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Targeting RET for thyroid cancer therapy
Cinzia Lanzi1, Giuliana Cassinelli, Valentina Nicolini
1Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy.
Abstract:
The limited efficacy of conventional treatments in progressive thyroid carcinomas indicates the need for new therapeutic options. Activating mutations of the receptor tyrosine kinase-encoding RET gene have been identified as driving oncogenic events in subsets of papillary (PTC) and medullary (MTC) thyroid carcinomas suggesting the interest of targeted therapy. The role of RET oncogenes and the encoded constitutively active oncoproteins as potential targets has been investigated by different strategies including gene therapy and pharmacological approaches, but targeted treatment for RET-driven cancers is not clinically available in current therapy. Small molecule tyrosine kinase inhibitors, including sorafenib, sunitinib, motesanib and vandetanib, which have already shown efficacy against other neoplastic diseases, are being evaluated in clinical trials for treatment of thyroid carcinomas. Most of them, also described as Ret inhibitors, are multi-kinase inhibitors with antiangiogenic activity related to inhibition of receptor tyrosine kinases, such as the vascular endothelial growth factor receptors. Preclinical evidence supports the relevance of Ret oncoproteins as therapeutic targets for a subset of thyroid neoplastic diseases and, although targeting the original causal genetic change may not be sufficient to control the disease efficiently, the available knowledge outlines therapeutic opportunities for exploiting Ret inhibition.
Insights
New targeted therapies are needed for progressive thyroid cancers. Research explores RET oncogenes and tyrosine kinase inhibitors, showing promise for future RET-driven cancer treatments.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Conventional treatments for progressive thyroid carcinomas show limited efficacy.
- Activating mutations in the RET gene drive oncogenesis in papillary (PTC) and medullary (MTC) thyroid carcinomas.
- Targeted therapies for RET-driven thyroid cancers are not yet clinically available.
Purpose of the Study:
- To investigate the therapeutic potential of targeting RET oncogenes in thyroid carcinomas.
- To evaluate the efficacy of small molecule tyrosine kinase inhibitors (TKIs) as a targeted treatment strategy.
- To explore the role of RET oncoproteins as therapeutic targets for subsets of thyroid neoplastic diseases.
Main Methods:
- Review of preclinical evidence and ongoing clinical trials for RET-targeted therapies.
- Investigation of pharmacological approaches, including multi-kinase inhibitors with antiangiogenic activity.
- Assessment of small molecule TKIs such as sorafenib, sunitinib, motesanib, and vandetanib.
Main Results:
- Preclinical data support RET oncoproteins as relevant therapeutic targets for specific thyroid cancers.
- Multi-kinase inhibitors targeting RET also exhibit antiangiogenic activity via inhibition of vascular endothelial growth factor receptors.
- Clinical trials are evaluating the efficacy of several TKIs in thyroid carcinoma treatment.
Conclusions:
- Targeting RET inhibition presents therapeutic opportunities for RET-driven thyroid neoplastic diseases.
- While targeting the initial genetic alteration may not be fully sufficient, RET inhibition is a promising strategy.
- Further development of targeted treatments for RET-driven thyroid cancers is warranted.
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