RESUMEN
Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.
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Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias Pancreáticas/metabolismo , Biosíntesis de Proteínas , Animales , Comunicación Autocrina , Cisteína/metabolismo , Glutatión/metabolismo , Humanos , Ratones , Organoides/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de SeñalRESUMEN
Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.
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Carcinoma Ductal Pancreático/patología , Modelos Biológicos , Técnicas de Cultivo de Órganos , Organoides/patología , Neoplasias Pancreáticas/patología , Animales , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Páncreas/metabolismo , Páncreas/patologíaRESUMEN
Neutrophils are expanded and abundant in cancer-bearing hosts. Under the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8+ T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.
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Trampas Extracelulares/metabolismo , Neoplasias Experimentales/terapia , Receptores de Quimiocina/agonistas , Receptores de Interleucina-8A/agonistas , Receptores de Interleucina-8B/agonistas , Animales , Línea Celular Tumoral , Citotoxicidad Inmunológica/inmunología , Células HT29 , Humanos , Microscopía Intravital/métodos , Células Asesinas Naturales/inmunología , Ligandos , Ratones , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/metabolismo , Receptores de Quimiocina/inmunología , Receptores de Quimiocina/metabolismo , Receptores de Interleucina-8A/inmunología , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/inmunología , Receptores de Interleucina-8B/metabolismo , Linfocitos T Citotóxicos/inmunologíaRESUMEN
BACKGROUND: Despite a potentially curative treatment, the prognosis after upfront surgery and adjuvant chemotherapy for patients with resectable pancreatic ductal adenocarcinoma (PDAC) is poor. Modified FOLFIRINOX (mFOLFIRINOX) is a cornerstone in the systemic treatment of PDAC, including the neoadjuvant setting. Pharmacokinetic-guided (PKG) dosing has demonstrated beneficial effects in other tumors, but scarce data is available in pancreatic cancer. METHODS: Forty-six patients with resected PDAC after mFOLFIRINOX neoadjuvant approach and included in an institutional protocol for anticancer drug monitoring were retrospectively analyzed. 5-Fluorouracil (5-FU) dosage was adjusted throughout neoadjuvant treatment according to pharmacokinetic parameters and Irinotecan (CPT-11) pharmacokinetic variables were retrospectively estimated. RESULTS: By exploratory univariate analyses, a significantly longer progression-free survival was observed for patients with either 5-FU area under the curve (AUC) above 28 mcg·h/mL or CPT-11 AUC values below 10 mcg·h/mL. In the multivariate analyses adjusted by age, gender, performance status and resectability after stratification according to both pharmacokinetic parameters, the risk of progression was significantly reduced in patients with 5-FU AUC ≥28 mcg·h/mL [HR = 0.251, 95% CI 0.096-0.656; p = 0.005] and CPT-11 AUC <10 mcg·h/mL [HR = 0.189, 95% CI 0.073-0.486, p = 0.001]. CONCLUSIONS: Pharmacokinetically-guided dose adjustment of standard chemotherapy treatments might improve survival outcomes in patients with pancreatic ductal adenocarcinoma.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Irinotecán/uso terapéutico , Terapia Neoadyuvante/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Retrospectivos , Monitoreo de Drogas , Oxaliplatino/uso terapéutico , Leucovorina/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/cirugía , Fluorouracilo/uso terapéutico , Neoplasias PancreáticasRESUMEN
BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence and related mortality is increasing. This study investigates the clinical course of CCA and subtypes (intrahepatic [iCCA], perihilar [pCCA], and distal [dCCA]) in a pan-European cohort. METHODS: The ENSCCA Registry is a multicenter observational study. Patients were included if they had a histologically proven diagnosis of CCA between 2010-2019. Demographic, histomorphological, biochemical, and clinical studies were performed. RESULTS: Overall, 2,234 patients were enrolled (male/female=1.29). iCCA (n = 1,243) was associated with overweight/obesity and chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA (n = 592) with primary sclerosing cholangitis; and dCCA (n = 399) with choledocholithiasis. At diagnosis, 42.2% of patients had local disease, 29.4% locally advanced disease (LAD), and 28.4% metastatic disease (MD). Serum CEA and CA19-9 showed low diagnostic sensitivity, but their concomitant elevation was associated with increased risk of presenting with LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD (odds ratio 5.88; 95% CI 3.69-9.25). Patients undergoing resection (50.3%) had the best outcomes, particularly with negative-resection margin (R0) (median overall survival [mOS] = 45.1 months); however, margin involvement (R1) (hazard ratio 1.92; 95% CI 1.53-2.41; mOS = 24.7 months) and lymph node invasion (hazard ratio 2.13; 95% CI 1.55-2.94; mOS = 23.3 months) compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%), and 4.0 months for those receiving best supportive care (20.6%). iCCAs were associated with worse outcomes than p/dCCAs. ECOG performance status, MD and CA19-9 were independent prognostic factors. CONCLUSION: CCA is frequently diagnosed at an advanced stage, a proportion of patients fail to receive cancer-specific therapies, and prognosis remains dismal. Identification of preventable risk factors and implementation of surveillance in high-risk populations are required to decrease cancer-related mortality. LAY SUMMARY: This is, to date, the largest international (pan-European: 26 hospitals and 11 countries) observational study, in which the course of cholangiocarcinoma has been investigated, comparing the 3 subtypes based on the latest International Classification of Diseases 11th Edition (ICD-11) (i.e., intrahepatic [2C12], perihilar [2C18], or distal [2C15] affected bile ducts), which come into effect in 2022. General and tumor-type specific features at diagnosis, risk factors, biomarker accuracy, as well as patient management and outcomes, are presented and compared, outlining the current clinical state of cholangiocarcinoma in Europe.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/epidemiología , Neoplasias de los Conductos Biliares/terapia , Conductos Biliares Intrahepáticos/patología , Antígeno CA-19-9 , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/epidemiología , Colangiocarcinoma/terapia , Femenino , Humanos , Masculino , Pronóstico , Sistema de RegistrosRESUMEN
BACKGROUND: Adoptive immunotherapy with tumour-infiltrating lymphocytes (TIL) may benefit from the use of selective markers, such as PD-1, for tumour-specific T-cell enrichment, and the identification of predictive factors that help identify those patients capable of rendering tumour-reactive TILs. We have investigated this in ovarian cancer (OC) patients as candidates for TIL therapy implementation. METHODS: PD-1- and PD-1+ CD8 TILs were isolated from ovarian tumours and expanded cells were tested against autologous tumour cells. Baseline tumour samples were examined using flow cytometry, multiplexed immunofluorescence and Nanostring technology, for gene expression analyses, as well as a next-generation sequencing gene panel, for tumour mutational burden (TMB) calculation. RESULTS: Tumour-reactive TILs were detected in half of patients and were exclusively present in cells derived from the PD-1+ fraction. Importantly, a high TIL density in the fresh tumour, the presence of CD137+ cells within the PD-1+CD8+ TIL subset and their location in the tumour epithelium, together with a baseline T-cell-inflamed genetic signature and/or a high TMB, are features that identify patients rendering tumour-reactive TIL products. CONCLUSION: We have demonstrated that PD-1 identifies ovarian tumour-specific CD8 TILs and has uncovered predictive factors that identify OC patients who are likely to render tumour-specific cells from PD-1+ TILs.
