Metformin's Effect on Differentiated Thyroid Cancer
The prevalence of differentiated thyroid cancer (papillary and follicular) and the mortality rate in older men are increasing at an alarming rate. Current modalities of treatment for differentiated thyroid cancer include thyroidectomy and iodine-131 therapy. In select cases, additional therapies such as external radiation and multikinase inhibitor (MKI) therapy may be considered in patients with progressive metastatic disease. MKI therapy is not approved by the US Food and Drug Administration (FDA) for use in differentiated thyroid cancer and is used off-label. The standard therapies are usually relatively effective in patients with stage 1 or 2 disease but are less frequently effective in patients with more aggressive disease (stage 3 and 4 disease). Unfortunately, despite therapy, about 20%-30% of patients will have evidence of persistent or recurrent disease, most often related to cervical nodal disease. Therefore, it is evident that many patients with differentiated thyroid cancer would also benefit from newer and novel therapies.
Targeted therapy refers to the use of agents that inhibit cellular pathways known or suspected to be active in the development or progression of tumor growth. MKI therapy is considered to represent potentially useful targeted agents. However, a separate but potentially beneficial approach is to explore the use of repositioned agents; that is, medications that are presently available and FDA-approved for use in other conditions. These agents have several potential benefits. In general, their cellular mechanism of action, side-effect profile, and pharmacokinetics are well-known, and these medications are available for use. One such agent is metformin. It has been suggested that metformin users have a lower risk of developing a variety of cancers compared with matched individuals who have not used metformin. Metformin may also increase sensitization to standard chemotherapy in breast cancer patients. Clinical trials are presently exploring the use of metformin as an antineoplastic agent in multiple diseases, including breast, endometrial, and pancreatic cancers.
It is with this background that the study by Klubo-Gwiezdzinska and colleagueswas performed. Using a clinical review of patient charts, the researchers showed that the use of metformin improved thyroid cancer parameters. