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2.
NPJ Precis Oncol ; 7(1): 109, 2023 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-37884744

RESUMEN

Analysis of selected cancer genes has become an important tool in precision oncology but cannot fully capture the molecular features and, most importantly, vulnerabilities of individual tumors. Observational and interventional studies have shown that decision-making based on comprehensive molecular characterization adds significant clinical value. However, the complexity and heterogeneity of the resulting data are major challenges for disciplines involved in interpretation and recommendations for individualized care, and limited information exists on how to approach multilayered tumor profiles in clinical routine. We report our experience with the practical use of data from whole-genome or exome and RNA sequencing and DNA methylation profiling within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) program of the National Center for Tumor Diseases (NCT) Heidelberg and Dresden and the German Cancer Research Center (DKFZ). We cover all relevant steps of an end-to-end precision oncology workflow, from sample collection, molecular analysis, and variant prioritization to assigning treatment recommendations and discussion in the molecular tumor board. To provide insight into our approach to multidimensional tumor profiles and guidance on interpreting their biological impact and diagnostic and therapeutic implications, we present case studies from the NCT/DKFZ molecular tumor board that illustrate our daily practice. This manual is intended to be useful for physicians, biologists, and bioinformaticians involved in the clinical interpretation of genome-wide molecular information.

3.
Sci Adv ; 9(35): eade7486, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37656784

RESUMEN

In-frame BRAF exon 12 deletions are increasingly identified in various tumor types. The resultant BRAFΔß3-αC oncoproteins usually lack five amino acids in the ß3-αC helix linker and sometimes contain de novo insertions. The dimerization status of BRAFΔß3-αC oncoproteins, their precise pathomechanism, and their direct druggability by RAF inhibitors (RAFi) has been under debate. Here, we functionally characterize BRAFΔLNVTAP>F and two novel mutants, BRAFdelinsFS and BRAFΔLNVT>F, and compare them with other BRAFΔß3-αC oncoproteins. We show that BRAFΔß3-αC oncoproteins not only form stable homodimers and large multiprotein complexes but also require dimerization. Nevertheless, details matter as aromatic amino acids at the deletion junction of some BRAFΔß3-αC oncoproteins, e.g., BRAFΔLNVTAP>F, increase their stability and dimerization propensity while conferring resistance to monomer-favoring RAFi such as dabrafenib or HSP 90/CDC37 inhibition. In contrast, dimer-favoring inhibitors such as naporafenib inhibit all BRAFΔß3-αC mutants in cell lines and patient-derived organoids, suggesting that tumors driven by such oncoproteins are vulnerable to these compounds.


Asunto(s)
Proteínas HSP90 de Choque Térmico , Proteínas Proto-Oncogénicas B-raf , Humanos , Dimerización , Proteínas Proto-Oncogénicas B-raf/genética , Aminoácidos
4.
Dtsch Med Wochenschr ; 148(18): 1174-1181, 2023 Sep.
Artículo en Alemán | MEDLINE | ID: mdl-37657455

RESUMEN

Considerable efforts concerning the molecular characterization and targeted treatment of cancer have significantly improved treatment options and prognosis of tumor patients. Nevertheless, in tumor entities without recurrent genetic alterations the application of molecular testing for potentially targetable lesions remains heterogeneous and, in most cases, the approval of targeted therapies is still restricted to defined tumor entities harboring corresponding predictive biomarkers.The broad genomic analysis of different tumor entities including rare cancers within several genome sequencing initiatives and precision oncology programs has revealed the occurrence of addressable molecular alterations across many tumor entities, although their incidence may differ significantly in the context of the underlying cancer type. The treatment of molecularly defined patient cohorts demonstrated an impressive tumor-agnostic efficacy of certain therapeutics such as NTRK inhibitors, while the outcome of other targeted therapies, such as ERBB or BRAF inhibitors, varied in the context of the underlying disease.In the meantime, a handful targeted therapeutics addressing NRTK and RET fusions, the BRAF V600E mutation or different features of defective DNA mismatch repair and high tumor mutational burden has been approved for histology-agnostic treatment of tumors harboring these target lesions. Ongoing molecularly stratified basket trials will further investigate the tumor-agnostic efficacy of different targeted treatment approaches.

