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WHAT IS THIS SUMMARY ABOUT?: This is a summary of two articles. The first article is about a clinical trial called SPOTLIGHT and it was published in the medical journal The Lancet in in April of 2023. The second article is about a clinical trial called GLOW and it was published in the medical journal Nature Medicine in July of 2023. WHAT ARE THE KEY TAKEAWAYS?: Until recently, chemotherapy was the first treatment given to people with stomach cancer or gastroesophageal junction (or GEJ) cancer that is locally advanced unresectable or metastatic. When cancer cells have high amounts of the protein CLDN18.2 but do not have high amounts of the protein HER2, the cancer is known as CLDN18.2-positive (or CLDN18.2+) and HER2-negative (or HER2-). New medicines to treat cancer are being developed. These medicines attach to proteins on cancer cells to help the body recognize and kill cancer cells.The clinical trials SPOTLIGHT and GLOW included participants with CLDN18.2+ and HER2- stomach or GEJ cancer that was locally advanced unresectable or metastatic. These trials looked at whether adding a medicine called zolbetuximab to chemotherapy as the first treatment for cancer helped people live longer before their tumors grew bigger or new tumors grew, after starting the trial. These studies also looked at whether adding zolbetuximab to chemotherapy helped people live longer after starting the trial. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: In SPOTLIGHT and GLOW, on average, participants assigned to zolbetuximab plus chemotherapy lived 1.4 to 1.9 months longer before their tumors grew bigger or new tumors grew, after starting the trial, than participants assigned to a placebo plus chemotherapy. On average, participants assigned to zolbetuximab plus chemotherapy also lived 2.2 to 2.7 months longer, after starting the trial, than participants assigned to a placebo plus chemotherapy. These results suggest that zolbetuximab plus chemotherapy could be a new first treatment for people with CLDN18.2+ and HER2- stomach or GEJ cancer that is locally advanced unresectable or metastatic.Clinical Trial Registration: NCT03504397 (SPOTLIGHT); NCT03653507 (GLOW).
The clinical trials SPOTLIGHT and GLOW showed that, on average, participants with stomach or GEJ cancer assigned to zolbetuximab plus chemotherapy lived 2.2 to 2.7 months longer than participants assigned to a placebo plus chemotherapy.
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Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers comprised of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of PGC-1α, a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNC types. PGC-1α correlated tightly with increased expression of the lineage marker ASCL1 through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. PGC-1α overexpression enhanced OXPHOS, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These findings reveal the metabolic heterogeneity among SCNC subtypes and identify PGC-1α-induced OXPHOS as a regulator of SCNC lineage plasticity.
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Trans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy resistance in multiple cancer types. To gain insight into the underlying molecular events of the trans-differentiation, we perform a multi-omics time course analysis of a pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells and identify a shared developmental, arc-like, and entropy-high trajectory among all transformation model replicates. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 or ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. TFAP4 and ASCL1/2 feedback are identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, as well as connections to normal neuroendocrine cell states.
Assuntos
Carcinoma de Células Pequenas , Neoplasias Pulmonares , Neoplasias da Próstata , Carcinoma de Pequenas Células do Pulmão , Masculino , Humanos , Neoplasias Pulmonares/genética , Carcinoma de Células Pequenas/genética , Fatores de Transcrição/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Transdiferenciação Celular/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Carcinoma de Pequenas Células do Pulmão/genéticaRESUMO
PURPOSE: Zolbetuximab, an IgG1 monoclonal antibody, binds to claudin 18.2 (CLDN18.2) and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. We sought to examine zolbetuximab combinations in CLDN18.2-positive HER2-negative gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. PATIENTS AND METHODS: This phase II study assessed efficacy and safety of zolbetuximab, alone or with modified FOLFOX6 (mFOLFOX6) or pembrolizumab, in CLDN18.2-positive advanced/metastatic G/GEJ adenocarcinoma. Patients received zolbetuximab as monotherapy in third/later-line (Cohort 1A, n = 30), with mFOLFOX6 in first-line (Cohort 2, n = 21), or with pembrolizumab in third/later-line (Cohort 3A, n = 3) treatment. The primary endpoint for Cohort 1A was objective response rate (ORR). Key secondary endpoints were ORR (Cohorts 2 and 3A), overall survival (OS; Cohort 1A), and progression-free survival (PFS) and safety (all cohorts). RESULTS: ORR was 0% in Cohorts 1A and 3A, and 71.4% [95% confidence interval (CI), 47.82-88.72] in Cohort 2. Median PFS was 1.54 months (95% CI, 1.31-2.56) in Cohort 1A, 2.96 months (95% CI, 1.48-4.44) in Cohort 3A, and 17.8 months (95% CI, 8.05-25.69) in Cohort 2. Median OS in Cohort 1A was 5.62 months (95% CI, 2.27-11.53). Gastrointestinal adverse events occurred across cohorts [nausea, 63%-90% (grade ≥ 3, 4.8%-6.7%) and vomiting, 33%-67% (grade ≥ 3, 6.7%-9.5%)]. CONCLUSIONS: Zolbetuximab plus mFOLFOX6 demonstrated promising efficacy in previously untreated patients with CLDN18.2-positive G/GEJ adenocarcinoma. These data support the first-line development of zolbetuximab in patients whose tumors are CLDN18.2-positive. Across cohorts, zolbetuximab treatment was tolerable with no new safety signals.
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Adenocarcinoma , Anticorpos Monoclonais , Claudinas , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Claudinas/metabolismo , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Junção Esofagogástrica/patologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapiaRESUMO
There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Claudin-18 isoform 2 (CLDN18.2) is expressed in normal gastric cells and maintained in malignant G/GEJ adenocarcinoma cells. GLOW (closed enrollment), a global, double-blind, phase 3 study, examined zolbetuximab, a monoclonal antibody that targets CLDN18.2, plus capecitabine and oxaliplatin (CAPOX) as first-line treatment for CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. Patients (n = 507) were randomized 1:1 (block sizes of two) to zolbetuximab plus CAPOX or placebo plus CAPOX. GLOW met the primary endpoint of progression-free survival (median, 8.21 months versus 6.80 months with zolbetuximab versus placebo; hazard ratio (HR) = 0.687; 95% confidence interval (CI), 0.544-0.866; P = 0.0007) and key secondary endpoint of overall survival (median, 14.39 months versus 12.16 months; HR = 0.771; 95% CI, 0.615-0.965; P = 0.0118). Grade ≥3 treatment-emergent adverse events were similar with zolbetuximab (72.8%) and placebo (69.9%). Zolbetuximab plus CAPOX represents a potential new first-line therapy for patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. ClinicalTrials.gov identifier: NCT03653507 .
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Claudinas/uso terapêutico , Junção Esofagogástrica/patologia , Oxaliplatina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Zolbetuximab, a monoclonal antibody targeting claudin-18 isoform 2 (CLDN18.2), has shown efficacy in patients with CLDN18.2-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. We report the results of the SPOTLIGHT trial, which investigated the efficacy and safety of first-line zolbetuximab plus mFOLFOX6 (modified folinic acid [or levofolinate], fluorouracil, and oxaliplatin regimen) versus placebo plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. METHODS: SPOTLIGHT is a global, randomised, placebo-controlled, double-blind, phase 3 trial that enrolled patients from 215 centres in 20 countries. Eligible patients were aged 18 years or older with CLDN18.2-positive (defined as ≥75% of tumour cells showing moderate-to-strong membranous CLDN18 staining), HER2-negative (based on local or central evaluation), previously untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma, with radiologically evaluable disease (measurable or non-measurable) according to Response Evaluation Criteria in Solid Tumors version 1.1; an Eastern Cooperative Oncology Group performance status score of 0 or 1; and adequate organ function. Patients were randomly assigned (1:1) via interactive response technology and stratified according to region, number of organs with metastases, and previous gastrectomy. Patients received zolbetuximab (800 mg/m2 loading dose followed by 600 mg/m2 every 3 weeks) plus mFOLFOX6 (every 2 weeks) or placebo plus mFOLFOX6. The primary endpoint was progression-free survival assessed by independent review committee in all randomly assigned patients. Safety was assessed in all treated patients. The study is registered with ClinicalTrials.gov, NCT03504397, and is closed to new participants. FINDINGS: Between June 21, 2018, and April 1, 2022, 565 patients were randomly assigned to receive either zolbetuximab plus mFOLFOX6 (283 patients; the zolbetuximab group) or placebo plus mFOLFOX6 (282 patients; the placebo group). At least one dose of treatment was administered to 279 (99%) of 283 patients in the zolbetuximab group and 278 (99%) of 282 patients in the placebo group. In the zolbetuximab group, 176 (62%) patients were male and 107 (38%) were female. In the placebo group, 175 (62%) patients were male and 107 (38%) were female. The median follow-up duration for progression-free survival was 12·94 months in the zolbetuximab group versus 12·65 months in the placebo group. Zolbetuximab treatment showed a significant reduction in the risk of disease progression or death compared with placebo (hazard ratio [HR] 0·75, 95% CI 0·60-0·94; p=0·0066). The median progression-free survival was 10·61 months (95% CI 8·90-12·48) in the zolbetuximab group versus 8·67 months (8·21-10·28) in the placebo group. Zolbetuximab treatment also showed a significant reduction in the risk of death versus placebo (HR 0·75, 95% CI 0·60-0·94; p=0·0053). Treatment-emergent grade 3 or worse adverse events occurred in 242 (87%) of 279 patients in the zolbetuximab group versus 216 (78%) of 278 patients in the placebo group. The most common grade 3 or worse adverse events were nausea, vomiting, and decreased appetite. Treatment-related deaths occurred in five (2%) patients in the zolbetuximab group versus four (1%) patients in the placebo group. No new safety signals were identified. INTERPRETATION: Targeting CLDN18.2 with zolbetuximab significantly prolonged progression-free survival and overall survival when combined with mFOLFOX6 versus placebo plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Zolbetuximab plus mFOLFOX6 might represent a new first-line treatment in these patients. FUNDING: Astellas Pharma, Inc.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Masculino , Feminino , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias Gástricas/patologia , Junção Esofagogástrica/patologia , Anticorpos Monoclonais/efeitos adversos , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Método Duplo-Cego , Claudinas/uso terapêuticoRESUMO
The increased treatment of metastatic castration-resistant prostate cancer (mCRPC) with second-generation antiandrogen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost dependence on androgen receptor (AR) signaling. These AR-independent tumors may also transdifferentiate to express neuroendocrine lineage markers and are termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing several AR-independent to AR-dependent prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-independent cell lines. Clinical NEPC patient samples and NEPC patient-derived xenografts displayed upregulated RET transcript and RET pathway activity. Genetic knockdown or pharmacologic inhibition of RET kinase in multiple mouse and human models of NEPC dramatically reduced tumor growth and decreased cell viability. Our results suggest that targeting RET in NEPC tumors with high RET expression could be an effective treatment option. Currently, there are limited treatment options for patients with aggressive neuroendocrine prostate cancer and none are curative. IMPLICATIONS: Identification of aberrantly expressed RET kinase as a driver of tumor growth in multiple models of NEPC provides a significant rationale for testing the clinical application of RET inhibitors in patients with AVPC.
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Carcinoma Neuroendócrino/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Proteômica/métodos , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Animais , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Masculino , Camundongos , Células PC-3 , Fosforilação , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Small cell carcinoma of the bladder (SCCB) is a rare and lethal phenotype of bladder cancer. The pathogenesis and molecular features are unknown. Here, we established a genetically engineered SCCB model and a cohort of patient SCCB and urothelial carcinoma samples to characterize molecular similarities and differences between bladder cancer phenotypes. We demonstrate that SCCB shares a urothelial origin with other bladder cancer phenotypes by showing that urothelial cells driven by a set of defined oncogenic factors give rise to a mixture of tumor phenotypes, including small cell carcinoma, urothelial carcinoma, and squamous cell carcinoma. Tumor-derived single-cell clones also give rise to both SCCB and urothelial carcinoma in xenografts. Despite this shared urothelial origin, clinical SCCB samples have a distinct transcriptional profile and a unique transcriptional regulatory network. Using the transcriptional profile from our cohort, we identified cell surface proteins (CSPs) associated with the SCCB phenotype. We found that the majority of SCCB samples have PD-L1 expression in both tumor cells and tumor-infiltrating lymphocytes, suggesting that immune checkpoint inhibitors could be a treatment option for SCCB. We further demonstrate that our genetically engineered tumor model is a representative tool for investigating CSPs in SCCB by showing that it shares a similar a CSP profile with clinical samples and expresses SCCB-up-regulated CSPs at both the mRNA and protein levels. Our findings reveal distinct molecular features of SCCB and provide a transcriptional dataset and a preclinical model for further investigating SCCB biology.
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Carcinoma de Células Pequenas/patologia , Carcinoma de Células de Transição/patologia , Transformação Celular Neoplásica/genética , Neoplasias da Bexiga Urinária/patologia , Bexiga Urinária/patologia , Urotélio/patologia , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/terapia , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/terapia , Transformação Celular Neoplásica/efeitos dos fármacos , Células Cultivadas , Cistectomia , Conjuntos de Dados como Assunto , Células Epiteliais , Regulação Neoplásica da Expressão Gênica , Engenharia Genética , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Cultura Primária de Células , RNA-Seq , Bexiga Urinária/citologia , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/terapia , Urotélio/citologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.
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Resistencia a Medicamentos Antineoplásicos , Terapia de Alvo Molecular , Neoplasias da Próstata/tratamento farmacológico , Receptores de Interleucina-8B/antagonistas & inibidores , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Progressão da Doença , Humanos , Masculino , Camundongos Nus , Gradação de Tumores , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Tumores Neuroendócrinos/irrigação sanguínea , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Sistemas Neurossecretores/patologia , Fenótipo , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/patologia , Receptores de Interleucina-8B/metabolismo , Transdução de Sinais , Microambiente TumoralRESUMO
Small-cell neuroendocrine cancers (SCNCs) are an aggressive cancer subtype. Transdifferentiation toward an SCN phenotype has been reported as a resistance route in response to targeted therapies. Here, we identified a convergence to an SCN state that is widespread across epithelial cancers and is associated with poor prognosis. More broadly, non-SCN metastases have higher expression of SCN-associated transcription factors than non-SCN primary tumors. Drug sensitivity and gene dependency screens demonstrate that these convergent SCNCs have shared vulnerabilities. These common vulnerabilities are found across unannotated SCN-like epithelial cases, small-round-blue cell tumors, and unexpectedly in hematological malignancies. The SCN convergent phenotype and common sensitivity profiles with hematological cancers can guide treatment options beyond tissue-specific targeted therapies.
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Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/etiologia , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/etiologia , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/etiologia , Fenótipo , Carcinoma de Células Pequenas/tratamento farmacológico , Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Suscetibilidade a Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Mutação , Tumores Neuroendócrinos/tratamento farmacológico , TranscriptomaRESUMO
The use of potent therapies inhibiting critical oncogenic pathways active in epithelial cancers has led to multiple resistance mechanisms, including the development of highly aggressive, small cell neuroendocrine carcinoma (SCNC). SCNC patients have a dismal prognosis due in part to a limited understanding of the molecular mechanisms driving this malignancy and the lack of effective treatments. Here, we demonstrate that a common set of defined oncogenic drivers reproducibly reprograms normal human prostate and lung epithelial cells to small cell prostate cancer (SCPC) and small cell lung cancer (SCLC), respectively. We identify shared active transcription factor binding regions in the reprogrammed prostate and lung SCNCs by integrative analyses of epigenetic and transcriptional landscapes. These results suggest that neuroendocrine cancers arising from distinct epithelial tissues may share common vulnerabilities that could be exploited for the development of drugs targeting SCNCs.
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Carcinogênese/genética , Carcinoma Neuroendócrino/patologia , Reprogramação Celular/genética , Neoplasias Pulmonares/patologia , Pulmão/patologia , Próstata/patologia , Neoplasias da Próstata/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma Neuroendócrino/genética , Linhagem Celular Tumoral , Linhagem da Célula , Técnicas de Reprogramação Celular , Sistemas de Liberação de Medicamentos , Células Epiteliais/patologia , Epitélio/patologia , Humanos , Masculino , Neoplasias da Próstata/genética , Proteína do Retinoblastoma/genética , Carcinoma de Pequenas Células do Pulmão/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
Cancer progression to an aggressive phenotype often co-opts aspects of stem cell biology. Here, we developed gene signatures for normal human stem cell populations to understand the relationship between epithelial cancers and stem cell transcriptional programs. Using a pan-cancer approach, we reveal that aggressive epithelial cancers are enriched for a transcriptional signature shared by epithelial adult stem cells. The adult stem cell signature selected for epithelial cancers with worse overall survival and alterations of oncogenic drivers. Lethal small cell neuroendocrine lung, prostate, and bladder cancers transcriptionally converged onto the adult stem cell signature and not other stem cell signatures tested. We found that DNA methyltransferase expression correlated with adult stem cell signature status and was enriched in small cell neuroendocrine cancers. DNA methylation analysis uncovered a shared epigenomic profile between small cell neuroendocrine cancers. These pan-cancer findings establish a molecular link between human adult stem cells and aggressive epithelial cancers.
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Células-Tronco Adultas/metabolismo , Células Epiteliais/metabolismo , Neoplasias Pulmonares/genética , Neoplasias da Próstata/genética , Transcriptoma , Neoplasias da Bexiga Urinária/genética , Animais , Linhagem Celular , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Neoplasias da Próstata/metabolismo , Neoplasias da Bexiga Urinária/metabolismoRESUMO
Prostate cancer is a heterogeneous disease composed of divergent molecular and histologic subtypes, including prostate adenocarcinoma (PrAd) and neuroendocrine prostate cancer (NEPC). While PrAd is the major histology in prostate cancer, NEPC can evolve from PrAd as a mechanism of treatment resistance that involves a transition from an epithelial to a neurosecretory cancer phenotype. Cell surface markers are often associated with specific cell lineages and differentiation states in normal development and cancer. Here, we show that PrAd and NEPC can be broadly discriminated by cell-surface profiles based on the analysis of prostate cancer gene expression datasets. To overcome a dependence on predictions of human cell-surface genes and an assumed correlation between mRNA levels and protein expression, we integrated transcriptomic and cell-surface proteomic data generated from a panel of prostate cancer cell lines to nominate cell-surface markers associated with these cancer subtypes. FXYD3 and CEACAM5 were validated as cell-surface antigens enriched in PrAd and NEPC, respectively. Given the lack of effective treatments for NEPC, CEACAM5 appeared to be a promising target for cell-based immunotherapy. As a proof of concept, engineered chimeric antigen receptor T cells targeting CEACAM5 induced antigen-specific cytotoxicity in NEPC cell lines. Our findings demonstrate that the surfaceomes of PrAd and NEPC reflect unique cancer differentiation states and broadly represent vulnerabilities amenable to therapeutic targeting.
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Antígenos de Superfície/análise , Antígenos de Superfície/imunologia , Carcinoma Neuroendócrino/terapia , Neoplasias da Próstata/terapia , Proteoma/análise , Linfócitos T/transplante , Transcriptoma , Antígeno Carcinoembrionário/genética , Antígeno Carcinoembrionário/imunologia , Antígeno Carcinoembrionário/metabolismo , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/imunologia , Carcinoma Neuroendócrino/metabolismo , Diferenciação Celular , Células Cultivadas , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Proteínas de Neoplasias/metabolismo , Próstata/imunologia , Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Proteoma/imunologia , Linfócitos T/citologia , Linfócitos T/imunologiaRESUMO
Importance: The androgen receptor inhibitor enzalutamide prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC). In controlled clinical studies, 0.5% (10 of 2051) of patients experienced seizure, but patients with a history of or risk factors for seizure were excluded. Men with mCRPC and seizure risk factors have an estimated seizure rate of 2.8 per 100 patient-years without enzalutamide exposure. Objective: To assess seizure incidence in patients with seizure risk factors who were receiving enzalutamide for mCRPC. Design, Setting, and Participants: The UPWARD study (A Study to Evaluate the Potential Increased Risk of Seizures Among Metastatic Castration-Resistant Prostate Cancer Patients Treated With Enzalutamide) is an international, multicenter (73 sites in 20 countries), single-arm, open-label safety study in institutional practice. Data were collected from September 25, 2013, to February 1, 2016. Patients had at least 1 risk factor for seizure at baseline, including medications that lower seizure threshold, history of stroke, or history of seizure. Exclusion criteria included seizure (assessed by neurologic examination and history) requiring antiseizure medication within the past 12 months. Intervention: Treatment with oral enzalutamide, 160 mg/d. Main Outcomes and Measures: The primary end point was the proportion of evaluable patients with 1 or more independently confirmed seizures during the 4-month study period; evaluable patients were defined as those who had 3 months or more of treatment or 1 or more confirmed seizures during this treatment period. Results: Of 423 patients with mCRPC receiving enzalutamide, 366 were evaluated. At baseline, risk factors for seizure included medications that lowered seizure threshold (242 of 423 patients [57.2%]), history of brain injury (112 [26.5%]), and history of cerebrovascular accident or transient ischemic attack (94 [22.2%]). Four of the 366 evaluable patients (1.1%) had at least 1 confirmed seizure within 4 months of enzalutamide initiation, and 3 (0.8%) additional patients experienced a seizure within 4 months following the 4-month study period. The incidence of confirmed seizure was 2.6 per 100 patient-years (7 seizures). Of the 423 patients receiving enzalutamide, 357 (84.4%) experienced at least 1 treatment-emergent adverse event (an adverse event temporally related to the study treatment); 141 (33.3%) had at least 1 serious treatment-emergent adverse event, and 29 (6.9%) had at least 1 drug-related serious adverse event. Thirty-eight deaths (9.0%) were reported during treatment or within 30 days of drug discontinuation; 4 were considered possibly drug related. Conclusions and Relevance: Incidence of seizure is similar in patients with mCRPC and similar seizure risk factors with or without enzalutamide exposure. The risk profile presented, along with the previously established efficacy of enzalutamide, suggests that enzalutamide can benefit patients with a history of seizures or other predisposing factors, but each patient should be closely monitored for the duration of treatment.
Assuntos
Antineoplásicos/efeitos adversos , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/complicações , Convulsões/epidemiologia , Convulsões/etiologia , Antineoplásicos/uso terapêutico , Benzamidas , Humanos , Incidência , Masculino , Nitrilas , Feniltioidantoína/efeitos adversos , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Medição de Risco , Fatores de Risco , Convulsões/diagnósticoRESUMO
The median survival of patients with small cell neuroendocrine carcinoma is significantly shorter than that of patients with classic acinar-type adenocarcinoma. Small cell neuroendocrine carcinoma is traditionally diagnosed based on histologic features because expression of current immunohistochemical markers is inconsistent. This is a challenging diagnosis even for expert pathologists and particularly so for pathologists who do not specialize in prostate cancer. New biomarkers to aid in the diagnosis of small cell neuroendocrine carcinoma are therefore urgently needed. We discovered that FOXA2, a pioneer transcription factor, is frequently and specifically expressed in small cell neuroendocrine carcinoma compared with prostate adenocarcinoma from published mRNA-sequencing data of a wide range of human prostate cancers. We verified the expression of FOXA2 in human prostate cancer cell lines and xenografts, patient biopsy specimens, tissue microarrays of prostate cancers with lymph node metastasis, primary small cell neuroendocrine carcinoma, and metastatic treatment-related small cell neuroendocrine carcinoma and cases from a rapid autopsy program. FOXA2 expression was present in NCI-H660 and PC3 neuroendocrine cell lines, but not in LNCAP and CWR22 adenocarcinoma cell lines. Of the human prostate cancer specimens, 20 of 235 specimens (8.5%) showed diagnostic histologic features of small cell neuroendocrine carcinoma as judged histologically. Fifteen of 20 small cell neuroendocrine carcinoma tissues (75%) showed strong expression of FOXA2 (staining intensity 2 or 3). FOXA2 expression was also detected in 9 of 215 prostate cancer tissues (4.2%) that were histologically defined as adenocarcinoma. Our findings demonstrate that FOXA2 is a sensitive and specific molecular marker that may be extremely valuable in the pathologic diagnosis of small cell neuroendocrine carcinoma.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/metabolismo , Carcinoma de Células Pequenas/metabolismo , Fator 3-beta Nuclear de Hepatócito/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Biomarcadores Tumorais/genética , Biópsia , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/secundário , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/secundário , Linhagem Celular Tumoral , Proliferação de Células , Diagnóstico Diferencial , Regulação Neoplásica da Expressão Gênica , Fator 3-beta Nuclear de Hepatócito/genética , Xenoenxertos , Humanos , Imuno-Histoquímica , Masculino , Camundongos Endogâmicos NOD , Transplante de Neoplasias , Valor Preditivo dos Testes , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Análise Serial de Tecidos , Carga TumoralRESUMO
Precise measurement of postvoid residual (PVR) urine volume is a key factor in assessing patients with voiding dysfunction, including those with lower urinary tract problems. The safe and noninvasive ultrasound bladder scan is the preferred mode to measure PVR volume. However, this procedure has a false-positive rate up to 9%, in the presence of ovarian cysts, renal cysts, ascites, or uterine myoma with cystic degeneration. Until now, cystic lesions are known to cause false positivity in ultrasound bladder scanner. However, we encountered falsely-elevated PVR in two cases of non-cystic uterine myomas. We present these cases with detailed radiologic images and volume measurement data.
RESUMO
Inflammation is a risk factor for prostate cancer, but the mechanisms by which inflammation increases that risk are poorly understood. Here, we demonstrate that low expression of CD38 identifies a progenitor-like subset of luminal cells in the human prostate. CD38lo luminal cells are enriched in glands adjacent to inflammatory cells and exhibit epithelial nuclear factor κB (NF-κB) signaling. In response to oncogenic transformation, CD38lo luminal cells can initiate human prostate cancer in an in vivo tissue-regeneration assay. Finally, the CD38lo luminal phenotype and gene signature are associated with disease progression and poor outcome in prostate cancer. Our results suggest that prostate inflammation expands the pool of progenitor-like target cells susceptible to tumorigenesis.
Assuntos
ADP-Ribosil Ciclase 1/genética , Transformação Celular Neoplásica/genética , Inflamação/genética , Neoplasias da Próstata/genética , ADP-Ribosil Ciclase 1/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/genética , Transformação Celular Neoplásica/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , NF-kappa B/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologiaRESUMO
Fanconi anemia (FA) is a rare genetic disorder caused by defects in DNA damage repair. FA patients often develop squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) are known to cause cancer, including the cervix. However, SCCs found in human FA patients are often HPV negative, even though the majority of female FA patients with anogenital cancers had preexisting HPV-positive dysplasia. We hypothesize that HPVs contribute to the development of SCCs in FA patients but that the continued expression of HPV oncogenes is not required for the maintenance of the cancer state because FA deficiency leads to an accumulation of mutations in cellular genes that render the cancer no longer dependent upon viral oncogenes. We tested this hypothesis, making use of Bi-L E7 transgenic mice in which we temporally controlled expression of HPV16 E7, the dominant viral oncogene in HPV-associated cancers. As seen before, the persistence of cervical neoplastic disease was highly dependent upon the continued expression of HPV16 E7 in FA-sufficient mice. However, in mice with FA deficiency, cervical cancers persisted in a large fraction of the mice after HPV16 E7 expression was turned off, indicating that these cancers had escaped from their dependency on E7. Furthermore, the severity of precancerous lesions also failed to be reduced significantly in the mice with FA deficiency upon turning off expression of E7. These findings confirm our hypothesis and may explain the fact that, while FA patients have a high frequency of infections by HPVs and HPV-induced precancerous lesions, the cancers are frequently HPV negative. IMPORTANCE : Fanconi anemia (FA) patients are at high risk for developing squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) frequently cause cancer. Yet these SCCs are often HPV negative. FA patients have a genetic defect in their capacity to repair damaged DNA. HPV oncogenes cause an accumulation of DNA damage. We hypothesize, therefore, that DNA damage induced by HPV leads to an accumulation of mutations in patients with FA deficiency and that such mutations allow HPV-driven cancers to become independent of the viral oncogenes. Consistent with this hypothesis, we found that cervical cancers arising in HPV16 transgenic mice with FA deficiency frequently escape from dependency on the HPV16 oncogene that drove its development. Our report provides further support for vaccination of FA patients against HPVs and argues for the need to define mutational profiles of SCCs arising in FA patients in order to inform precision medicine-based approaches to treating these patients.
Assuntos
Carcinoma de Células Escamosas/virologia , Anemia de Fanconi/genética , Expressão Gênica , Papillomavirus Humano 16/genética , Proteínas E7 de Papillomavirus/genética , Neoplasias do Colo do Útero/virologia , Animais , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/genética , Reparo do DNA , Anemia de Fanconi/complicações , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Componente 7 do Complexo de Manutenção de Minicromossomo/genética , Proteínas Repressoras/genética , Neoplasias do Colo do Útero/complicações , Neoplasias do Colo do Útero/genéticaRESUMO
The cell of origin for prostate cancer remains a subject of debate. Genetically engineered mouse models have demonstrated that both basal and luminal cells can serve as cells of origin for prostate cancer. Using a human prostate regeneration and transformation assay, our group previously demonstrated that basal cells can serve as efficient targets for transformation. Recently, a subpopulation of multipotent human luminal cells defined by CD26 expression that retains progenitor activity in a defined organoid culture was identified. We transduced primary human prostate basal and luminal cells with lentiviruses expressing c-Myc and activated AKT1 (myristoylated AKT1 or myrAKT1) to mimic theMYCamplification andPTENloss commonly detected in human prostate cancer. These cells were propagated in organoid culture before being transplanted into immunodeficient mice. We found that c-Myc/myrAKT1-transduced luminal xenografts exhibited histological features of well-differentiated acinar adenocarcinoma, with strong androgen receptor (AR) and prostate-specific antigen (PSA) expression. In contrast, c-Myc/myrAKT1-transduced basal xenografts were histologically more aggressive, with a loss of acinar structures and low/absent AR and PSA expression. Our findings imply that distinct subtypes of prostate cancer may arise from luminal and basal epithelial cell types subjected to the same oncogenic insults. This study provides a platform for the functional evaluation of oncogenes in basal and luminal epithelial populations of the human prostate. Tumors derived in this fashion with defined genetics can be used in the preclinical development of targeted therapeutics.
Assuntos
Diferenciação Celular , Transformação Celular Neoplásica/metabolismo , Células Epiteliais/metabolismo , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Células Epiteliais/patologia , Xenoenxertos , Humanos , Calicreínas/biossíntese , Calicreínas/genética , Lentivirus , Masculino , Camundongos , Camundongos SCID , Transplante de Neoplasias , Organoides/metabolismo , Organoides/patologia , PTEN Fosfo-Hidrolase/biossíntese , PTEN Fosfo-Hidrolase/genética , Próstata/patologia , Antígeno Prostático Específico/biossíntese , Antígeno Prostático Específico/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/biossíntese , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteínas Proto-Oncogênicas c-myc/genética , Receptores Androgênicos/biossíntese , Receptores Androgênicos/genética , Transdução GenéticaRESUMO
MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention.