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1.
Mol Cancer Ther ; 19(5): 1157-1164, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32127465

RESUMO

Expression of the DNA/RNA helicase schlafen family member 11 (SLFN11) has been identified as a sensitizer of tumor cells to DNA-damaging agents including platinum chemotherapy. We assessed the impact of SLFN11 expression on response to platinum chemotherapy and outcomes in patients with metastatic castration-resistant prostate cancer (CRPC). Tumor expression of SLFN11 was assessed in 41 patients with CRPC treated with platinum chemotherapy by RNA sequencing (RNA-seq) of metastatic biopsy tissue (n = 27) and/or immunofluorescence in circulating tumor cells (CTC; n = 20). Cox regression and Kaplan-Meier methods were used to evaluate the association of SLFN11 expression with radiographic progression-free survival (rPFS) and overall survival (OS). Multivariate analysis included tumor histology (i.e., adenocarcinoma or neuroendocrine) and the presence or absence of DNA repair aberrations. Patient-derived organoids with SLFN11 expression and after knockout by CRISPR-Cas9 were treated with platinum and assessed for changes in dose response. Patients were treated with platinum combination (N = 38) or platinum monotherapy (N = 3). Median lines of prior therapy for CRPC was two. Median OS was 8.7 months. Overexpression of SLFN11 in metastatic tumors by RNA-seq was associated with longer rPFS compared with those without overexpression (6.9 vs. 2.8 months, HR = 3.72; 95% confidence interval (CI), 1.56-8.87; P < 0.001); similar results were observed for patients with SLFN11-positive versus SLFN11-negative CTCs (rPFS 6.0 vs. 2.2 months, HR = 4.02; 95% CI, 0.77-20.86; P = 0.002). A prostate-specific antigen (PSA) decline of ≥50% was observed in all patients with SLFN11 overexpression. No association was observed between SLFN11 expression and OS. On multivariable analysis, SLFN11 was an independent factor associated with rPFS on platinum therapy. Platinum response of organoids expressing SLFN11 was reduced after SLFN11 knockout. Our data suggest that SLFN11 expression might identify patients with CRPC with a better response to platinum chemotherapy independent of histology or other genomic alterations. Additional studies, also in the context of PARP inhibitors, are warranted.

2.
Mol Oncol ; 14(5): 974-990, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32146726

RESUMO

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.

3.
J Clin Invest ; 130(4): 1653-1668, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32091413

RESUMO

Loss of androgen receptor (AR) signaling dependence occurs in approximately 15%-20% of advanced treatment-resistant prostate cancers, and this may manifest clinically as transformation from a prostate adenocarcinoma histology to a castration-resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE currently relies on a metastatic tumor biopsy, which is invasive for patients and sometimes challenging to diagnose due to morphologic heterogeneity. By studying whole-exome sequencing and whole-genome bisulfite sequencing of cell free DNA (cfDNA) and of matched metastatic tumor biopsies from patients with metastatic prostate adenocarcinoma and CRPC-NE, we identified CRPC-NE features detectable in the circulation. Overall, there was markedly higher concordance between cfDNA and biopsy tissue genomic alterations in patients with CRPC-NE compared with castration-resistant adenocarcinoma, supporting greater intraindividual genomic consistency across metastases. Allele-specific copy number and serial sampling analyses allowed for the detection and tracking of clonal and subclonal tumor cell populations. cfDNA methylation was indicative of circulating tumor content fraction, reflective of methylation patterns observed in biopsy tissues, and was capable of detecting CRPC-NE-associated epigenetic changes (e.g., hypermethylation of ASXL3 and SPDEF; hypomethylation of INSM1 and CDH2). A targeted set combining genomic (TP53, RB1, CYLD, AR) and epigenomic (hypo- and hypermethylation of 20 differential sites) alterations applied to ctDNA was capable of identifying patients with CRPC-NE.

