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Current treatments for advanced prostate cancer (PCa) primarily target androgen receptor (AR)-pathways. However, the emergence of castration-resistant prostate cancer (CRPC) and resistance to AR signaling inhibitors (ARSI) remains a significant clinical challenge. This study introduces BSJ-5-63, a novel triple degrader targeting cyclin-dependent kinases (CDKs) CDK12, CDK7, and CDK9, with potential to transform CRPC therapy. BSJ-5-63 effectively downregulates homologous recombination repair (HRR) genes, including BRCA1 and BRCA2, through CDK12 degradation, and attenuates AR signaling through CDK7 and CDK9 degradation, further enhancing its therapeutic impact. Importantly, BSJ-5-63 induces a "BRCAness" state that persists for a significant duration, enabling sequential combination therapy with PARP inhibitors (PARPis) while potentially minimizing drug-related toxicity and resistance. In both in vitro and in vivo studies, BSJ-5-63 exhibited potent antiproliferative effects in both AR-positive and AR-negative CRPC models. This study presents a promising multi-pronged approach for CRPC treatment, addressing both DNA repair mechanisms and AR signaling, with the potential to benefit a wide range of patients regardless of their BRCA1/2 mutational status. SIGNIFICANCE: This study introduces BSJ-5-63, a triple degrader designed to target CDK12, CDK7, and CDK9, making a significant advancement in CRPC therapy. The distinctive mechanism of BSJ-5-63 involves downregulating HRR genes and inhibiting AR signaling, thereby inducing a BRCAness state. This enhances sensitivity to PARP inhibition, effectively addressing ARSI resistance and improving the overall efficacy of treatment. The development of BSJ-5-63 represents a promising therapeutic approach, with the potential to benefit a broad spectrum of CRPC patients.
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INTRODUCTION: Bladder cancer (BC) is sensitive to radiation treatment and a subset of patients experience radiation-induced injuries including shrinkage of bladder due to bladder fibrosis. METHODS: This study is a retrospective cohort study. Three Japanese BC patients were randomly selected. Using a microRNA (miRNA) array, comparing their samples with or without radiation-induced injuries, we have checked the clustering of miRNA expression. RESULTS: Hsa-miR-130a, hsa-miR-200c, hsa-miR-141, and hsa-miR-96 were found to be highly expressed (>50 times) in patients with fibrotic bladder shrinkage (FBS) compared to those with intact bladder (IB) function. In patients with FBS, hsa-miR-6835, hsa-miR-4675, hsa-miR-371a, and hsa-miR-6885 were detected to have lesser than half expression to IB patients. We have analyzed the significance of these genes in relation to overall survival of 409 BC patients retrieved from the Cancer Genome Atlas data set. All available cutoff values between the lower and upper quartiles of expression are used for the selected genes, and false discovery rate using the Benjamini-Hochberg method is computed to correct for multiple hypothesis testing. We have run combined survival analysis of the mean expression of these four miRNAs highly expressed in FBS patients. 175 patients with high expression had a longer median survival of 98.47 months than 23.73 months in 233 patients with low expression (hazard ratio [HR]: 0.53; 0.39-0.72, log-rank p value: 7.3e-0.5). Combination analysis of all 8 genes including hsa-miR-6835, hsa-miR-4675, hsa-miR-371a, and hsa-miR-6885 showed the same HR for OS. Target scanning for these miRNAs matched specific cytokines known as an early biomarker to develop radiation-induced fibrosis. CONCLUSIONS: BC patients with fibrotic radiation injury have specific miRNA expression profile targeting profibrotic cytokines and these miRNAs possibly render to favorable survival.
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MicroARNs , Traumatismos por Radiación , Neoplasias de la Vejiga Urinaria , Vejiga Urinaria , Humanos , MicroARNs/genética , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/radioterapia , Neoplasias de la Vejiga Urinaria/patología , Masculino , Estudios Retrospectivos , Femenino , Traumatismos por Radiación/genética , Traumatismos por Radiación/patología , Anciano , Vejiga Urinaria/patología , Vejiga Urinaria/efectos de la radiación , Vejiga Urinaria/metabolismo , Persona de Mediana Edad , Anciano de 80 o más Años , Fibrosis/genéticaRESUMEN
PURPOSE: This study investigates the utility of ureteroscopic surgery (URS) as an alternative to radical nephroureterectomy (RNU) in managing upper tract urothelial carcinoma (UTUC), with a focus on survival outcomes and re-evaluation of current the European Association of Urology guidelines criteria. METHODS: We conducted a retrospective, multi-institutional review of 143 UTUC patients treated with URS (n = 35) or RNU (n = 108). Clinicopathological factors were analyzed, and survival outcomes were assessed using Kaplan-Meier analysis and Cox proportional-hazards models. RESULTS: The median follow-up period was 27 months. Overall survival (OS) and radiographic progression-free survival (rPFS) were comparable between the URS and RNU groups (OS: HR 2.42, 95% CI 0.63-9.28, P = 0.0579; rPFS: HR 1.82, 95% CI 0.60-5.47, P = 0.1641). URS conferred superior renal function preservation. In patients characterized by factors such as radiographically invisible lesions, negative cytology, pTa stage, low-grade tumors, and multiple lesions, the OS outcomes with URS were comparable to those with RNU as follows: radiographically invisible lesions (P = 0.5768), negative cytology (P = 0.7626), pTa stage (P = 0.6694), low-grade tumors (P = 0.9870), and multiple lesions (P = 0.8586). CONCLUSION: URS offers survival outcomes similar to RNU, along with better renal function preservation, especially in low-risk UTUC patients. These findings underscore the urgency of re-evaluating the current EAU guidelines and encourage further research into determining the ideal patient selection for URS in UTUC treatment.
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Carcinoma de Células Transicionales , Neoplasias Ureterales , Neoplasias de la Vejiga Urinaria , Humanos , Nefroureterectomía , Neoplasias de la Vejiga Urinaria/cirugía , Carcinoma de Células Transicionales/patología , Ureteroscopía , Estudios Retrospectivos , Neoplasias Ureterales/patología , Nefronas/cirugía , Nefronas/patologíaRESUMEN
BACKGROUND: Currently, only limited knowledge is available regarding the phenotypic association between fibroblast growth factor receptor 3 (FGFR3) alterations and the tumor microenvironment (TME) in bladder cancer (BLCA). METHODS: A multi-omics analysis on 389 BLCA and 35 adjacent normal tissues from a cohort of OMPU-NCC Consortium Japan was retrospectively performed by integrating the whole-exome and RNA-sequence dataset and clinicopathological record. A median follow-up duration of all BLCA cohort was 31 months. RESULTS: FGFR3 alterations (aFGFR3), including recurrent mutations and fusions, accounted for 44% of non-muscle invasive bladder cancer (NMIBC) and 15% of muscle-invasive bladder cancer (MIBC). Within MIBC, the consensus subtypes LumP was significantly more prevalent in aFGFR3, whereas the Ba/Sq subtype exhibited similarity between intact FGFR3 (iFGFR3) and aFGFR3 cases. We revealed that basal markers were significantly increased in MIBC/aFGFR3 compared to MIBC/iFGFR3. Transcriptome analysis highlighted TIM3 as the most upregulated immune-related gene in iFGFR3, with differential immune cell compositions observed between iFGFR3 and aFGFR3. Using EcoTyper, TME heterogeneity was discerned even within aFGFR cases, suggesting potential variations in the response to checkpoint inhibitors (CPIs). Among 72 patients treated with CPIs, the objective response rate (ORR) was comparable between iFGFR3 and aFGFR3 (20% vs 31%; p = 0.467). Strikingly, a significantly higher ORR was noted in LumP/aFGFR3 compared to LumP/iFGFR3 (50% vs 5%; p = 0.022). This trend was validated using data from the IMvigor210 trial. Additionally, several immune-related genes, including IDO1, CCL24, IL1RL1, LGALS4, and NCAM (CD56) were upregulated in LumP/iFGFR3 compared to LumP/aFGFR3 cases. CONCLUSIONS: Differential pathways influenced by aFGFR3 were observed between NMIBC and MIBC, highlighting the upregulation of both luminal and basal markers in MIBC/aFGFR3. Heterogeneous TME was identified within MIBC/aFGFR3, leading to differential outcomes for CPIs. Specifically, a favorable ORR in LumP/aFGFR3 and a poor ORR in LumP/iFGFR3 were observed. We propose TIM3 as a potential target for iFGFR3 (ORR: 20%) and several immune checkpoint genes, including IDO1 and CCL24, for LumP/iFGFR3 (ORR: 5%), indicating promising avenues for precision immunotherapy for BLCA.