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1.
Adv Sci (Weinh) ; : e2307695, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38885414

RESUMO

Cancer cells must develop strategies to adapt to the dynamically changing stresses caused by intrinsic or extrinsic processes, or therapeutic agents. Metabolic adaptability is crucial to mitigate such challenges. Considering metabolism as a central node of adaptability, it is focused on an energy sensor, the AMP-activated protein kinase (AMPK). In a subtype of pancreatic ductal adenocarcinoma (PDAC) elevated AMPK expression and phosphorylation is identified. Using drug repurposing that combined screening experiments and chemoproteomic affinity profiling, it is identified and characterized PF-3758309, initially developed as an inhibitor of PAK4, as an AMPK inhibitor. PF-3758309 shows activity in pre-clinical PDAC models, including primary patient-derived organoids. Genetic loss-of-function experiments showed that AMPK limits the induction of ferroptosis, and consequently, PF-3758309 treatment restores the sensitivity toward ferroptosis inducers. The work established a chemical scaffold for the development of specific AMPK-targeting compounds and deciphered the framework for the development of AMPK inhibitor-based combination therapies tailored for PDAC.

2.
Endosc Int Open ; 12(3): E361-E366, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38464982

RESUMO

Background and study aims The prognosis for pancreatic cancer remains poor. Molecular diagnostics and customized therapies are becoming increasingly important in clinical routine. Patient-derived, predictive model systems such as organoids have the potential to substantially increase the depth of information from biopsy material by functional and molecular characterization. We compared the extent to which the use of fine-needle aspiration needles (FNA, 22G) or fine-needle biopsy needles (FNB, 22G) influences the generation of pancreatic cancer patient-derived organoids (PDOs) to establish endoscopic standards of organoid technology. Patients and methods Endoscopic ultrasound (EUS)-guided punctures by EUS-FNA and EUS-FNB of pancreatic masses highly suspicious for adenocarcinoma (detected by computed tomography and/or magnetic resonance imaging) were prospectively evaluated. Consecutive patients received EUS-FNA and EUS-FNB in a randomized order without the need to exchange the needle shaft (only the inner needle type (FNA/-B) was exchanged) between the passes. With each needle type, the specimens for histological analysis and for PDOs were obtained separately. Results Fifty patients were enrolled in the study. Histology revealed malignancy in 42 of 50 cases (84%). In total PDOs were generated from 17 patients (34%). Of these, nine were established by FNB only, two by FNA only, and six by both FNA and FNB. Histology revealed malignancy in 13 of 17 PDO cases (76%). In two histologically false-negative cases, PDOs could be established. Conclusions EUS-FNB was superior to EUS-FNA in terms of successful generation of PDOs, although it failed to show statistical significance.

4.
JCI Insight ; 7(24)2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36546480

RESUMO

Primary atopic disorders are a group of inborn errors of immunity that skew the immune system toward severe allergic disease. Defining the biology underlying these extreme monogenic phenotypes reveals shared mechanisms underlying common polygenic allergic disease and identifies potential drug targets. Germline gain-of-function (GOF) variants in JAK1 are a cause of severe atopy and eosinophilia. Modeling the JAK1GOF (p.A634D) variant in both zebrafish and human induced pluripotent stem cells (iPSCs) revealed enhanced myelopoiesis. RNA-Seq of JAK1GOF human whole blood, iPSCs, and transgenic zebrafish revealed a shared core set of dysregulated genes involved in IL-4, IL-13, and IFN signaling. Immunophenotypic and transcriptomic analysis of patients carrying a JAK1GOF variant revealed marked Th cell skewing. Moreover, long-term ruxolitinib treatment of 2 children carrying the JAK1GOF (p.A634D) variant remarkably improved their growth, eosinophilia, and clinical features of allergic inflammation. This work highlights the role of JAK1 signaling in atopic immune dysregulation and the clinical impact of JAK1/2 inhibition in treating eosinophilic and allergic disease.


Assuntos
Eosinofilia , Hipersensibilidade Imediata , Hipersensibilidade , Células-Tronco Pluripotentes Induzidas , Criança , Animais , Humanos , Mutação com Ganho de Função , Peixe-Zebra , Hipersensibilidade/genética , Inflamação/genética , Eosinofilia/genética , Janus Quinase 1/genética
5.
JCI Insight ; 7(10)2022 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-35439169

RESUMO

Systemic therapies for pancreatic ductal adenocarcinoma (PDAC) remain unsatisfactory. Clinical prognosis is particularly poor for tumor subtypes with activating aberrations in the MYC pathway, creating an urgent need for novel therapeutic targets. To unbiasedly find MYC-associated epigenetic dependencies, we conducted a drug screen in pancreatic cancer cell lines. Here, we found that protein arginine N-methyltransferase 5 (PRMT5) inhibitors triggered an MYC-associated dependency. In human and murine PDACs, a robust connection of MYC and PRMT5 was detected. By the use of gain- and loss-of-function models, we confirmed the increased efficacy of PRMT5 inhibitors in MYC-deregulated PDACs. Although inhibition of PRMT5 was inducing DNA damage and arresting PDAC cells in the G2/M phase of the cell cycle, apoptotic cell death was executed predominantly in cells with high MYC expression. Experiments in primary patient-derived PDAC models demonstrated the existence of a highly PRMT5 inhibitor-sensitive subtype. Our work suggests developing PRMT5 inhibitor-based therapies for PDAC.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Detecção Precoce de Câncer , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Epigênese Genética , Humanos , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Neoplasias Pancreáticas
7.
EMBO Mol Med ; 14(4): e14876, 2022 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-35119792

RESUMO

Despite the advance and success of precision oncology in gastrointestinal cancers, the frequency of molecular-informed therapy decisions in pancreatic ductal adenocarcinoma (PDAC) is currently neglectable. We present a longitudinal precision oncology platform based on functional model systems, including patient-derived organoids, to identify chemotherapy-induced vulnerabilities. We demonstrate that treatment-induced tumor cell plasticity in vivo distinctly changes responsiveness to targeted therapies, without the presence of a selectable genetic marker, indicating that tumor cell plasticity can be functionalized. By adding a mechanistic layer to precision oncology, adaptive processes of tumors under therapy can be exploited, particularly in highly plastic tumors, such as pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Humanos , Organoides/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Medicina de Precisão , Neoplasias Pancreáticas
8.
Proc Natl Acad Sci U S A ; 119(9)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35197278

RESUMO

Evasion from drug-induced apoptosis is a crucial mechanism of cancer treatment resistance. The proapoptotic protein NOXA marks an aggressive pancreatic ductal adenocarcinoma (PDAC) subtype. To identify drugs that unleash the death-inducing potential of NOXA, we performed an unbiased drug screening experiment. In NOXA-deficient isogenic cellular models, we identified an inhibitor of the transcription factor heterodimer CBFß/RUNX1. By genetic gain and loss of function experiments, we validated that the mode of action depends on RUNX1 and NOXA. Of note is that RUNX1 expression is significantly higher in PDACs compared to normal pancreas. We show that pharmacological RUNX1 inhibition significantly blocks tumor growth in vivo and in primary patient-derived PDAC organoids. Through genome-wide analysis, we detected that RUNX1-loss reshapes the epigenetic landscape, which gains H3K27ac enrichment at the NOXA promoter. Our study demonstrates a previously unknown mechanism of NOXA-dependent cell death, which can be triggered pharmaceutically. Therefore, our data show a way to target a therapy-resistant PDAC, an unmet clinical need.


Assuntos
Apoptose/genética , Carcinoma Ductal Pancreático/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Expressão Gênica , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Mutações Sintéticas Letais , Carcinoma Ductal Pancreático/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/antagonistas & inibidores , Humanos , Neoplasias Pancreáticas/patologia , Regiões Promotoras Genéticas , Regulação para Cima
9.
Bioorg Chem ; 119: 105505, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34838332

RESUMO

Targeted protein degradation offers new opportunities to inactivate cancer drivers and has successfully entered the clinic. Ways to induce selective protein degradation include proteolysis targeting chimera (PROTAC) technology and immunomodulatory (IMiDs) / next-generation Cereblon (CRBN) E3 ligase modulating drugs (CELMoDs). Here, we aimed to develop a MYC PROTAC based on the MYC-MAX dimerization inhibitor 10058-F4 derivative 28RH and Thalidomide, called MDEG-541. We show that a subgroup of gastrointestinal cancer cell lines and primary patient-derived organoids are MDEG-541 sensitive. Although MYC expression was regulated in a CRBN-, proteasome- and ubiquitin-dependent manner, we provide evidence that MDEG-541 induced the degradation of CRBN neosubstrates, including G1 to S phase transition 1/2 (GSPT1/2) and the Polo-like kinase 1 (PLK1). In sum, we have established a CRBN-dependent degrader of relevant cancer targets with activity in gastrointestinal cancers.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Gastrointestinais/tratamento farmacológico , Talidomida/farmacologia , Tiazóis/farmacologia , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Talidomida/síntese química , Talidomida/química , Tiazóis/síntese química , Tiazóis/química , Células Tumorais Cultivadas , Ubiquitina-Proteína Ligases/metabolismo
10.
JCI Insight ; 5(15)2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32614802

RESUMO

One of the major challenges in using pancreatic cancer patient-derived organoids (PDOs) in precision oncology is the time from biopsy to functional characterization. This is particularly true for endoscopic ultrasound-guided fine-needle aspiration biopsies, typically resulting in specimens with limited tumor cell yield. Here, we tested conditioned media of individual PDOs for cell-free DNA to detect driver mutations already early on during the expansion process to accelerate the genetic characterization of PDOs as well as subsequent functional testing. Importantly, genetic alterations detected in the PDO supernatant, collected as early as 72 hours after biopsy, recapitulate the mutational profile of the primary tumor, indicating suitability of this approach to subject PDOs to drug testing in a reduced time frame. In addition, we demonstrated that this workflow was practicable, even in patients for whom the amount of tumor material was not sufficient for molecular characterization by established means. Together, our findings demonstrate that generating PDOs from very limited biopsy material permits molecular profiling and drug testing. With our approach, this can be achieved in a rapid and feasible fashion with broad implications in clinical practice.


Assuntos
Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/análise , Ácidos Nucleicos Livres/genética , Organoides/patologia , Neoplasias Pancreáticas/patologia , Medicina de Precisão , Animais , Apoptose , Biomarcadores Tumorais/análise , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Nus , Organoides/metabolismo , Neoplasias Pancreáticas/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Gut ; 69(8): 1472-1482, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32001555

RESUMO

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies. DESIGN: We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC. RESULTS: We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition. CONCLUSION: SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.


Assuntos
Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Idoso , Animais , Apoptose , Carcinoma Ductal Pancreático/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Inibidores Enzimáticos/farmacologia , Ésteres/farmacologia , Feminino , Amplificação de Genes , Expressão Gênica , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Transplante de Neoplasias , Organoides/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Prognóstico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Proteína SUMO-1/genética , Proteína SUMO-1/metabolismo , Ácidos Sulfônicos , Sumoilação/efeitos dos fármacos , Sumoilação/genética , Transcriptoma/efeitos dos fármacos , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Enzimas Ativadoras de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/genética , Ubiquitinas/genética , Ubiquitinas/metabolismo
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