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Biomarcadores de Tumor/genética , Linfocitos T CD8-positivos/inmunología , Regulación Neoplásica de la Expresión Génica , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Ováricas/patología , Receptor de Muerte Celular Programada 1/metabolismo , Biomarcadores de Tumor/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Ováricas/genética , Neoplasias Ováricas/inmunología , Fenotipo , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a neoplasia of the biliary tract driven by genetic, epigenetic and transcriptional mechanisms. Herein, we investigated the role of the transcription factor FOSL1, as well as its downstream transcriptional effectors, in the development and progression of CCA. METHODS: FOSL1 was investigated in human CCA clinical samples. Genetic inhibition of FOSL1 in human and mouse CCA cell lines was performed in in vitro and in vivo models using constitutive and inducible short-hairpin RNAs. Conditional FOSL1 ablation was done using a genetically engineered mouse (GEM) model of CCA (mutant KRAS and Trp53 knockout). Follow-up RNA and chromatin immunoprecipitation (ChIP) sequencing analyses were carried out and downstream targets were validated using genetic and pharmacological inhibition. RESULTS: An inter-species analysis of FOSL1 in CCA was conducted. First, FOSL1 was found to be highly upregulated in human and mouse CCA, and associated with poor patient survival. Pharmacological inhibition of different signalling pathways in CCA cells converged on the regulation of FOSL1 expression. Functional experiments showed that FOSL1 is required for cell proliferation and cell cycle progression in vitro, and for tumour growth and tumour maintenance in both orthotopic and subcutaneous xenograft models. Likewise, FOSL1 genetic abrogation in a GEM model of CCA extended mouse survival by decreasing the oncogenic potential of transformed cholangiocytes. RNA and ChIP sequencing studies identified direct and indirect transcriptional effectors such as HMGCS1 and AURKA, whose genetic and pharmacological inhibition phenocopied FOSL1 loss. CONCLUSIONS: Our data illustrate the functional and clinical relevance of FOSL1 in CCA and unveil potential targets amenable to pharmacological inhibition that could enable the implementation of novel therapeutic strategies. LAY SUMMARY: Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention.
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Colangiocarcinoma/genética , Hidroximetilglutaril-CoA Sintasa/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/efectos adversos , Anciano , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/etiología , Femenino , Humanos , Hidroximetilglutaril-CoA Sintasa/genética , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-fos/genética , Activación Transcripcional/efectos de los fármacos , Activación Transcripcional/genéticaRESUMEN
Cytokines are soluble proteins that mediate cell-to-cell communication. Based on the discovery of the potent anti-tumour activities of several pro-inflammatory cytokines in animal models, clinical research led to the approval of recombinant interferon-alpha and interleukin-2 for the treatment of several malignancies, even if efficacy was only modest. These early milestones in immunotherapy have been followed by the recent addition to clinical practice of antibodies that inhibit immune checkpoints, as well as chimeric antigen receptor T cells. A renewed interest in the anti-tumour properties of cytokines has led to an exponential increase in the number of clinical trials that explore the safety and efficacy of cytokine-based drugs, not only as single agents, but also in combination with other immunomodulatory drugs. These second-generation drugs under clinical development include known molecules with novel mechanisms of action, new targets, and fusion proteins that increase half-life and target cytokine activity to the tumour microenvironment or to the desired effector immune cells. In addition, the detrimental activity of immunosuppressive cytokines can be blocked by antagonistic antibodies, small molecules, cytokine traps or siRNAs. In this review, we provide an overview of the novel trends in the cytokine immunotherapy field that are yielding therapeutic agents for clinical trials.
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Inmunoterapia Adoptiva , Inmunoterapia , Neoplasias/terapia , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Citocinas/inmunología , Citocinas/uso terapéutico , Humanos , Interferón-alfa/genética , Interferón-alfa/inmunología , Interferón-alfa/uso terapéutico , Interleucina-2/genética , Interleucina-2/inmunología , Interleucina-2/uso terapéutico , Neoplasias/genética , Neoplasias/inmunología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
Cholangiocarcinoma (CCA) is a heterogeneous group of tumours, derived from cells of the biliary tree, which represent the second most frequent primary liver tumour. According to the most recent classifications, CCA can be subdivided into intrahepatic (iCCA) and extrahepatic (eCCA) which include perihilar (pCCA) and distal (dCCA) CCA. CCA are usually identified at advanced stages, when the primary tumour grows enough to produce a large liver mass or when jaundice has developed because of biliary tree obstruction. The ongoing challenges in the identification of risk factors and definition of a specific population at higher risk of developing CCA are the main challenges for the development of screening programs. Therefore, late diagnosis remains an unresolved issue in CCA. Imaging plays an important role in the detection and characterization of CCA, helping with radiological diagnosis, guiding biopsy procedures and allowing staging of the tumour. This review focuses on clinical presentations and diagnosis and staging techniques of CCA.