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias de la Vejiga Urinaria , Humanos , Pronóstico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Biomarcadores de Tumor/genética , Estudios Retrospectivos , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Microambiente Tumoral , Receptor 2 Celular del Virus de la Hepatitis A , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Emerging evidence suggests that the presence of tertiary lymphoid structures (TLS) and neutrophil-lymphocyte ratio (NLR) in peripheral blood is associated with the treatment response to checkpoint inhibitors (CPIs), whereas there is limited knowledge regarding whether these factors reciprocally impact the treatment outcomes of CPIs in metastatic urothelial carcinoma (mUC). Herein, we investigated treatment outcomes of platinum-refractory mUC patients (50 cases with whole-exome and transcriptome sequencing) treated with pembrolizumab. The pathological review identified 24% of cases of TLS in the specimens. There was no significant difference in the NLR between the TLS- and TLS+ groups (p = 0.153). In the lower NLR group, both overall survival and progression-free survival were significantly longer in patients with TLS than in those without TLS, whereas the favorable outcomes associated with TLS were not observed in patients in the higher NLR group. We explored transcriptomic differences in UC with TLS. The TLS was comparably observed between luminal (20%) and basal (25%) tumor subtypes (p = 0.736). Exploring putative immune-checkpoint genes revealed that ICOSLG (B7-H2) was significantly increased in tumors with lower NLR. KRT expression levels exhibited higher basal cell markers (KRT5 and KRT17) in the higher NLR group and lower differentiated cell markers (KRT8 and KRT18) in patients with TLS. In conclusion, the improved outcomes of pembrolizumab treatment in mUC are restricted to patients with lower NLR. Our findings begin to elucidate a distinct molecular pattern for the presence of TLS according to the NLR in peripheral blood.
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Carcinoma de Células Transicionales , Estructuras Linfoides Terciarias , Neoplasias de la Vejiga Urinaria , Humanos , Neutrófilos , Linfocitos , Pronóstico , Estudios RetrospectivosRESUMEN
Prostate cancer harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibition. Here, we perform genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient prostate cancer cells and identify previously unknown genes whose loss has a profound impact on PARP inhibitor response. Specifically, MMS22L deletion, frequently observed (up to 14%) in prostate cancer, renders cells hypersensitive to PARP inhibitors by disrupting RAD51 loading required for homologous recombination repair, although this response is TP53-dependent. Unexpectedly, loss of CHEK2 confers resistance rather than sensitivity to PARP inhibition through increased expression of BRCA2, a target of CHEK2-TP53-E2F7-mediated transcriptional repression. Combined PARP and ATR inhibition overcomes PARP inhibitor resistance caused by CHEK2 loss. Our findings may inform the use of PARP inhibitors beyond BRCA1/2-deficient tumors and support reevaluation of current biomarkers for PARP inhibition in prostate cancer.
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Antineoplásicos , Neoplasias de la Próstata , Humanos , Masculino , Antineoplásicos/farmacología , Proteína BRCA1/metabolismo , Reparación del ADN/genética , Genes BRCA2 , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Resistencia a AntineoplásicosRESUMEN
Current targeted cancer therapies are largely guided by mutations of a single gene, which overlooks concurrent genomic alterations. Here, we show that RNASEH2B, RB1, and BRCA2, three closely located genes on chromosome 13q, are frequently deleted in prostate cancer individually or jointly. Loss of RNASEH2B confers cancer cells sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition due to impaired ribonucleotide excision repair and PARP trapping. When co-deleted with RB1, however, cells lose their sensitivity, in part, through E2F1-induced BRCA2 expression, thereby enhancing homologous recombination repair capacity. Nevertheless, loss of BRCA2 resensitizes RNASEH2B/RB1 co-deleted cells to PARP inhibition. Our results may explain some of the disparate clinical results from PARP inhibition due to interaction between multiple genomic alterations and support a comprehensive genomic test to determine who may benefit from PARP inhibition. Last, we show that ATR inhibition can disrupt E2F1-induced BRCA2 expression and overcome PARP inhibitor resistance caused by RB1 loss.