5.
Eur Urol ; 77(5): 573-575, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32037142
6.
Eur Urol ; 77(4): 508-547, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32001144

RESUMO

BACKGROUND: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence. OBJECTIVE: To present the results from the APCCC 2019. DESIGN, SETTING, AND PARTICIPANTS: Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process. RESULTS AND LIMITATIONS: Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material. CONCLUSIONS: These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.

7.
Bioinformatics ; 36(9): 2665-2674, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31922552

RESUMO

MOTIVATION: The use of liquid biopsies for cancer patients enables the non-invasive tracking of treatment response and tumor dynamics through single or serial blood drawn tests. Next-generation sequencing assays allow for the simultaneous interrogation of extended sets of somatic single-nucleotide variants (SNVs) in circulating cell-free DNA (cfDNA), a mixture of DNA molecules originating both from normal and tumor tissue cells. However, low circulating tumor DNA (ctDNA) fractions together with sequencing background noise and potential tumor heterogeneity challenge the ability to confidently call SNVs. RESULTS: We present a computational methodology, called Adaptive Base Error Model in Ultra-deep Sequencing data (ABEMUS), which combines platform-specific genetic knowledge and empirical signal to readily detect and quantify somatic SNVs in cfDNA. We tested the capability of our method to analyze data generated using different platforms with distinct sequencing error properties and we compared ABEMUS performances with other popular SNV callers on both synthetic and real cancer patients sequencing data. Results show that ABEMUS performs better in most of the tested conditions proving its reliability in calling low variant allele frequencies somatic SNVs in low ctDNA levels plasma samples. AVAILABILITY AND IMPLEMENTATION: ABEMUS is cross-platform and can be installed as R package. The source code is maintained on Github at http://github.com/cibiobcg/abemus, and it is also available at CRAN official R repository. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

8.
Cancer ; 126(7): 1407-1412, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31905251

RESUMO

BACKGROUND: The progression of prostate cancer is a complex, multistep process that involves molecular alterations in cells of the tumor and the microenvironment, with associated interactions between the stroma and epithelium. Genomic expression analyses of stromal infiltration markers were performed to determine the significance thereof in prostate cancer. METHODS: Genome-wide expression profiles of formalin-fixed, paraffin-embedded radical prostatectomy samples were evaluated from a prospective registry cohort (n = 5239) and 3 retrospective institutional cohorts (n = 1135). Two independent stromal gene expression signatures implied stromal infiltration. Cox proportional hazards regression defined the association between stromal infiltration expression and metastasis-free survival (MFS). RESULTS: Stromal expression scores were correlated with stromal signature genes and with other key stromal markers (CAV1, VIM, and TAGLN), basal activity, and CD3 and CD4 immune biomarkers (r > 0.5 for all). The top decile of stromal expression was associated with high genomic risk scores (Decipher ≥ 0.6) , high Cancer of the Prostate Risk Assessment-Postsurgical scores, Gleason 9 to 10 disease, and a higher risk for metastasis (hazard ratio, 2.35; 95% CI, 1.37-4.02; P = .001). A higher stromal infiltration score was also associated with decreased expression of DNA repair genes and higher radiation sensitivity genomic scores. Postoperative radiation therapy (RT) was associated with an MFS benefit for patients with high stromal scores, but not for patients with low stromal scores (Pinteraction  = .02). CONCLUSIONS: Expression of stromal infiltration markers is correlated with prostate cancer aggressiveness/progression and may be predictive of a response to RT. Stromal infiltration markers should be studied and considered for incorporation into clinical prognostication and decision making.