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Neoplasias de los Conductos Biliares/diagnóstico por imagen , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/diagnóstico por imagen , Colangiocarcinoma/patología , Diagnóstico por Imagen/métodos , Conductos Biliares Extrahepáticos/patología , Conductos Biliares Intrahepáticos/patología , Humanos , Estadificación de Neoplasias , Factores de RiesgoRESUMEN
BACKGROUND: The degree of histopathological response after neoadjuvant therapy in locally advanced gastric cancer (GC) is a key determinant of patients' long-term outcome. We aimed to assess the pattern of histopathological regression after two neoadjuvant approaches and its impact on survival times. METHODS: Regression grade of the primary tumour (Becker criteria) and the degree of nodal response by a 4-point scale (grades A-D) were assessed. Grade A-true negative lymph nodes (LNs); grade B and C-infiltrated LNs with any or little evidence of nodal response; and grade D-complete pathological response in a previously infiltrated LN. A favourable pathological response was defined as Becker Ia-b and grade D. RESULTS: From 2004 to 2014, 80 patients with GC (cT3-4/N+ by CT-scan/EUS) were treated with either preoperative chemotherapy (ChT, n=34) or chemoradiation (CRT, n=46). Patients in the CRT group had a higher likelihood of achieving a Becker Ia-b response (58 vs 32%, P=0.001), a grade D nodal regression (30 vs 6%, P=0.009) and a favourable pathological response (23 vs 3%; P=0.019). Patients with a grade D nodal response had a longer 5-year PFS and OS compared with those with a grade B or C response. Patients with a baseline negative LN status had similar outcomes irrespective of the preoperative therapy received (5-year OS; ChT vs CRT, 58 vs 51%, P=0.92). CONCLUSIONS: Preoperative chemoradiation increases the likelihood of achieving favourable histopathological features that correlate with a 5-year OS>70% in GC patients.
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Adenocarcinoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia , Terapia Neoadyuvante/métodos , Radioterapia Conformacional , Radioterapia de Intensidad Modulada , Neoplasias Gástricas/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Adenocarcinoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Astenia/inducido químicamente , Capecitabina/administración & dosificación , Supervivencia sin Enfermedad , Docetaxel , Femenino , Fluorouracilo/administración & dosificación , Gastrectomía , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Hematológicas/inducido químicamente , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Paclitaxel/administración & dosificación , Radioterapia Conformacional/efectos adversos , Radioterapia de Intensidad Modulada/efectos adversos , Estudios Retrospectivos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/terapia , Taxoides/administración & dosificación , Resultado del TratamientoRESUMEN
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) upregulates CD73, potentially contributing to immune surveillance evasion. Combining oleclumab (CD73 inhibitor) and durvalumab with chemotherapy may identify an effective treatment option. PATIENTS AND METHODS: Multicenter Phase 1b/2 randomized clinical trial in patients with metastatic PDAC, untreated (Cohort A) or previously received gemcitabine-based chemotherapy (Cohort B) (NCT03611556). During escalation, patients received oleclumab 1500 or 3000 mg, durvalumab 1500 mg, and gemcitabine plus nab-paclitaxel (GnP) (Cohort A; n=14) or modified FOLFOX (Cohort B; n=11). During expansion, Cohort A patients (n=170) were randomized to: GnP (Arm A1), oleclumab (recommended Phase 2 dose; RP2D) with GnP (Arm A2), or oleclumab (RP2D) with durvalumab plus GnP (Arm A3). Primary objectives were safety (escalation) and objective response rate (ORR) (expansion). Secondary objectives included progression-free survival (PFS) and overall survival (OS). RESULTS: During escalation, 1/11 patients from Cohort B (oleclumab 3000 mg) experienced two dose-limiting toxicities. Oleclumab RP2D was 3000 mg. During expansion, Grade ≥3 treatment-related adverse events occurred in 67.7% (42/62) of patients in A1, 73.7% (28/38) in A2, and 77.1% (54/70) in A3. ORR was 29.0%, 21.1%, and 32.9% in A1, A2, and A3, respectively (A1 vs A3; p=0.650). PFS (hazard ratio [HR]=0.72; 95% confidence interval [CI]: 0.47, 1.11) and OS (HR=0.75; 95% CI: 0.50, 1.13) were similar for A3 versus A1. Patients with high CD73 expression had improved PFS and OS in A3 versus A1, although this should be interpreted with caution. CONCLUSIONS: Although the safety profile was acceptable, this study did not meet its primary efficacy endpoint.