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Inhibidores de Poli(ADP-Ribosa) Polimerasas , Neoplasias de la Próstata , Proteína BRCA2 , Reparación del ADN , Replicación del ADN , Genes BRCA2 , Humanos , Masculino , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Proteínas de Unión a Retinoblastoma/genética , Ribonucleasa H , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
BACKGROUND: We assessed the prognostic value of body mass index (BMI) in Asian patients with localized RCC who underwent nephrectomy. METHODS: A total of 665 patients who underwent nephrectomy for localized RCC were enrolled in the present study and divided into the two BMI groups: i.e., BMI < 25 in 463 (69.6%) and BMI > 25 in 202 (30.4%) patients. RESULTS: In total, there were 482 (72.5%) males and 183 (27.5%) females. Five-year cancer-specific survival (CSS) rates were significantly higher in increased BMI than the lower BMI group (97.1 and 92.5%: P = 0.007). When stratified by sex, significantly longer CSS in higher BMI was confirmed in males (5-year CSS of 92.7% in BMI < 25 and 98.1% in BMI > 25, p = 0.005), while there was no difference in CSS between BMI groups for female patients. Multivariable analysis exhibited that higher BMI was an independent predictor for favorable CSS in male (cox model: p = 0.041, Fine & Gray regression model: p = 0.014), but not in the female. Subgroup analysis for CSS revealed that favorable CSS with higher BMI was observed in patient subgroups of age < 65 (p = 0.019), clear cell histology (p = 0.018), and tumor size > 4 cm, p = 0.020) as well as male (p = 0.020). CONCLUSION: Our findings collected from the multi-institutional Japanese dataset demonstrated longer survival in patients with higher BMI than lower BMI for non-metastatic RCC treated with nephrectomy. Intriguingly, this finding was restricted to males, but not to females.
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Índice de Masa Corporal , Carcinoma de Células Renales/cirugía , Neoplasias Renales/cirugía , Nefrectomía , Factores Sexuales , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Carcinoma de Células Renales/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Japón/epidemiología , Estimación de Kaplan-Meier , Neoplasias Renales/complicaciones , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Adulto JovenRESUMEN
A 19-year-old Japanese male recipient, who received a living related kidney transplantation from his father at 5 years old, was hospitalized for second renal transplantation from a cadaveric donor. The recipient had had an antibody-mediated rejection (AMR) to the first transplanted kidney. HLA typing of A, B, and DRB showed 2 of 6 mismatches. Lymphocyte cytotoxicity test (LCT) and flow cytometry crossmatches (FCXM) were negative on T cells. Tacrolimus, mycophenolate mofetil, methylprednisolone, and basiliximab induction were used as the standard immunosuppressive therapy. After second renal transplantation, his serum creatinine level favorably decreased until postoperative day (POD) 7, but his serum creatinine level raised from POD 8. We performed steroid pulse and intravenous immunoglobulin (IVIG). The episode biopsy showed AMR although FCXM and LCT were still negative on T cell. To determine the cause of AMR, we examined LABScreen single antigen test (One Lambda, Canoga Park, Calif., United States), and there was a donor-specific antibody (DSA) that is DQB8 in pre- and post-second renal transplantation. The DSA was suspected de novo DSA for the first transplanted kidney. AMR was successfully treated with plasma exchange, IVIG, and rituximab.
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Rechazo de Injerto/inmunología , Cadenas beta de HLA-DQ/inmunología , Isoanticuerpos/inmunología , Trasplante de Riñón/efectos adversos , Reoperación , Cadáver , Rechazo de Injerto/tratamiento farmacológico , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Isoanticuerpos/efectos adversos , Masculino , Donantes de Tejidos , Adulto JovenRESUMEN
OBJECTIVE: Whether adjuvant chemotherapy (AC) for patients with upper tract urothelial carcinoma (UTUC) offers survival benefit is still controversial. To explore the impact of AC on overall survival (OS) of cN0M0 UTUC patients, we conducted a propensity score-matched analysis using the regression model, including pathologic features such as lymphatic and vascular invasion. METHODS: A multi-institutional cohort of 413 UTUC patient record was used. Propensity score matching was performed to reduce bias by potential confounding factors for survival, including pathologic features from the specimen of radical nephroureterectomy (RNU), RESULTS: Ninety-eight patients were identified as pair-matched groups (49 patients in RNU and 49 patients in RNU + AC). Kaplan-Meier curves demonstrated that a 5-year OS rate of 72.7% for patients treated with RNU + AC was significantly higher than 51.6% for those treated with RNU (p = 0.0156). On multivariate analysis, pathologic vascular invasion (HR 3.41, 95% CI 1.24-10.66, p = 0.0166) and administration of AC (HR 0.45, 95% CI 0.19-0.98, p = 0.0438) still remained as the significant predictors for OS. In patients with pathologic vascular invasion (51 of 98 patients), a significantly longer OS in RNU + AC groups was observed (median OS of 30 and 70 months in RNU and RNU + AC groups, respectively: p = 0.0432), whereas there was no significant difference in the OS between RNU (median OS: not reached) and RNU + AC (median OS: not reached) groups in patients without the invasion (p = 0.4549). CONCLUSION: The result indicates a significant benefit for OS by the administration of AC, and pathologic vascular invasion in the specimen of RNU could help the patient selection to better predict the effect of AC.