9.
Nat Commun ; 11(1): 384, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959826

RESUMO

Emergence of an aggressive androgen receptor (AR)-independent neuroendocrine prostate cancer (NEPC) after androgen-deprivation therapy (ADT) is well-known. Nevertheless, the majority of advanced-stage prostate cancer patients, including those with SPINK1-positive subtype, are treated with AR-antagonists. Here, we show AR and its corepressor, REST, function as transcriptional-repressors of SPINK1, and AR-antagonists alleviate this repression leading to SPINK1 upregulation. Increased SOX2 expression during NE-transdifferentiation transactivates SPINK1, a critical-player for maintenance of NE-phenotype. SPINK1 elicits epithelial-mesenchymal-transition, stemness and cellular-plasticity. Conversely, pharmacological Casein Kinase-1 inhibition stabilizes REST, which in cooperation with AR causes SPINK1 transcriptional-repression and impedes SPINK1-mediated oncogenesis. Elevated levels of SPINK1 and NEPC markers are observed in the tumors of AR-antagonists treated mice, and in a subset of NEPC patients, implicating a plausible role of SPINK1 in treatment-related NEPC. Collectively, our findings provide an explanation for the paradoxical clinical-outcomes after ADT, possibly due to SPINK1 upregulation, and offers a strategy for adjuvant therapies.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Tumores Neuroendócrinos/genética , Neoplasias da Próstata/genética , Inibidor da Tripsina Pancreática de Kazal/metabolismo , Antagonistas de Receptores de Andrógenos/uso terapêutico , Animais , Caseína Quinase I/antagonistas & inibidores , Caseína Quinase I/metabolismo , Linhagem Celular Tumoral , Proteínas Correpressoras/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Próstata/efeitos dos fármacos , Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Transcrição Genética/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Clin Oncol ; : JCO1902768, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31829902

RESUMO

PURPOSE: This guideline provides recommendations for available tissue-based prostate cancer biomarkers geared toward patient selection for active surveillance, identification of clinically significant disease, choice of postprostatectomy adjuvant versus salvage radiotherapy, and to address emerging questions such as the relative value of tissue biomarkers compared with magnetic resonance imaging. METHODS: An ASCO multidisciplinary Expert Panel, with representatives from the European Association of Urology, American Urological Association, and the College of American Pathologists, conducted a systematic literature review of localized prostate cancer biomarker studies between January 2013 and January 2019. Numerous tissue-based molecular biomarkers were evaluated for their prognostic capabilities and potential for improving management decisions. Here, the Panel makes recommendations regarding the clinical use and indications of these biomarkers. RESULTS: Of 555 studies identified, 77 were selected for inclusion plus 32 additional references selected by the Expert Panel. Few biomarkers had rigorous testing involving multiple cohorts and only 5 of these tests are commercially available currently: Oncotype Dx Prostate, Prolaris, Decipher, Decipher PORTOS, and ProMark. With various degrees of value and validation, multiple biomarkers have been shown to refine risk stratification and can be considered for select men to improve management decisions. There is a paucity of prospective studies assessing short- and long-term outcomes of patients when these markers are integrated into clinical decision making. RECOMMENDATIONS: Tissue-based molecular biomarkers (evaluating the sample with the highest volume of the highest Gleason pattern) may improve risk stratification when added to standard clinical parameters, but the Expert Panel endorses their use only in situations in which the assay results, when considered as a whole with routine clinical factors, are likely to affect a clinical decision. These assays are not recommended for routine use as they have not been prospectively tested or shown to improve long-term outcomes-for example, quality of life, need for treatment, or survival. Additional information is available at www.asco.org/genitourinary-cancer-guidelines.

11.
Oncoimmunology ; 8(12): e1670019, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31741771

RESUMO

Organotypic tumor slices represent a physiologically-relevant culture system for studying the tumor microenvironment. Systematic characterization of the tumor slice culture system will enable its effective application for translational research. Here, using flow cytometry-based immunophenotyping, we performed a comprehensive characterization of the immune cell composition in organotypic tumor slices prepared from four syngeneic mouse tumor models and a human liver tumor. We found that the immune cell compositions of organotypic tumor slices prepared on the same day as the tumor cores were harvested are similar. Differences were primarily observed in the lymphocyte population of a clinical hepatocellular carcinoma case. Viable populations of immune cells persisted in the tumor slices for 7 days. Despite some changes in the immune cell populations, we showed the utility of mouse tumor slices for assessing responses to immune-modulatory agents. Further, we demonstrated the ability to use patient-derived xenograft tumor slices for assessing responses to targeted and cytotoxic drugs. Overall, tumor slices provide a broadly useful platform for studying the tumor microenvironment and evaluating the preclinical efficacy of cancer therapeutics.

