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Proteasome inhibitors in medullary thyroid carcinoma: time to restart with clinical trials?

Introduction: Medullary thyroid cancer (MTC) is a rare thyroid tumour whose management in advanced stages is challenging, despite effective therapeutic options having expanded in recent years. Proteasome inhibitors (PrIn) have shown the ability to improve patient outcomes, including survival and quality of life, in several malignancies, due to their ability to impair cell proliferation and cause apoptosis through the inhibition of the proteasome activity. Consequently, these drugs could represent a useful tool, alone or in combination with other treatments, in MTC patients.

Aim of the study: This review aims to summarize the available in vitro and in vivo data about the role of PrIn in MTC.

Materials and methods: We performed an extensive search for relevant data sources, including full-published articles in international online databases (PubMed, Web of Science, Scopus), preliminary reports in selected international meeting abstract repositories, and short articles published as supplements of international meetings, by using the following terms: medullary thyroid carcinoma, proteasome inhibitors, bortezomib, carfilzomib, ixazomib, delanzomib, marizomib, oprozomib, and MG132. Additionally, we conducted with the same keywords, an in-depth search in registered clinical trials repositories.

Results: Our search revealed in vitro studies in human and murine MTC cell lines, based on the use of PrIns, both alone and in combination with other anticancer drugs, and two pertinent clinical trials.

Conclusion: We found a strong discrepancy between the evidence of PrIns effects in preclinical studies, and the scarcity or early interruption of clinical trials. We might speculate that difficulties in enrolling patients, as happens in other rare diseases, may have discouraged trials' implementation in favor of drugs already approved for MTC. However, given the concrete improvement in the comprehension of the molecular basis of PrIn effects in MTC, new clinical trials with accurate inclusion criteria of enrollment might be warranted, in order to ascertain whether this treatment, alone or in combination with other drugs, could indeed represent an option to enhance the therapeutic response, and to ultimately improve patients' outcome and survival.

 

Comments:

Medullary thyroid cancer (MTC) is a rare tumor of the thyroid gland, and managing advanced stages of the disease remains challenging despite recent advancements in therapy. Proteasome inhibitors (PrIn) have demonstrated the ability to improve patient outcomes, including survival and quality of life, in various malignancies by inhibiting proteasome activity, impairing cell proliferation, and inducing apoptosis. Therefore, PrIn could potentially be a valuable tool, either alone or in combination with other treatments, for MTC patients.

The objective of this review is to summarize the available in vitro and in vivo data regarding the role of PrIn in MTC.

Methods: Extensive searches were conducted using various online databases (PubMed, Web of Science, Scopus), as well as selected international meeting abstract repositories and supplementary articles published in association with international meetings. The search terms included medullary thyroid carcinoma, proteasome inhibitors, bortezomib, carfilzomib, ixazomib, delanzomib, marizomib, oprozomib, and MG132. Additionally, registered clinical trial repositories were searched using the same keywords.

Results: The search yielded in vitro studies using human and murine MTC cell lines that investigated the use of PrIns alone or in combination with other anticancer drugs. Additionally, two relevant clinical trials were identified.

Conclusion: A notable disparity was observed between the evidence of PrIn effects in preclinical studies and the limited number of ongoing or completed clinical trials. Difficulties in patient enrollment, often encountered in rare diseases, might have discouraged the implementation of trials in favor of already approved drugs for MTC. However, considering the improved understanding of the molecular basis of PrIn effects in MTC, it may be warranted to conduct new clinical trials with precise inclusion criteria to determine whether PrIn treatment, alone or in combination with other drugs, could indeed enhance therapeutic response, improve patient outcomes, and increase survival rates.

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S7504 Marizomib (Salinosporamide A) Marizomib (Salinosporamide A) is a novel marine derived proteasome inhibitor which inhibits CT-L β5, C-L β1, and T-L β2 proteasome activities in human erythrocyte-derived 20S proteasomes with IC50 of 3.5 nM, 430 nM, 28 nM.

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Proteasome