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PURPOSE: In this study, we report the results from the esophageal squamous cell carcinoma (SCC) cohort of a phase II, noncomparative, basket study evaluating the antitumor activity and safety of fibroblast activation protein-IL2 variant (FAP-IL2v) plus atezolizumab in patients with advanced/metastatic solid tumors (NCT03386721). PATIENTS AND METHODS: Eligible patients had an Eastern Cooperative Oncology Group performance status of 0 to 1; measurable metastatic, persistent, or recurrent esophageal SCC; progression on ≥1 prior therapy; and were checkpoint inhibitor-naïve. Patients received FAP-IL2v 10 mg plus atezolizumab 1,200 mg intravenously every 3 weeks, or FAP-IL2v weekly for 4 weeks and then every 2 weeks plus atezolizumab 840 mg intravenously every 2 weeks. The primary endpoint was investigator-assessed objective response rate (ORR). RESULTS: In the response-evaluable population (N = 34), the best confirmed ORR was 20.6% [95% confidence interval (CI), 10.4-36.8], with a complete response seen in 1 patient and partial responses in 6 patients. The disease control rate was 44.1% (complete response = 2.9%; partial response = 17.6%; stable disease = 23.5%), and the median duration of response was 10.1 mon/ths (95% CI, 5.6-26.7). The median progression-free survival was 1.9 months (95% CI, 1.8-3.7). Analysis of response by PDL1 expression (Ventana SP263) resulted in an ORR of 26.7% for patients with PDL1-positive tumors (tumor area positivity cutoff ≥1%; n = 15) and 7.1% for patients with PDL1-negative tumors (tumor area positivity cutoff <1%; n = 14). Overall, the treatment combination was tolerable, and adverse events were consistent with the known safety profiles of each drug. CONCLUSIONS: FAP-IL2v plus atezolizumab demonstrated clinical activity and was tolerable in patients with previously treated esophageal SCC.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Esofágicas , Humanos , Femenino , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Masculino , Persona de Mediana Edad , Anciano , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Anciano de 80 o más Años , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Endopeptidasas/genética , Proteínas de la Membrana/genética , Gelatinasas/genética , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversosAsunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Transformación Celular Neoplásica/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Proteínas ras/metabolismo , Vía de Señalización Hippo , Humanos , Factores de Transcripción , Proteínas Señalizadoras YAPRESUMEN
PURPOSE: The identification of pancreatic ductal adenocarcinoma (PDAC) dysregulated genes may unveil novel molecular targets entering inhibitory strategies. Laminins are emerging as potential targets in PDAC given their role as diagnostic and prognostic markers. Here, we investigated the cellular, functional, and clinical relevance of LAMC2 and its regulated network, with the ultimate goal of identifying potential therapies. EXPERIMENTAL DESIGN: LAMC2 expression was analyzed in PDAC tissues, a panel of human and mouse cell lines, and a genetically engineered mouse model. Genetic perturbation in 2D, 3D, and in vivo allograft and xenograft models was done. Expression profiling of a LAMC2 network was performed by RNA-sequencing, and publicly available gene expression datasets from experimental and clinical studies examined to query its human relevance. Dual inhibition of pharmacologically targetable LAMC2-regulated effectors was investigated. RESULTS: LAMC2 was consistently upregulated in human and mouse experimental models as well as in human PDAC specimens, and associated with tumor grade and survival. LAMC2 inhibition impaired cell cycle, induced apoptosis, and sensitized PDAC to MEK1/2 inhibitors (MEK1/2i). A LAMC2-regulated network was featured in PDAC, including both classical and quasi-mesenchymal subtypes, and contained downstream effectors transcriptionally shared by the KRAS signaling pathway. LAMC2 regulated a functional FOSL1-AXL axis via AKT phosphorylation. Furthermore, genetic LAMC2 or pharmacological AXL inhibition elicited a synergistic antiproliferative effect in combination with MEK1/2is that was consistent across 2D and 3D human and mouse PDAC models, including primary patient-derived organoids. CONCLUSIONS: LAMC2 is a molecular target in PDAC that regulates a transcriptional network that unveils a dual drug combination for cancer treatment.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animales , Humanos , Ratones , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Laminina/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fosforilación , Transducción de Señal , Neoplasias PancreáticasRESUMEN
Radioembolization (RE) may help local control and achieve tumor reduction while hypertrophies healthy liver and provides a test of time. For liver transplant (LT) candidates, it may attain downstaging for initially non-candidates and bridging during the waitlist. METHODS: Patients diagnosed with HCC and ICC treated by RE with further liver resection (LR) or LT between 2005-2020 were included. All patients selected were discarded for the upfront surgical approach for not accomplishing oncological or surgical safety criteria after a multidisciplinary team assessment. Data for clinicopathological details, postoperative, and survival outcomes were retrospectively reviewed from a prospectively maintained database. RESULTS: A total of 34 patients underwent surgery following RE (21 LR and 13 LT). Clavien-Dindo grade III-IV complications and mortality rates were 19.0% and 9.5% for LR and 7.7% and 0% for LT, respectively. After RE, for HCC and ICC patients in the LR group, 10-year OS rates were 57% and 60%, and 10-year DFS rates were 43.1% and 60%, respectively. For HCC patients in the LT group, 10-year OS and DFS rates from RE were 51.3% and 43.3%, respectively. CONCLUSION: Liver resection after RE is safe and feasible with optimal short-term outcomes. Patients diagnosed with unresectable or high biological risk HCC or ICC, treated with RE, and rescued by LR may achieve optimal global and DFS rates. On the other hand, bridging or downstaging strategies to LT with RE in HCC patients show adequate recurrence rates as well as long-term survival.
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This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein α (FAP) binding site that costimulates T cells for improved tumor cell killing in FAP-expressing tumors. Patients with advanced or metastatic solid tumors received escalating weekly intravenous doses of RO7122290 as a single agent (n = 65) or in combination with a 1200-milligram fixed dose of the anti-programmed death-ligand 1 (anti-PD-L1) antibody atezolizumab given every 3 weeks (n = 50), across a tested RO7122290 dose range of 5 to 2000 milligrams and 45 to 2000 milligrams, respectively. Three dose-limiting toxicities were reported, two at different RO7122290 single-agent doses (grade 3 febrile neutropenia and grade 3 cytokine release syndrome) and one for the combination (grade 3 pneumonitis). No maximum tolerated dose was identified. The pharmacokinetic profile of RO7122290 suggested nonlinearity in elimination. The observed changes in peripheral and tissue pharmacodynamic (PD) biomarkers were consistent with the postulated mechanism of action. Treatment-induced PD changes included an increase in proliferating and activated T cells in peripheral blood both in the single-agent and combination arms. Increased infiltration of intratumoral CD8+ and Ki67+CD8+ T cells was observed for both treatment regimens, accompanied by the up-regulation of T cell activation genes and gene signatures. Eleven patients experienced a complete or partial response, six of whom were confirmed to be immune checkpoint inhibitor naive. These results support further evaluation of RO7122290 in combination with atezolizumab or other immune-oncology agents for the treatment of solid tumors.