5.
Cell Rep Med ; 4(10): 101200, 2023 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-37734378

RESUMEN

Targeted therapies are effective in treating cancer, but success depends on identifying cancer vulnerabilities. In our study, we utilize small RNA sequencing to examine the impact of pathway activation on microRNA (miRNA) expression patterns. Interestingly, we discover that miRNAs capable of inhibiting key members of activated pathways are frequently diminished. Building on this observation, we develop an approach that integrates a low-miRNA-expression signature to identify druggable target genes in cancer. We train and validate our approach in colorectal cancer cells and extend it to diverse cancer models using patient-derived in vitro and in vivo systems. Finally, we demonstrate its additional value to support genomic and transcriptomic-based drug prediction strategies in a pan-cancer patient cohort from the National Center for Tumor Diseases (NCT)/German Cancer Consortium (DKTK) Molecularly Aided Stratification for Tumor Eradication (MASTER) precision oncology trial. In conclusion, our strategy can predict cancer vulnerabilities with high sensitivity and accuracy and might be suitable for future therapy recommendations in a variety of cancer subtypes.


Asunto(s)
MicroARNs , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , MicroARNs/genética , MicroARNs/metabolismo , Medicina de Precisión , Genómica , Transcriptoma
6.
Nat Commun ; 13(1): 4485, 2022 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-35918329

RESUMEN

The benefit of molecularly-informed therapies in cancer of unknown primary (CUP) is unclear. Here, we use comprehensive molecular characterization by whole genome/exome, transcriptome and methylome analysis in 70 CUP patients to reveal substantial mutational heterogeneity with TP53, MUC16, KRAS, LRP1B and CSMD3 being the most frequently mutated known cancer-related genes. The most common fusion partner is FGFR2, the most common focal homozygous deletion affects CDKN2A. 56/70 (80%) patients receive genomics-based treatment recommendations which are applied in 20/56 (36%) cases. Transcriptome and methylome data provide evidence for the underlying entity in 62/70 (89%) cases. Germline analysis reveals five (likely) pathogenic mutations in five patients. Recommended off-label therapies translate into a mean PFS ratio of 3.6 with a median PFS1 of 2.9 months (17 patients) and a median PFS2 of 7.8 months (20 patients). Our data emphasize the clinical value of molecular analysis and underline the need for innovative, mechanism-based clinical trials.


Asunto(s)
Neoplasias Primarias Desconocidas , Epigenómica , Genómica , Homocigoto , Humanos , Mutación , Neoplasias Primarias Desconocidas/tratamiento farmacológico , Neoplasias Primarias Desconocidas/genética , Eliminación de Secuencia
7.
Eur J Cancer ; 172: 107-118, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35763870

RESUMEN

BACKGROUND: The multi-receptor tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, its clinical efficacy is highly variable, and no reliable predictors exist to select patients who are likely to benefit from this drug. PATIENTS AND METHODS: We analysed the molecular profiles and clinical outcomes of patients with pazopanib-treated sarcoma enrolled in a prospective observational study by the German Cancer Consortium, DKTK MASTER, that employs whole-genome/exome sequencing and transcriptome sequencing to inform the care of young adults with advanced cancer across histology and patients with rare cancers. RESULTS: Among 109 patients with available whole-genome/exome sequencing data, there was no correlation between clinical parameters, specific genetic alterations or mutational signatures and clinical outcome. In contrast, the analysis of a subcohort of 62 patients who underwent molecular analysis before pazopanib treatment and had transcriptome sequencing data available showed that mRNA levels of NTRK3 (hazard ratio [HR] = 0.53, p = 0.021), IGF1R (HR = 1.82, p = 0.027) and KDR (HR = 0.50, p = 0.011) were independently associated with progression-free survival (PFS). Based on the expression of these receptor tyrosine kinase genes, i.e. the features NTRK3-high, IGF1R-low and KDR-high, we developed a pazopanib efficacy predictor that stratified patients into three groups with significantly different PFS (p < 0.0001). Application of the pazopanib efficacy predictor to an independent cohort of patients with pazopanib-treated sarcoma from DKTK MASTER (n = 43) confirmed its potential to separate patient groups with significantly different PFS (p = 0.02), whereas no such association was observed in patients with sarcoma from DKTK MASTER (n = 97) or The Cancer Genome Atlas sarcoma cohort (n = 256) who were not treated with pazopanib. CONCLUSION: A score based on the combined expression of NTRK3, IGF1R and KDR allows the identification of patients with sarcoma and with good, intermediate and poor outcome following pazopanib therapy and warrants prospective investigation as a predictive tool to optimise the use of this drug in the clinic.


Asunto(s)
Sarcoma , Neoplasias de los Tejidos Blandos , Expresión Génica , Humanos , Indazoles/uso terapéutico , Estudios Prospectivos , Pirimidinas , Sarcoma/tratamiento farmacológico , Sarcoma/genética , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Sulfonamidas , Adulto Joven
9.
Cancer Discov ; 11(11): 2780-2795, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34112699

RESUMEN

The clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. On the basis of 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved overall response and disease control rates (23.9% and 55.3%) compared with previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients. These data demonstrate the benefit of molecular stratification in rare cancers and represent a resource that may promote clinical trial access and drug approvals in this underserved patient population. SIGNIFICANCE: Rare cancers are difficult to treat; in particular, molecular pathogenesis-oriented medical therapies are often lacking. This study shows that whole-genome/exome and RNA sequencing enables molecularly informed treatments that lead to clinical benefit in a substantial proportion of patients with advanced rare cancers and paves the way for future clinical trials.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659.


Asunto(s)
Neoplasias , Transcriptoma , Adulto , Perfilación de la Expresión Génica , Genómica , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Secuenciación del Exoma
10.
Int J Cancer ; 148(6): 1438-1451, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-32949162

RESUMEN

DNA sequencing and RNA sequencing are increasingly applied in precision oncology, where molecular tumor boards evaluate the actionability of genetic events in individual tumors to guide targeted treatment. To work toward an additional level of patient characterization, we assessed the abundance and activity of 27 proteins in 134 patients whose tumors had previously undergone whole-exome and RNA sequencing within the Molecularly Aided Stratification for Tumor Eradication Research (MASTER) program of National Center for Tumor Diseases, Heidelberg. Proteomic and phosphoproteomic targets were selected to reflect the most relevant therapeutic baskets in MASTER. Among six different therapeutic baskets, the proteomic data supported treatment recommendations that were based on DNA and RNA analyses in 10% to 57% and frequently suggested alternative treatment options. In several cases, protein activities explained the patients' clinical course and provided potential explanations for treatment failure. Our study indicates that the integrative analysis of DNA, RNA and protein data may refine therapeutic stratification of individual patients and, thus, holds potential to increase the success rate of precision cancer therapy. Prospective validation studies are needed to advance the integration of proteomic analysis into precision oncology.


Asunto(s)
Oncología Médica/métodos , Terapia Molecular Dirigida/métodos , Neoplasias , Medicina de Precisión/métodos , Proteómica/métodos , Adulto , Anciano , Biomarcadores de Tumor/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/genética , Neoplasias/terapia , Prueba de Estudio Conceptual
11.
Oncologist ; 26(1): 7-16, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32852072

RESUMEN

BACKGROUND: Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors. PATIENTS AND METHODS: This report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib. RESULTS: The six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day. CONCLUSION: This report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors. KEY POINTS: NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adulto , Afatinib/uso terapéutico , Anciano , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Mutación , Neurregulina-1/genética , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas
12.
Genes Chromosomes Cancer ; 59(10): 601-608, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32501622

RESUMEN

Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. Inactivating mutations or epigenetic deregulation of succinate dehydrogenase complex (SDH) genes are considered defining features of a subset of GIST occurring in the stomach. Based on comprehensive molecular profiling and biochemical analysis within a precision oncology program, we identified hallmarks of SDH deficiency (germline SDHB-inactivating mutation accompanied by somatic loss of heterozygosity, lack of SDHB expression, global DNA hypermethylation, and elevated succinate/fumarate ratio) in a 40-year-old woman with undifferentiated gastric spindle cell sarcoma that did not meet the diagnostic criteria for other mesenchymal tumors of the stomach, including GIST. These data reveal that the loss of SDH function can be involved in the pathogenesis of non-GIST sarcoma of the gastrointestinal tract.


Asunto(s)
Mutación de Línea Germinal , Sarcoma/genética , Neoplasias Gástricas/genética , Succinato Deshidrogenasa/genética , Adulto , Metilación de ADN , Femenino , Humanos , Mutación con Pérdida de Función , Pérdida de Heterocigocidad , Sarcoma/patología , Neoplasias Gástricas/patología
13.
Nat Commun ; 11(1): 2320, 2020 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-32385320

RESUMEN

Chromothripsis is a recently identified mutational phenomenon, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Considered as an early event in tumour development, this form of genome instability plays a prominent role in tumour onset. Chromothripsis prevalence might have been underestimated when using low-resolution methods, and pan-cancer studies based on sequencing are rare. Here we analyse chromothripsis in 28 tumour types covering all major adult cancers (634 tumours, 316 whole-genome and 318 whole-exome sequences). We show that chromothripsis affects a substantial proportion of human cancers, with a prevalence of 49% across all cases. Chromothripsis generates entity-specific genomic alterations driving tumour development, including clinically relevant druggable fusions. Chromothripsis is linked with specific telomere patterns and univocal mutational signatures in distinct tumour entities. Longitudinal analysis of chromothriptic patterns in 24 matched tumour pairs reveals insights in the clonal evolution of tumours with chromothripsis.


Asunto(s)
Cromotripsis , Neoplasias/genética , Adulto , Genoma Humano/genética , Inestabilidad Genómica/genética , Humanos , Telómero/genética , Telómero/metabolismo
14.
Pancreatology ; 20(3): 425-432, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32156527

RESUMEN

BACKGROUND: Pancreatoblastoma is a rare malignancy that occurs predominantly in children. Less than 50 adult cases, including 17 patients with metastatic disease, have been published to date. Recent outcome data from children with advanced-stage disease suggest an intensive multimodal treatment approach; however, little is known about the most beneficial therapy in adults. Molecular characterization of pancreatoblastoma is limited to a small number of pediatric cases and revealed few recurrent genetic events without immediate clinical relevance. METHODS: Patients were treated between 2013 and 2018 at a high-volume German university cancer center. Molecular analyses included whole genome, exome, transcriptome, and fusion gene panel sequencing. Molecularly guided treatment recommendations were discussed within a dedicated molecular tumor board (MTB) embedded in a precision oncology program (NCT MASTER). RESULTS: We identified four adult patients with metastatic pancreatoblastoma. In three patients, local approaches were combined with systemic treatment. Oxaliplatin-containing protocols showed an acceptable tumor control as well as an adequate toxicity profile. Overall survival was 15, 17, 18 and 24 months, respectively. Three tumors harbored genetic alterations involving the FGFR pathway that included an oncogenic FGFR2 fusion. CONCLUSION: Oxaliplatin-containing chemotherapy seems to be a reasonable approach in adult patients with advanced pancreatoblastoma, whereas the benefit of intensified treatment including local ablative techniques or surgical resection remains unclear. Our finding of FGFR alterations in three of four cases indicates a potential role of FGFR signaling in adult pancreatoblastoma whose clinical significance warrants further study.


Asunto(s)
Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Adulto , Antineoplásicos/uso terapéutico , Mapeo Cromosómico , Terapia Combinada , Exoma , Femenino , Fusión Génica , Genoma Humano , Humanos , Masculino , Metástasis de la Neoplasia , Oxaliplatino/uso terapéutico , Pancreaticoduodenectomía , Medicina de Precisión , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Análisis de Supervivencia , Transcriptoma , Adulto Joven
15.
J Clin Invest ; 130(5): 2488-2495, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-32017710

RESUMEN

BACKGROUNDNeurofibroma/schwannoma hybrid nerve sheath tumors (N/S HNSTs) are neoplasms associated with larger nerves that occur sporadically and in the context of schwannomatosis or neurofibromatosis type 2 or 1. Clinical management of N/S HNSTs is challenging, especially for large tumors, and established systemic treatments are lacking.METHODSWe used next-generation sequencing and array-based DNA methylation profiling to determine the clinically actionable genomic and epigenomic landscapes of N/S HNSTs.RESULTSWhole-exome sequencing within a precision oncology program identified an activating mutation (p.Asp769Tyr) in the catalytic domain of the ERBB2 receptor tyrosine kinase in a patient with schwannomatosis-associated N/S HNST, and targeted treatment with the small-molecule ERBB inhibitor lapatinib led to prolonged clinical benefit and a lasting radiographic and metabolic response. Analysis of a multicenter validation cohort revealed recurrent ERBB2 mutations (p.Leu755Ser, p.Asp769Tyr, p.Val777Leu) in N/S HNSTs occurring in patients who met diagnostic criteria for sporadic schwannomatosis (3 of 7 patients), but not in N/S HNSTs arising in the context of neurofibromatosis (6 patients) or outside a tumor syndrome (1 patient), and showed that ERBB2-mutant N/S HNSTs cluster in a distinct subgroup of peripheral nerve sheath tumors based on genome-wide DNA methylation patterns.CONCLUSIONThese findings uncover a key biological feature of N/S HNSTs that may have important diagnostic and therapeutic implications.FUNDINGThis work was supported by grant H021 from DKFZ-HIPO, the University Cancer Center Frankfurt, and the Frankfurt Research Funding Clinician Scientist Program.