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Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/mortalidad , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Neoplasias Ureterales/tratamiento farmacológico , Neoplasias Ureterales/mortalidad , Anciano , Carcinoma de Células Transicionales/patología , Quimioterapia Adyuvante , Estudios de Cohortes , Femenino , Humanos , Neoplasias Renales/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Neoplasias Ureterales/patología , Neoplasias Vasculares/secundarioRESUMEN
This study aimed to assess the clinical value of C-reactive protein-albumin ratio (CAR) at the initiation of first-line treatment for castration-resistant prostate cancer (CRPC). We identified 221 CRPC patients treated with either androgen-signaling inhibitors (ASIs: abiraterone and enzalutamide) or docetaxel as the first-line treatment. The value of CAR was evaluated at the initiation of first-line treatment. The optimal cutoff value of CAR for the prediction of lethality was defined by the receiver operating characteristic curve and the Youden Index. The primary endpoints of the study included overall survival (OS) and cancer-specific survival (CSS). The median age was 74 years. The optimal cutoff value of CAR in newly diagnosed CRPC patients was 0.5 (CAR > 0.5: n = 77 and CAR ≤ 0.5: n = 144). The 3-year OS and CSS rate in patients with CAR > 0.5 were significantly lower than those with CAR ≤ 0.5 (OS: 30.9% vs 55.5%, p < 0.001) (CSS: 42.5% vs 65.4%, p < 0.001). A multivariate analysis consistently demonstrated that CAR was an independent predictor for both OS and CSS. When stratified by the first-line treatments, patients with CAR > 0.5 has significantly shorter CSS than those with CAR ≤ 0.5 in abiraterone (median of 23 vs 49 months, p < 0.001) and enzalutamide (median of 23 vs 41 months, p = 0.0016), whereas no difference was observed in patients treated with docetaxel as the first-line treatment (median of 34 and 37 months, p = 0.7708). Despite the limited cohort size and retrospective design, increased CAR seemed to serve as an independent predictor of OS and CSS for patients newly diagnosed with CRPC.
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Albúminas/análisis , Antineoplásicos/uso terapéutico , Proteína C-Reactiva/análisis , Neoplasias de la Próstata Resistentes a la Castración , Anciano , Antagonistas de Andrógenos/uso terapéutico , Androstenos/uso terapéutico , Benzamidas , Docetaxel/uso terapéutico , Humanos , Masculino , Nitrilos , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/uso terapéutico , Valor Predictivo de las Pruebas , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: To examine the association between the body mass index (BMI) and the risk of survival, and to evaluate whether tumor characteristics differ by BMI in patients with upper tract urothelial carcinoma (UTUC) managed by surgery. METHODS: A clinical series on 876 patients with localized UTUC following nephroureterectomy with a bladder cuff, with data from Osaka Medical College registry (discovery cohort) and the Nagoya group (validation cohort) was examined. In addition to analyzing the overall survival and cancer-specific survival (CSS), the survival impact adjusted by pathological variables was also assessed by the BMI group. RESULTS: The percentage of high risk features including positive lymphovascular invasion was doubled in the discovery cohort compared to the validation cohort. The group of BMI ≥ 25 kg/m2 was associated with improved CSS in the discovery cohort (p = 0.004), and this tendency was verified in the validation cohort (p = 0.006). Nonproportional hazards existed for the group of BMI ≥ 25 kg/m2 and the BMI 18.5-25 kg/m2 relative to the group of BMI < 18.5 kg/m2, with a change in the CSS hazard. In multivariable Cox models, the BMI group had a superior predictive value compared with other pre-clinical factors both in the discovery cohort (HR = 3.85, p = 0.01; 95%CI: 0.09-0.73) and the validation cohort (HR = 1.56, p = 0.01; 95%CI: 0.45-0.91). When adjusted by lymphovascular invasion, the concordance of the model proposed by the discovery cohort (0.52) challenged in the validation cohort was 0.59. CONCLUSIONS: We found a clinically relevant signature for high risk patients with BMI grouping. Further research is necessary on whether tailoring recommendations for weight and nutrition management to tumor characteristics will improve outcomes.
