Preclinical evaluation of targeted therapies in Sdhb-mutated tumors

in Endocrine-Related Cancer
Authors:
Sophie Moog Université de Paris Cité, PARCC INSERM UMR970, Paris, France

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https://orcid.org/0000-0001-9920-0480
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Betty Salgues PARCC INSERM UMR970, Paris, France
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Radiologie, Paris, France

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https://orcid.org/0000-0002-0889-0226
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Yasmine Braik-Djellas Université de Paris Cité, PARCC INSERM UMR970, Paris, France

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Thomas Viel Université de Paris Cité, PARCC INSERM UMR970, Paris, France
Sorbonne Université, Service de Médecine Nucléaire, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Paris, France

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Daniel Balvay Université de Paris Cité, PARCC INSERM UMR970, Paris, France
Sorbonne Université, Service de Médecine Nucléaire, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Paris, France

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Gwennhael Autret Université de Paris Cité, PARCC INSERM UMR970, Paris, France
Sorbonne Université, Service de Médecine Nucléaire, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Paris, France

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Estelle Robidel Université de Paris Cité, PARCC INSERM UMR970, Paris, France

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Anne-Paule Gimenez-Roqueplo Université de Paris Cité, PARCC INSERM UMR970, Paris, France
Plateforme d’Imageries du Vivant, Université de Paris Cité, Faculté de Médecine, Paris, France

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Bertrand Tavitian Université de Paris Cité, PARCC INSERM UMR970, Paris, France
Sorbonne Université, Service de Médecine Nucléaire, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Paris, France
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France

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Charlotte Lussey-Lepoutre PARCC INSERM UMR970, Paris, France
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Radiologie, Paris, France

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Judith Favier Université de Paris Cité, PARCC INSERM UMR970, Paris, France

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https://orcid.org/0000-0001-8190-5853

Correspondence should be addressed to C Lussey-Lepoutre or J Favier: charlotte.lussey@inserm.fr or judith.favier@inserm.fr

J Favier is a member of the editorial board, she was not involved in the review or editorial process for this paper.

DOI:
https://doi.org/10.1530/ERC-22-0030
Volume/Issue:
Volume 29: Issue 6
Article Type:
Research Article
Page Range:
375–388
Online Publication Date:
11 May 2022
Copyright:
© Society for Endocrinology 2022
Restricted access
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Therapies for metastatic SDHB-dependent pheochromocytoma and paraganglioma (PPGL) are limited and poorly efficient. New targeted therapies and identification of early non-invasive biomarkers of response are thus urgently needed for these patients. We characterized an in vivo allograft model of spontaneously immortalized murine chromaffin cells (imCC) with inactivation of the Sdhb gene by dynamic contrast-enhanced MRI (DCE-MRI) and 18FDG-PET. We evaluated the response to several therapies: IACS-010759 (mitochondrial respiratory chain complex I inhibitor), sunitinib (tyrosine kinase inhibitor with anti-angiogenic activity), talazoparib (poly ADP ribose polymerase (PARP) inhibitor) combined or not to temozolomide (alkylating agent), pharmacological inhibitors of HIF2a (PT2385 and PT2977 (belzutifan)) and molecular inactivation of HIF2a (imCC Sdhb−/− shHIF2a). Multimodal imaging was performed, including magnetic resonance spectroscopy (1H-MRS) to monitor the level of succinate in vivo. The allografted model of Sdhb−/− imCC reflected SDHB-deficient tumors, with increased angiogenesis and a particular avidity for 18FDG. After 14 days of treatment, IACS-010759, sunitinib and talazoparib at high doses allowed a significant reduction of the tumor volumes. In contrast to the tumor growth inhibition observed in Sdhb−/− shHIF2a imCC tumors, pharmacological inhibitors of HIF2a (PT2385 and belzutifan) showed no antitumor action in this model, alone or in combination with sunitinib. 1H-MRS, but not DCE-MRI, enabled the monitoring response to sunitinib, which was the best treatment in this study, promoting a decrease in succinate levels detected in vivo. This study paves the way for new therapeutic options and reveals a potential new early biomarker of response to treatment in SDHB-dependent PPGL.

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© Society for Endocrinology 2022
Page(s):
14
Received Date:
18 Mar 2022
Accepted Date:
29 Mar 2022
Print Publication Date:
01 Jun 2022
Online Publication Date:
11 May 2022
Keywords:
metastatic pheochromocytoma and paraganglioma; targeted therapies; HIF2a inhibitors; preclinical model; succinate

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