Asunto(s)
Mutación Missense , Neoplasias de la Vaina del Nervio/genética , Neurilemoma/genética , Neurofibroma/genética , Receptor ErbB-2/genética , Adulto , Sustitución de Aminoácidos , Femenino , Humanos , Neoplasias de la Vaina del Nervio/patología , Neurilemoma/patología , Neurofibroma/patología
16.
Case Rep Gastroenterol ; 14(3): 658-667, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33442346

RESUMEN

Combined hepatocellular-cholangiocarcinoma (cHCC/CCA) represents a rare type of primary liver cancer with a very limited prognosis. Although just recently genomic studies have contributed to a better understanding of the disease's genetic landscape, therapeutic options, especially for advanced-stage patients, are limited and often experimental, as no standardized treatment protocols have been established to date. Here, we report the case of a 38-year-old male patient who was diagnosed with extensive intrahepatic cHCC/CCA in an otherwise healthy liver without signs of chronic liver disease. An interdisciplinary stepwise therapeutic approach including locoregional liver-targeted therapy, systemic chemotherapy, liver transplantation, surgical pulmonary metastasis resection, and next-generation sequencing-based targeted therapy led to a prolonged overall survival beyond 5 years with an excellent quality of life. This case report comprises several provocative treatment decisions that are extensively discussed in light of the existing literature on this rare but highly aggressive malignancy.

17.
Oncogene ; 39(4): 814-832, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31558800

RESUMEN

Fusion proteins involving the BRAF serine/threonine kinase occur in many cancers. The oncogenic potential of BRAF fusions has been attributed to the loss of critical N-terminal domains that mediate BRAF autoinhibition. We used whole-exome and RNA sequencing in a patient with glioblastoma multiforme to identify a rearrangement between TTYH3, encoding a membrane-resident, calcium-activated chloride channel, and BRAF intron 1, resulting in a TTYH3-BRAF fusion protein that retained all features essential for BRAF autoinhibition. Accordingly, the BRAF moiety of the fusion protein alone, which represents full-length BRAF without the amino acids encoded by exon 1 (BRAFΔE1), did not induce MEK/ERK phosphorylation or transformation. Likewise, neither the TTYH3 moiety of the fusion protein nor full-length TTYH3 provoked ERK pathway activity or transformation. In contrast, TTYH3-BRAF displayed increased MEK phosphorylation potential and transforming activity, which were caused by TTYH3-mediated tethering of near-full-length BRAF to the (endo)membrane system. Consistent with this mechanism, a synthetic approach, in which BRAFΔE1 was tethered to the membrane by fusing it to the cytoplasmic tail of CD8 also induced transformation. Furthermore, we demonstrate that TTYH3-BRAF signals largely independent of a functional RAS binding domain, but requires an intact BRAF dimer interface and activation loop phosphorylation sites. Cells expressing TTYH3-BRAF exhibited increased MEK/ERK signaling, which was blocked by clinically achievable concentrations of sorafenib, trametinib, and the paradox breaker PLX8394. These data provide the first example of a fully autoinhibited BRAF protein whose oncogenic potential is dictated by a distinct fusion partner and not by a structural change in BRAF itself.


Asunto(s)
Glioblastoma/genética , Glioblastoma/patología , Compuestos Heterocíclicos con 2 Anillos/farmacología , Proteínas de Fusión Oncogénica , Proteínas Proto-Oncogénicas B-raf/genética , Piridonas/farmacología , Pirimidinonas/farmacología , Sulfonamidas/farmacología , Anciano , Antineoplásicos/farmacología , Línea Celular Tumoral , Canales de Cloruro/genética , Canales de Cloruro/metabolismo , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosforilación , Dominios Proteicos , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismo , Transducción de Señal
18.
ESMO Open ; 4(6): e000583, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31798980

RESUMEN

Objective: Measuring the success of molecularly guided therapies is a major challenge in precision oncology trials. A commonly used endpoint is an intra-patient progression-free survival (PFS) ratio, defined as the PFS interval associated with molecularly guided therapy (PFS2) divided by the PFS interval associated with the last prior systemic therapy (PFS1), above 1.3 or, in some studies, above 1.33 or 1.5. Methods: To investigate if the concept of PFS ratios is in agreement with actual response evaluations by physicians, we conducted a survey among members of the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) Programme of the German Cancer Consortium who were asked to classify the success of molecularly guided therapies in 194 patients enrolled in the MOSCATO 01 trial based on PFS1 and PFS2 times. Results: A comparison of classification profiles revealed three distinct clusters of PFS benefit assessments. Only 29% of assessments were consistent with a PFS ratio threshold of 1.3, whereas the remaining 71% of participants applied a different classification scheme that did not rely on the relation between PFS times alone, but also took into account absolute PFS1 intervals. Based on these community-driven insights, we developed a modified PFS ratio that incorporates the influence of absolute PFS1 intervals on the judgement of clinical benefit by physicians. Application of the modified PFS ratio to outcome data from two recent precision oncology trials, MOSCATO 01 and WINTHER, revealed significantly improved concordance with physician-perceived clinical benefit and identified comparable proportions of patients who benefited from molecularly guided therapies. Conclusions: The modified PFS ratio may represent a meaningful clinical endpoint that could aid in the design and interpretation of future precision oncology trials.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Oncología Médica/métodos , Neoplasias/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud/métodos , Medicina de Precisión/métodos , Ensayos Clínicos como Asunto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Oncología Médica/normas , Neoplasias/genética , Neoplasias/mortalidad , Oncólogos , Evaluación de Resultado en la Atención de Salud/normas , Medicina de Precisión/normas , Supervivencia sin Progresión , Proyectos de Investigación/normas , Sociedades Médicas/normas
19.
Stud Health Technol Inform ; 264: 950-953, 2019 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-31438064

RESUMEN

With the novel approach of molecularly stratified therapies based on genetic characteristics of individual tumors, the need for databases providing information on molecular alterations and targeted treatment options is increasing rapidly. In Molecular Tumor Boards (MTB) professionals discuss molecular alterations and provide biological context for therapeutic options using external knowledge databases. The identification of informative databases and the information on their specific contents can greatly facilitate and standardize the functioning of a MTB. In this work we present a list of databases which have been deemed useful and relevant for MTB in a clinical setting. We describe workflows to recommend the use of specific databases at different steps in the clinical curation process. Information obtained from these databases is a necessary prerequisite to evaluate molecular alterations and devise rational targeted therapies in MTB.


Asunto(s)
Neoplasias , Medicina de Precisión , Humanos , Oncología Médica , Nivel de Atención , Flujo de Trabajo
20.
Int J Cancer ; 145(11): 2996-3010, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31008532

RESUMEN

Next-generation sequencing has become a cornerstone of therapy guidance in cancer precision medicine and an indispensable research tool in translational oncology. Its rapidly increasing use during the last decade has expanded the options for targeted tumor therapies, and molecular tumor boards have grown accordingly. However, with increasing detection of genetic alterations, their interpretation has become more complex and error-prone, potentially introducing biases and reducing benefits in clinical practice. To facilitate interdisciplinary discussions of genetic alterations for treatment stratification between pathologists, oncologists, bioinformaticians, genetic counselors and medical scientists in specialized molecular tumor boards, several systems for the classification of variants detected by large-scale sequencing have been proposed. We review three recent and commonly applied classifications and discuss their individual strengths and weaknesses. Comparison of the classifications underlines the need for a clinically useful and universally applicable variant reporting system, which will be instrumental for efficient decision making based on sequencing analysis in oncology. Integrating these data, we propose a generalizable classification concept featuring a conservative and a more progressive scheme, which can be readily applied in a clinical setting.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias/genética , Humanos , Terapia Molecular Dirigida , Mutación , Neoplasias/tratamiento farmacológico , Medicina de Precisión , Análisis de Secuencia de ADN
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