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Background: There is emerging evidence that radiographic progression-free survival (rPFS) is highly correlated with overall survival (OS), potentially serving as an indicator of treatment outcome for castration-resistant prostate cancer (CRPC). The objective of this study is to assess rPFS and prostate specific antigen (PSA) response in sequential treatment using androgen signaling inhibitors (ASIs) including abiraterone and enzalutamide in newly diagnosed CRPC. Methods: Propensity score matching was performed to reduce bias by confounding factors between first-line ASIs. The primary endpoints of the study included rPFS, time to PSA progression (TTPP), and PSA response. Results: A paired-matched group of 184 patients were identified. From the initiation of first-line ASIs, there was no significant difference in rPFS, TTPP, and PSA response between treatment arms. From the initiation of second-line ASIs, enzalutamide following abiraterone consistently exhibited longer rPFS (median: 7 and 15 months, p = 0.04), TTPP, and better PSA response compared to the reverse, whereas OS did not reach significance (median: 14 and 23 months, p = 0.35). Conclusion: Although the effect of ASIs as the first line was similar, the extent of cross-resistance might differ towards less resistance in enzalutamide following abiraterone than the reverse.
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Androgen receptor (AR) is a ligand-activated transcription factor and a key driver of prostate cancer (PCa) growth and progression. Understanding the factors influencing AR-mediated gene expression provides new opportunities for therapeutic intervention. Poly(ADP-ribose) Polymerase (PARP) is a family of enzymes, which posttranslationally modify a range of proteins and regulate many different cellular processes. PARP-1 and PARP-2 are two well-characterized PARP members, whose catalytic activity is induced by DNA-strand breaks and responsible for multiple DNA damage repair pathways. PARP inhibitors are promising therapeutic agents that show synthetic lethality against many types of cancer (including PCa) with homologous recombination (HR) DNA-repair deficiency. Here, we show that, beyond DNA damage repair function, PARP-2, but not PARP-1, is a critical component in AR transcriptional machinery through interacting with the pioneer factor FOXA1 and facilitating AR recruitment to genome-wide prostate-specific enhancer regions. Analyses of PARP-2 expression at both mRNA and protein levels show significantly higher expression of PARP-2 in primary PCa tumors than in benign prostate tissues, and even more so in castration-resistant prostate cancer (CRPC) tumors. Selective targeting of PARP-2 by genetic or pharmacological means blocks interaction between PARP-2 and FOXA1, which in turn attenuates AR-mediated gene expression and inhibits AR-positive PCa growth. Next-generation antiandrogens act through inhibiting androgen synthesis (abiraterone) or blocking ligand binding (enzalutamide). Selective targeting of PARP-2, however, may provide an alternative therapeutic approach for AR inhibition by disruption of FOXA1 function, which may be beneficial to patients, irrespective of their DNA-repair deficiency status.
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Factor Nuclear 3-alfa del Hepatocito/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Animales , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Línea Celular Tumoral , Conjuntos de Datos como Asunto , Supervivencia sin Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes , Humanos , Estimación de Kaplan-Meier , Masculino , Ratones , Ftalazinas/farmacología , Ftalazinas/uso terapéutico , Piperazinas/farmacología , Piperazinas/uso terapéutico , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/genética , Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , ARN Interferente Pequeño/metabolismo , RNA-Seq , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Análisis de Matrices Tisulares , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: A myriad of studies have demonstrated the clinical association of systemic inflammatory and nutrition status (SINS) including C-reactive protein/albumin ratio (CAR), the neutrophil/lymphocyte ratio (NLR), and the platelet/hemoglobin ratio (PHR). This study aimed to investigate the predictive value of the score integrating these variables (CANLPH) in patients with renal cell carcinoma (RCC). METHODS: Using cohort data from a multi-institutional study, 757 of 1109 patients were retrospectively analyzed. The optimal cutoff value for outcome prediction of continuous variables in CAR, NLR, and PHR was determined and the CANLPH score was then calculated as the sum score of 0 or 1 by the cutoff value in each ratio. RESULTS: The median follow-up time was 76 months for the patients who survived (n = 585) and 31 months for those who died (n = 172). The Youden Index offered an optimal cutoff of 1.5 for CAR and 2.8 for NLR, and a higher value from the cutoff was assigned as a score of 1. The cutoff value of the PHR was defined as 2.1 for males and 2.3 for females. The patients were assigned a CANLPH score of 0 (47.2%), 1 (31.3%), 2 (13.1%), or 3 (8.5%). In the multivariate analysis, the CANLPH score served as an independent predictor of cancer-specific mortality in both localized and metastatic RCC. CONCLUSION: The score was well-correlated with clinical outcome for the RCC patients. Because this score can be concisely measured at the point of diagnosis, physicians may be encouraged to incorporate this model into the treatment for RCC.
