Here, we investigated guilds’ relationships with prior exposure to ATB, TKI [axitinib (axi), sunitinib (suni) or other] and clinical outcomes of RCC patients treated with nivolumab (nivo). Results Considering prior exposure to ATB (n = 11, 22%), axi (n = 13, 19%), suni (n = 49, 71%) or other TKI (n = 20, 29%), n = 36 (52%) patients were NR and 33 (48%) R to nivo. Cross-validation of overall fecal microbiota composition stratified RCC patients with different predictive power (ATB=84%; axi=81%; suni=69%; outcome=49%). Network analysis revealed six guilds (G1 to G6). G1-G2 behaved in an opposite way and topologically separated by negative correlations. G1-G2 were both related to NR, while G1 was dominated by species related to ATB. Conversely G2 was mainly represented by species related to no ATB (X2=8.98, P = 0.0027) and more susceptible to prior TKI exposure (where axi and suni behaved in an opposite way) compared to the other guilds (X2=10.68, P = 0.0011). G4 was mainly inhabited by species related to other TKI (no axi and no suni). Random forest analysis found definite bacterial species able to drive the stratification into guilds of the global RCC network, such as Akkermansia muciniphila for R and Dorea formicigenerans for no ATB. Conclusions We show that ATB and suni are the most powerful external features able to drive fecal microbiota compositional shifts in RCC patients treated with nivo. Analysis of the gut microbiota using bacterial communities guilds provides a novel theranostic approach to stratify RCC patients. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure L. Albiges: Honoraria (self): Novartis, BMS, Amgen, Ipsen, Roche, Pfizer, Astellas, Merck. K. Fizazi: Advisory / Consultancy: Participation to advisory boards/honorarium for: Astellas, AAA, Bayer, Clovis, Curevac, Incyte, Janssen, MSD, Orion, Sanofi. B. Escudier: Advisory / Consultancy: IPSEN, BMS, AZ, Novartis, Roche, Oncorena. L. Zitvogel: Advisory / Consultancy: BMS, AstraZeneca,; Research grant / Funding (self): Incyte, GSK, Transgene, Innovate Biopharma, Pilege; Advisory / Consultancy: Everimmune. All other authors have declared no conflicts of interest.

Validation of vimentin and Ki67 staining using the CellSearch platform. Figure S2. Prognostic impact of total CTC in two cohorts of patients with CRPC. Figure S3. Prognostic impact of vimentin/Ki67 CTC proportions and their presence in the unfavourable subgroup. Important validation work performed to justify subsequent experiments and conclusions. Figure S1. details the optimisation on CellSearch of Vimentin and Ki67 antibodies. Figure S2. shows that prognostic analysis of total CTC (regardless of vimentin and Ki67 measurements) is consistent with previous reports. Figure S3. shows that there is no prognostic significance of KI67 or vimentin CTC in the unfavourable prognosis subgroup, and that proportion of Ki67- or vimentin-CTC is less prognostically important than their presence or absence. (PDF 1030 kb)

Germ cell tumour is the most frequent malignant tumour type in young men with a 100% rise in the incidence every 20 years. Despite this, the high sensitivity of germ cell tumours to platinum-based chemotherapy, together with radiation and surgical measures, leads to the high cure rate of > or = 99% in early stages and 90%, 75-80% and 50% in advanced disease with 'good', 'intermediate' and 'poor' prognostic criteria (IGCCCG classification), respectively. The high cure rate in patients with limited metastatic disease allows the reduction of overall treatment load, and therefore less acute and long-term toxicity, e.g. organ sparing surgery for specific cases, reduced dose and treatment volume of irradiation or substitution of node dissection by surveillance or adjuvant chemotherapy according to the presence or absence of vascular invasion. Thus, different treatment options according to prognostic factors including histology, stage and patient factors and possibilities of the treating centre as well may be used to define the treatment strategy which is definitively chosen for an individual patient. However, this strategy of reduction of treatment load as well as the treatment itself require very high expertise of the treating physician with careful management and follow-up and thorough cooperation by the patient as well to maintain the high rate for cure. Treatment decisions must be based on the available evidence which has been the basis for this consensus guideline delivering a clear proposal for diagnostic and treatment measures in each stage of gonadal and extragonadal germ cell tumour and individual clinical situations. Since this guideline is based on the highest evidence level available today, a deviation from these proposals should be a rare and justified exception

Some researchers have found higher cholesterol levels linearly related to hostility, whereas others have found no relation. Even so, it remains unclear whether research should seek to find a linear relation between hostility and cholesterol levels. We hypothesized that a U-curved association was the proper test of the relation between hostility and cholesterol. Total fasting and low-density lipoprotein (LDL) cholesterol levels were collected from a population-based sample of 2,306 Canadians. Barefoot’s (1989) scoring of the Cook-Medley Hostility Scale was used to assess hostility levels. Both a linear and a U-curved relation among hostility scores, fasting total, and LDL cholesterol levels were significant. Participants with low and high cholesterol levels had significantly higher hostility scores than the normal cholesterol group. A U-curved relation between hostility and serum cholesterol levels may be a more appropriate function to consider given the all-cause mortality findings we seek to explain.

Chemotherapy is one the therapeutic options in prostate cancer. Docetaxel once every three weeks is the current standard for castration-refractory disease with cancer-related symptoms. The docetaxel plus estramustine association is likely more active than docetaxel alone. Docetaxel is currently tested in early stages: first results of phase III trials are expected by 2009-2010.