13.
Nat Rev Urol ; 16(11): 645-654, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31591549

RESUMO

Metastatic biopsy programmes combined with advances in genomic sequencing have provided new insights into the molecular landscape of castration-resistant prostate cancer (CRPC), identifying actionable targets, and emerging resistance mechanisms. The detection of DNA repair aberrations, such as mutation of BRCA2, could help select patients for poly(ADP-ribose) polymerase (PARP) inhibitor or platinum chemotherapy, and mismatch repair gene defects and microsatellite instability have been associated with responses to checkpoint inhibitor immunotherapy. Poor prognostic features, such as the presence of RB1 deletion, might help guide future therapeutic strategies. Our understanding of the molecular features of CRPC is now being translated into the clinic in the form of increased molecular testing for use of these agents and for clinical trial eligibility. Genomic testing offers opportunities for improving patient selection for systemic therapies and, ultimately, patient outcomes. However, challenges for precision oncology in advanced prostate cancer still remain, including the contribution of tumour heterogeneity, the timing and potential cooperation of multiple driver gene aberrations, and diverse resistant mechanisms. Defining the optimal use of molecular biomarkers in the clinic, including tissue-based and liquid biopsies, is a rapidly evolving field.


Assuntos
Medicina de Precisão , Neoplasias de Próstata Resistentes à Castração/terapia , Humanos , Masculino , Oncologia/métodos , Estadiamento de Neoplasias , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-31475242

RESUMO

Purpose: To understand the clinical context of tumor mutational burden (TMB) when comparing a pan-cancer threshold and a cancer-specific threshold. Materials and Methods: Using whole exome sequencing (WES) data from primary tumors in The Cancer Genome Atlas (TCGA) (n=3,534) and advanced/metastatic tumors from Weill Cornell Medicine (WCM Advanced) (n=696), TMB status was determined using a pan-cancer and cancer-specific threshold. Survival curves, number of samples classified as TMB high, and predicted neoantigens were used to evaluate the differences between thresholds. Results: The distribution of TMB varied dramatically between cancer types. A cancer-specific threshold was able to adjust for the different TMB distributions, while the pan-cancer threshold was often too stringent. The dynamic nature of the cancer-specific threshold resulted in more tumors being classified as TMB high compared to the static pan-cancer threshold. Additionally, no significant difference in survival outcomes was found with the cancer-specific threshold compared to the pan-cancer one. Further, the cancer-specific threshold maintains higher predicted neoantigen load for the TMB high samples compared to the TMB low samples, even when the threshold is lower than the pan-cancer threshold. Conclusion: TMB is relative to the context of cancer type, metastatic state, and disease stage. Compared to a pan-cancer threshold, a cancer-specific threshold classifies more patients as TMB high while maintaining clinical outcomes that were not significantly different. Furthermore, the cancer-specific threshold identifies patients with a high number of predicted neoantigens. Due to the potential impact in cancer patient care, TMB status should be determined in a cancer-specific manner.

15.
Eur J Cancer ; 121: 7-18, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31525487

RESUMO

BACKGROUND: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may arise de novo or in patients previously treated with hormonal therapies for prostate adenocarcinoma as a mechanism of resistance. Despite being important to recognise, the clinical features of NEPC are poorly defined and could help guide when to perform a biopsy to look for NEPC histologic transformation. METHODS: We reviewed baseline, treatment and outcome data of 87 patients with metastatic prostate cancer and tumour biopsy confirming NEPC histology. Forty-seven (54.0%) NEPC cases presented de novo, and 40 (46.0%) were therapy-related (t-NEPC). Thirty-six (41.4%) were classified as pure small-cell carcinoma, and 51 (58.6%) demonstrated mixed features with both small-cell carcinoma and adenocarcinoma present. Genomic data were available for 47 patients. RESULTS: The median age at time of NEPC was 68.1 years, median prostate-specific antigen (PSA) was 1.20 ng/ml (0.14 ng/mL small-cell carcinoma, 1.55 ng/mL mixed carcinoma) and sites of metastases included bone (72.6%), lymph node (47.0%), and viscera (65.5%). Median time from adenocarcinoma to t-NEPC diagnosis was 39.7 months (range, 24.5-93.8) with a median of two lines of prior systemic therapy. Platinum chemotherapy was used to treat 57.5% of patients, with a median progression-free survival of 3.9 months. Small-cell carcinoma was associated with worse overall survival (OS) than mixed histology (8.9 months from NEPC diagnosis versus 26.1 months, P < 0.001). Median OS of de novo NEPC was shorter than that of t-NEPC (16.8 months from prostate cancer diagnosis versus 53.5 months, P = 0.043). An average PSA rise per month of ≤0.7 ng/ml before t-NEPC; elevated lactate dehydrogenase levels, RB1 and TP53 loss and liver metastases were poor prognostic features. CONCLUSIONS: We describe the clinical features of a cohort of patients with NEPC. These characteristics may inform future diagnostic strategies.