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Linfocitos T CD8-positivos , Neoplasias , Humanos , Linfocitos T CD8-positivos/metabolismo , Neoplasias/patología , Fibroblastos/patologíaRESUMEN
Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Reposicionamiento de Medicamentos , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Combinación de Medicamentos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Mutación , Línea Celular TumoralRESUMEN
Liver cancer including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) is the third leading cause of cancer-related deaths worldwide. HCC arises from hepatocyte or hepatic stem cells, while iCCA originates from biliary epithelial cells, and the respective biological context are very different. Despite screening programs, the diagnosis of liver cancer is in most cases made when curative treatments such as surgery or ablation are not possible. In 2020, after a decade of using only tyrosine kinase inhibitors (TKI), a combination of an immune-check point inhibitor (ICI) and a VEGF antagonist proved superior to a TKI as first line therapy of advanced HCC. In 2022, the addition of an ICI to standard chemotherapy demonstrated an improvement of patient survival in iCCA. Moreover, ICI offer an unprecedented rate of durable responses to HCC and iCCA patients. Nevertheless, still two thirds of patients do not respond to ICI-based combinations, and research efforts are focused on deciphering the mechanisms of immune evasion of these lethal cancers. Reliable predictive and prognostic biomarkers are still lacking, but the molecular phenotyping of the tumor microenvironment is currently providing potential candidates for patient stratification. In this review, we will summarize the current knowledge on the immune biology of the liver, the discovery of cell-intrinsic and immune cell-mediated mechanisms of immune evasion by means of high-resolution single cell data, the main targets of current immunotherapy approaches, and the recent milestones in immunotherapy of HCC and iCCA.
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Neoplasias de los Conductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/terapia , Conductos Biliares Intrahepáticos/patología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Colangiocarcinoma/tratamiento farmacológico , Humanos , Inmunoterapia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamiento farmacológico , Microambiente TumoralRESUMEN
PURPOSE: This retrospective analysis of the largest available clinico-genomic database used de-identified patient-level electronic health record-derived real-world data (RWD) combined with FoundationOne comprehensive genomic profiling (CGP) to characterize patients with metastatic urothelial carcinoma (mUC) treated in the real-world setting, detect potential biomarkers, and develop a bladder immune performance index (BIPI). EXPERIMENTAL DESIGN: Patients with mUC who started front-line single-agent immune checkpoint inhibitors (ICI) and an unmatched group treated with front-line platinum-based chemotherapy between January 1, 2011, and September 30, 2019, were selected. Clinical and genomic data were correlated with overall survival (OS). A novel BIPI predicting outcome with ICIs was developed using machine learning methods and validated using data from a phase II trial (NCT02951767). RESULTS: In ICI-treated patients (n = 118), high tumor mutational burden (≥10 mutations/megabase) was associated with improved OS (HR, 0.58; 95% CI, 0.35-0.95; P = 0.03). In chemotherapy-treated patients (n = 268), those with high APOBEC mutational signature had worse OS (HR, 1.43; 95% CI, 1.06-1.94; P = 0.02). Neither FGFR3 mutations nor DNA damage-repair pathway alterations were associated with OS. A novel BIPI combining clinical and genomic variables (nonmetastatic at initial diagnosis, normal or above normal albumin level at baseline, prior surgery for organ-confined disease, high tumor mutational burden) identified ICI-treated patients with longest OS and was validated in an independent dataset. CONCLUSIONS: Contemporary RWD including FoundationOne CGP can be used to characterize outcomes in real-world patients according to biomarkers beyond PD-L1. A validated, novel clinico-genomic BIPI demonstrated satisfactory prognostic performance for OS in patients with mUC receiving front-line ICI therapy.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Carcinoma de Células Transicionales/tratamiento farmacológico , Ensayos Clínicos Fase II como Asunto , Genómica , Humanos , Estudios Retrospectivos , Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genéticaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a high mortality rate. The presence of a dense desmoplastic stroma rich in fibroblasts, extracellular matrix, and immune cells plays a critical role in disease progression, therapy response and is a distinguishing feature of PDAC. PDAC is currently treated with a combination of surgery, chemotherapy and radiation therapy in selected cases which results in long-term survival only in a small percentage of patients. Cancer therapies that incorporate immunotherapy-based techniques have become increasingly common in recent years. While such a strategy has been shown to be effective for immunogenic, "hot" tumors like melanoma and lung cancer, thus far PDAC patients display poor responses to this therapeutic approach. Various factors, such as low tumor mutational burden, increased infiltration of immunosuppressive cells, like MDSCs and Treg cells promote tolerance and immune deviation, further aggravating adaptive immunity in PDAC. In this review we will elaborate on the ability of PDAC tumors to evade immune detection. We will also discuss various 3D model system that can be used as a platform in preclinical research to investigate rational combinations of immunotherapy with chemotherapy or targeted therapy, to prime the immune microenvironment to enhance antitumor activity.