STRN-ALK rearranged pediatric malignant peritoneal mesothelioma - Functional testing of 527 cancer drugs in patient-derived cancer cells

Our plain-English summary of STRN-ALK rearranged pediatric malignant peritoneal mesothelioma - Functional testing of 527 cancer drugs in patient-derived cancer cells, by A. Murumägi, D. Ungureanu, M. Arjama, et al (Translational Oncology, 2021).

The study

• Authors: A. Murumägi, D. Ungureanu, M. Arjama, R. Bützow, J. Lohi, H. Sariola, J. Kanerva, M. Koskenvuo, O. Kallioniemi
• Journal: Translational Oncology
• Published: 2021;14(4):101027
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

Copyright © 2021. Published by Elsevier Inc.

In plain English

This article was a case report of one 5-year-old child with widespread malignant peritoneal mesothelioma, treated in Helsinki, combined with laboratory drug testing of cancer cells grown from the tumor. The article does not mention asbestos. Gene testing of the tumor found a STRN-ALK fusion gene. The authors tested a panel of 527 cancer drugs on the cultured cells. Of eight ALK inhibitor drugs, six showed selective activity against the cancer cells, with brigatinib, ensartinib and crizotinib scoring highest. Most standard chemotherapy drugs, including gemcitabine and cisplatin, were not very effective in these tests. Combining crizotinib or ceritinib with cobimetinib or gedatolisib showed strong synergy in the laboratory. The child received crizotinib (1200 mg per week) together with cisplatin and gemcitabine, had the remaining tumor surgically removed, and took crizotinib for about 20 months in total. Three years after diagnosis and 16 months after treatment ended, MRI showed no signs of remaining tumor. The authors concluded that they had demonstrated the feasibility of patient-derived cancer cells and the relevance of functional drug testing for personalized cancer treatment.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Case report of a single patient, combined with laboratory (ex vivo) drug sensitivity testing of cancer cells grown from the patient's tumor biopsy
• Who was studied: One 5-year-old patient (described at follow-up as an 8-year-old girl) with widespread malignant peritoneal mesothelioma, referred to Helsinki University Central Hospital, Finland
• Exposure: The article does not mention asbestos or any asbestos exposure. What was studied was the effect of 527 approved and investigational cancer drugs on the patient's tumor cells in the laboratory, and treatment of the patient with crizotinib plus cisplatin and gemcitabine.
• Main results:
  • Next-generation sequencing of the patient's tumor biopsy found a STRN-ALK fusion gene, which was also supported by ALK staining and FISH.
  • In the patient-derived cancer cells, six of the eight ALK inhibitors tested showed selective cancer cell-specific sensitivity, with brigatinib, ensartinib and crizotinib showing the highest sensitivities.
  • Other drugs showing selective activity against the patient's cancer cells included apoptotic inhibitors (navitoclax, A-1155463, A-1331852) and drugs targeting the MAPK pathway (TAK-530, cobimetinib, trametinib).
  • Most cytotoxic chemotherapy drugs, including gemcitabine and cisplatin, were not very effective against the patient's cancer cells in the laboratory.
  • In 3D spheroid cultures of the patient's cancer cells, six ALK inhibitors had drug sensitivity scores between 15 and 20.8, with brigatinib highest (20.8). Alectinib reduced cell viability by only 50%.
  • In the patient's cancer cells, the ALK inhibitors crizotinib and ceritinib showed strong synergy with the MEK inhibitor cobimetinib and the mTOR/PI3K inhibitor gedatolisib. The synergy was stronger for ceritinib.
  • The patient received six cycles of crizotinib with cisplatin and gemcitabine. When the residual tumor was removed by surgery, examination showed a small percentage of intact tumor cells.
  • The patient received crizotinib at 1200 mg/week (approximately 11 mg/kg/day) for about 20 months in total.
  • Three years after diagnosis and 16 months after completing treatment, MRI showed no signs of residual tumor in the patient.
• The authors' conclusion: The authors concluded that they had demonstrated the feasibility of patient-derived cancer cells and the relevance of functional drug testing in highlighting opportunities for personalized cancer treatment.

Topics

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Chemotherapy, Cisplatin, Gemcitabine.

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• Spiroergometric parameters at maximal exercise testing assessed functional respiratory impairment in asbestos-induced fibrosis — J. Schneider, R. Arhelger, et al. (2014)
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