16.
Clin Cancer Res ; 25(22): 6839-6851, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31439587

RESUMO

PURPOSE: In this study, we addressed the underlying mechanisms for the association between enzalutamide (ENZ) treatment and neuroendocrine prostate cancer (NEPC), and the critical involvement of MYCN, and loss of RB1 function in neuroendocrine differentiation (NED) of prostatic epithelial cells, and the development of NEPC. We further sought to determine whether PARP inhibition could suppress NEPC, and to identify molecular determinants of this therapeutic activity. EXPERIMENTAL DESIGN: We used a novel prostate cancer patient-derived xenograft (PDX) treatment model, prostatic adenocarcinoma and NEPC cell lines, an NEPC organoid line, and NEPC xenograft models to address the mechanistic basis of ENZ-induced NED, and to analyze suppression of NED and NEPC growth by PARP inhibition. RESULTS: We identified an ENZ treatment-associated glucocorticoid receptor (GR)-MYCN-CDK5-RB1-E2F1 signaling pathway that drives NED in prostatic adenocarcinoma PDX and cell line models. Mechanistically, long-term ENZ treatment transcriptionally upregulates signaling of the GR-MYCN axis, leading to CDK5R1 and CDK5R2 upregulation, Rb1 phosphorylation, and N-Myc-mediated and E2F1-mediated NED gene expression. Importantly, olaparib (OLA) or talazoparib (TALA) suppressed these activities, and the combination of OLA and dinaciclib (DINA), an inhibitor of CDK2 and CDK5, which also inhibits Rb1 phosphorylation, suppressed NED and significantly improved therapeutic efficiency in NEPC cells in vitro and in NEPC tumors in vivo. CONCLUSIONS: The results of our study indicate an important role of GR-MYCN-CDK5R1/2-RB1-NED signaling in ENZ-induced and PARP inhibitor-suppressed NEPC. We also demonstrated efficacy for OLA+DINA combination therapy in NEPC xenograft models.

17.
Clin Cancer Res ; 25(23): 6916-6924, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31363002

RESUMO

Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer. Treatment-refractory prostate cancers are increasingly associated with loss of luminal prostate markers, and in many cases induction of developmental programs, stem cell-like phenotypes, and neuroendocrine/neuronal features. Clinically, lineage plasticity may manifest as low PSA progression, resistance to androgen receptor (AR) pathway inhibitors, and sometimes small cell/neuroendocrine pathologic features observed on metastatic biopsy. This mechanism is not restricted to prostate cancer as other malignancies also demonstrate lineage plasticity during resistance to targeted therapies. At present, there is no established therapeutic approach for patients with advanced prostate cancer developing lineage plasticity or small cell neuroendocrine prostate cancer (NEPC) due to knowledge gaps in the underlying biology. Few clinical trials address questions in this space, and the outlook for patients remains poor. To move forward, urgently needed are: (i) a fundamental understanding of how lineage plasticity occurs and how it can best be defined; (ii) the temporal contribution and cooperation of emerging drivers; (iii) preclinical models that recapitulate biology of the disease and the recognized phenotypes; (iv) identification of therapeutic targets; and (v) novel trial designs dedicated to the entity as it is defined. This Perspective represents a consensus arising from the NCI Workshop on Lineage Plasticity and Androgen Receptor-Independent Prostate Cancer. We focus on the critical questions underlying lineage plasticity and AR-independent prostate cancer, outline knowledge and resource gaps, and identify strategies to facilitate future collaborative clinical translational and basic studies in this space.

18.
Proc Natl Acad Sci U S A ; 116(34): 16987-16996, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31387980

RESUMO

Repetitive sequences are hotspots of evolution at multiple levels. However, due to difficulties involved in their assembly and analysis, the role of repeats in tumor evolution is poorly understood. We developed a rigorous motif-based methodology to quantify variations in the repeat content, beyond microsatellites, in proteomes and genomes directly from proteomic and genomic raw data. This method was applied to a wide range of tumors and normal tissues. We identify high similarity between repeat instability patterns in tumors and their patient-matched adjacent normal tissues. Nonetheless, tumor-specific signatures both in protein expression and in the genome strongly correlate with cancer progression and robustly predict the tumorigenic state. In a patient, the hierarchy of genomic repeat instability signatures accurately reconstructs tumor evolution, with primary tumors differentiated from metastases. We observe an inverse relationship between repeat instability and point mutation load within and across patients independent of other somatic aberrations. Thus, repeat instability is a distinct, transient, and compensatory adaptive mechanism in tumor evolution and a potential signal for early detection.

19.
J Clin Invest ; 130: 3924-3940, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260412

RESUMO

Despite recent therapeutic advances, prostate cancer remains a leading cause of cancer-related death. A subset of castration resistant prostate cancers become androgen receptor (AR) signaling-independent and develop neuroendocrine prostate cancer (NEPC) features through lineage plasticity. These NEPC tumors, associated with aggressive disease and poor prognosis, are driven, in part, by aberrant expression of N-Myc, through mechanisms that remain unclear. Integrative analysis of the N-Myc transcriptome, cistrome and interactome using in vivo, in vitro and ex vivo models (including patient-derived organoids) identified a lineage switch towards a neural identity associated with epigenetic reprogramming. N-Myc and known AR-co-factors (e.g., FOXA1 and HOXB13) overlapped, independently of AR, at genomic loci implicated in neural lineage specification. Moreover, histone marks specifically associated with lineage-defining genes were reprogrammed by N-Myc. We also demonstrated that the N-Myc-induced molecular program accurately classifies our cohort of patients with advanced prostate cancer. Finally, we revealed the potential for EZH2 inhibition to reverse the N-Myc-induced suppression of epithelial lineage genes. Altogether, our data provide insights on how N-Myc regulates lineage plasticity and epigenetic reprogramming associated with lineage-specification. The N-Myc signature we defined could also help predict the evolution of prostate cancer and thus better guide the choice of future therapeutic strategies.

20.
Nat Commun ; 10(1): 2977, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278255

RESUMO

Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype. To define the biological features driving this phenotype, we performed an integrated analysis of whole-exome and RNA sequencing of UTUC. Here we report several key insights from our molecular dissection of this disease: 1) Most UTUCs are luminal-papillary; 2) UTUC has a T-cell depleted immune contexture; 3) High FGFR3 expression is enriched in UTUC and correlates with its T-cell depleted immune microenvironment; 4) Sporadic UTUC is characterized by a lower total mutational burden than urothelial carcinoma of the bladder. Our findings lay the foundation for a deeper understanding of UTUC biology and provide a rationale for the development of UTUC-specific treatment strategies.


Assuntos
Carcinoma de Células de Transição/patologia , Neoplasias Renais/patologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Linfócitos T/imunologia , Neoplasias Ureterais/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/imunologia , Análise Mutacional de DNA , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Análise de Sequência de RNA , Transdução de Sinais/genética , Microambiente Tumoral/imunologia , Neoplasias Ureterais/genética , Neoplasias Ureterais/imunologia , Urotélio/patologia , Sequenciamento Completo do Exoma
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