Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling.

Abstract

Parathyroid carcinoma (PC) is an ultra-rare malignancy with a high risk of recurrence after surgery. Tumour-directed systemic treatments for PC are not established. We used whole-genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (a) immune checkpoint inhibition with pembrolizumab based on high tumour mutational burden and a single-base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) overactivation; (b) multi-receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 (Fibroblast Growth Factor Receptor 1) and RET (Ret Proto-Oncogene) and, (c) later in the course of the disease, PARP (Poly(ADP-Ribose) Polymerase) inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome-wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra-rare cancers based on insight into disease biology.

• Authors: Maria-Veronica Teleanu, Carmina T Fuss, Nagarajan Paramasivam, Sebastian Pirmann, Andreas Mock, Christoph Terkamp, Stefan Kircher, Laura-Sophie Landwehr, Christina Lenschow, Nicolas Schlegel, Albrecht Stenzinger, Arne Jahn, Martin Fassnacht, Hanno Glimm, Daniel Hübschmann, Stefan Fröhling, Matthias Kroiss
• Journal: Molecular oncology (Mol Oncol) Vol. 17 Issue 7 Pg. 1343-1355 (07 2023) ISSN: 1878-0261 [Electronic] United States
• PMID: 36808802 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Topics

• Humans
• Parathyroid Neoplasms (drug therapy, genetics, pathology)
• Transcriptome (genetics)
• Mutation (genetics)
• Genomics (methods)
• Gene Expression Profiling (methods)
• Carcinoma (genetics)