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Biomarcadores de Tumor/análisis , Carcinoma de Células Renales/patología , Inflamación/patología , Neoplasias Renales/patología , Nefrectomía/mortalidad , Estado Nutricional , Albúminas/análisis , Proteína C-Reactiva/análisis , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/cirugía , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Japón , Neoplasias Renales/metabolismo , Neoplasias Renales/cirugía , Linfocitos/patología , Masculino , Persona de Mediana Edad , Neutrófilos/patología , Pronóstico , Tasa de SupervivenciaRESUMEN
INTRODUCTION: The C-reactive protein to albumin ratio (CAR) has been shown to provide prognostic information in several cancers. The objective in the study is to examine the prognostic value of CAR in patients with RCC who underwent nephrectomy. MATERIAL AND METHODS: The record data from multi-institutional study of 1,028 patients was analyzed in the study. The cut-off value of the CAR was defined by receive operating characteristic (ROC) analysis. Overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) were evaluated, and univariate and multivariate analyses were conducted to assess the predictive value of the variables including CAR. RESULT: The optimal cut-off value of 0.073 in CAR was defined according to the ROC analysis. The AUC in CAR for CSS was greater than that of NLR and PLR, and that for RFS was also greater than GPS and mGPS. Multivariate analysis demonstrated that the CAR was an independent prognostic factor for OS (P < 0.001), CSS (P < 0.001) in total cohort and RFS (Pâ¯=â¯0.029) in nonmetastatic cohort. CONCLUSION: The findings of the present study suggested that the preoperative CAR is an independent prognostic indicator of OS, CSS and RFS for patients with RCC. Since CAR can be assessed prior to surgery, clinicians should this take into account for the treatment decision making.
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Proteína C-Reactiva/metabolismo , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Albúmina Sérica/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/cirugía , Femenino , Humanos , Inflamación , Japón , Neoplasias Renales/metabolismo , Neoplasias Renales/mortalidad , Neoplasias Renales/cirugía , Masculino , Persona de Mediana Edad , Nefrectomía , Pronóstico , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
It has been well established that microRNA (miR)-143 is downregulated in human bladder cancer (BC). Recent precision medicine has shown that mutations in BC are frequently observed in FGFR3, RAS and PIK3CA genes, all of which correlate with RAS signaling networks. We have previously shown that miR-143 suppresses cell growth by inhibiting RAS signaling networks in several cancers including BC. In the present study, we showed that synthetic miR-143 negatively regulated the RNA-binding protein Musashi-2 (MSI2) in BC cell lines. MSI2 is an RNA-binding protein that regulates the stability of certain mRNAs and their translation by binding to the target sequences of the mRNAs. Of note, the present study clarified that MSI2 positively regulated KRAS expression through directly binding to the target sequence of KRAS mRNA and promoting its translation, thus contributing to the maintenance of KRAS expression. Thus, miR-143 silenced KRAS and MSI2, which further downregulated KRAS expression through perturbation of the MSI2/KRAS cascade.
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MicroARNs/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas de Unión al ARN/genética , Neoplasias de la Vejiga Urinaria/patología , Animales , Línea Celular Tumoral , Proliferación Celular , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Trasplante de Neoplasias , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteínas de Unión al ARN/metabolismo , Regulación hacia Arriba , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
To understand the role of RAS-signaling networks in the pathogenesis of renal cell carcisnoma, we clarified the relationship between miR-143 and RAS. The expression of miR-143 was extremely downregulated in tumor tissues from renal cell carcinoma patients compared with that in the adjacent normal tissues and Caki-1 cells. We developed a synthetic miR-143#12, and we found that the ectopic expression of it inhibited cell growth with autophagy in Caki-1 cells. Also, the expression level of c-Myc was markedly decreased, resulting in the perturbation of cancer-specific energy metabolism by negatively modulating the expression of GLUT1 and the PTBP1/PKMs axis. A partial metabolic shift from glycolysis to oxidative phosphorylation induced autophagy through increasing the intracellular level of reactive oxygen species (ROS). In an in vivo study, the potent anti-tumor activity of polyion complex (PIC)-loaded miR-143#12 (miR-143#12/PIC) was shown by systemic administration of it to Caki-1 cell-xenografted mice. Higher levels of miR-143 were found in both blood and tumor tissues after the systemic administration with miR-143#12/PIC compared to those with lipoplexes in the xenografted mice. These findings indicated that this synthetic miR-143#12 induced a marked growth inhibition by impairing K-RAS-signaling networks in vitro and in vivo.
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Carcinoma de Células Renales/genética , Carcinoma de Células Renales/terapia , MicroARNs/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Animales , Autofagia/genética , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Transportador de Glucosa de Tipo 1/genética , Glucólisis/genética , Ribonucleoproteínas Nucleares Heterogéneas/genética , Humanos , Ratones , MicroARNs/farmacología , Fosforilación Oxidativa/efectos de los fármacos , Proteína de Unión al Tracto de Polipirimidina/genética , Proteínas Proto-Oncogénicas c-myc/genética , Transducción de Señal/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We developed a novel chemically modified miR-143 (miR-143#12), and with it we investigated the contribution of miR-143 to the pathogenesis of bladder cancer (BC), in which miR-143 is extremely downregulated. Since miR-143 silenced K-RAS and RAS effector-signaling molecules Erk and Akt, we performed the ectopic expression of miR-143 in human BC 253J-BV cells, and we examined the growth inhibition and the mechanism of it in vitro and in orthotopic model mice. As a result, miR-143#12 induced a marked growth inhibition with apoptosis through impairing RAS-signaling networks, including SOS1, which exchanges guanosine diphosphate (GDP)/RAS for active guanosine triphosphate (GTP)/RAS. In the in vivo study, miR-143#12 exhibited a marked anti-tumor activity by either systemic or intravesical administration with polyionic copolymer (PIC) as the carrier, compared with the activity obtained by use of lipofection. These findings raised the possibility that the chemically modified miR-143#12 would be a candidate of microRNA (miRNA) medicine for BC delivered by intravesical infusion.
RESUMEN
INTRODUCTION AND OBJECTIVES: MicroRNA (miRNA) expression is altered in urologic malignancies, including urothelial carcinoma of the bladder (UCB). Individual miRNAs have been shown to modulate multiple signaling pathways that contribute to BC. To identify a panel of miRNA signature that can predict aggressive phenotype from normal nonaggressive counterpart using miRNA expression levels and to assess the prognostic value of this specific miRNA markers in patients with UCB. METHODS: To determine candidate miRNAs as prognostic biomarkers for dividing aggressive type of UCB, miRNA expression was profiled in patients' samples with an aggressive phenotype or nonaggressive phenotype using 3D-Gene miRNA labeling kit (Toray, Japan). To create a prognostic index model, we used the panel of 9-miRNA signature based on Cancer Genome Atlas (TCGA) data portal (TCGA Data Portal (https://tcgadata.nci.nih.gov/tcga/tcgaHome2.jsp)). miRNA expression data and corresponding clinical data, including outcome and staging information of 84 UCB patients, were obtained. The Kaplan-Meier and log-rank test were performed to quantify the survival functions in two groups. RESULTS: Deregulation of nine miRNAs (hsa-miR-99a-5p, hsa-miR-100-5p, hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-4324, hsa-miR-34b-5p, hsa-miR-29c-3p, hsa-miR-135a-3p, and hsa-miR-33b-3p) was determined in UCB patients with aggressive phenotype compared with nonaggressive subject. To validate the prognostic power of the nine-signature miRNAs using the TCGA dataset of bladder cancer, the survival status and tumor miRNA expression of all 84 TCGA UCB patients were ranked according to the prognostic score values. Of nine miRNAs, six were associated with high risk (hsa-miR-99a-5p, hsa-miR-100-5p, hsa-miR-125b-5p, hsa-miR-4324, hsa-miR-34b-5p, and hsa-miR-135a-3p) and three were shown to be protective (hsa-miR-145-5p, hsa-miR-29c-3p, and hsa-miR-33b-3p). Patients with the high-risk miRNA signature exhibited poorer OS than patients expressing the low-risk miRNA profile (HR = 7.05, p < 0.001). CONCLUSIONS: The miRNA array identified nine dysregulated miRNAs from clinical samples. This panel of nine-miRNA signature provides predictive and prognostic value of patients with UCB.