STRN-ALK rearranged pediatric malignant peritoneal mesothelioma - Functional testing of 527 cancer drugs in patient-derived cancer cells
| العنوان: | STRN-ALK rearranged pediatric malignant peritoneal mesothelioma - Functional testing of 527 cancer drugs in patient-derived cancer cells |
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| المؤلفون: | Daniela Ungureanu, Hannu Sariola, Astrid Murumägi, Minna Koskenvuo, Olli Kallioniemi, Jukka Kanerva, Mariliina Arjama, Ralf Bützow, Jouko Lohi |
| المساهمون: | Institute for Molecular Medicine Finland, Precision Systems Medicine, Helsinki Institute of Life Science HiLIFE, University of Helsinki, ATG - Applied Tumor Genomics, Research Programs Unit, Faculty of Medicine, HUSLAB, Department of Pathology, Helsinki University Hospital Area, Helsinki One Health (HOH), Hannu Sariola / Principal Investigator, Department of Biochemistry and Developmental Biology, HUS Children and Adolescents, Children's Hospital, Clinicum, Tampere University, BioMediTech |
| المصدر: | Translational Oncology Translational Oncology, Vol 14, Iss 4, Pp 101027-(2021) |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Pediatric cancer, medicine.drug_class, HIPEC, heated intraperitoneal chemotherapy, 3122 Cancers, Patient-derived cancer cells, lcsh:RC254-282, DSS, drug sensitivity score, PDC, patient-derived cancer cells, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, STRN-ALK, medicine, Anaplastic lymphoma kinase, Malignant peritoneal mesothelioma, Original Research, Cisplatin, Crizotinib, CRS, cytoreductive surgery, business.industry, Cancer, MPeM, malignant peritoneal mesothelioma, hemic and immune systems, Drug testing, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, NACT, neoadjuvant chemotherapy, Gemcitabine, 3. Good health, CT, computed tomography, ALK inhibitor, PET-CT, positron emission tomography-computed tomography, 030104 developmental biology, Oncology, Kinase inhibitors, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, DSRT, drug sensitivity and resistance testing, 3111 Biomedicine, business, MRI, magnetic resonance imaging, CRP, C-reactive protein levels, medicine.drug |
| الوصف: | Highlights • First study to establish in real-time STRN-ALK fusion positive pediatric patient-derived cancer cells (PDCs). • Ex vivo sensitivity testing of PDCs to 527 oncology drugs was analysed by high-throughput drug testing. • Comparison of efficacies of eight ALK inhibitors towards PDCs both in 2D and 3D. • Drug combination synergies identified between ALK and MEK and ALK and PI3K/mTOR inhibitors. • Our precision medicine platform supported successful clinical use of crizotinib in patient treatment. Genetic rearrangements involving the anaplastic lymphoma kinase (ALK) gene create oncogenic drivers for several cancers, including malignant peritoneal mesothelioma (MPeM). Here, we report genomic and functional precision oncology profiling on a rare case of a 5-year old patient diagnosed with wide-spread and aggressive MPeM, driven by STRN-ALK rearrangement. We established genomically representative patient-derived cancer cells (PDCs) from the tumor sample and performed high-throughput drug sensitivity testing with 527 oncology compounds to identify potent inhibitors. As expected, the PDCs were overall sensitive to the ALK inhibitors, although the eight different inhibitors tested had variable efficacy. We also discovered other effective inhibitors, such as MEK/ERK inhibitors and those targeting pathways downstream of ALK as well as Bcl-xl inhibitors. In contrast, most cytotoxic drugs were not very effective. ALK inhibitors synergized with MEK and PI3K/mTOR inhibitors, highlighting potential combinatorial strategies to enhance drug efficacy and tackle drug resistance. Based on genomic data and associated functional validation, the patient was treated with the ALK inhibitor crizotinib in combination with conventional chemotherapy (cisplatin and gemcitabine). A complete disease remission was reached, lasting now for over 3 years. Our results illustrate a rare pediatric cancer case, and highlight the potential of functional precision oncology to discover pathogenetic drivers, validate dependency on driver signals, compare different inhibitors against each other and potentially enhance targeted treatments by drug combinations. Such real-time implementation of functional precision oncology could pave the way towards safer and more effective personalized cancer therapies for individual pediatric cancer patients with rare tumors. |
| وصف الملف: | fulltext |
| تدمد: | 1936-5233 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ae8b98e6534d26d81bcc08e02649f702 https://pubmed.ncbi.nlm.nih.gov/33530027 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....ae8b98e6534d26d81bcc08e02649f702 |
| قاعدة البيانات: | OpenAIRE |
Full Text via ClinicalKey | تدمد: | 19365233 |
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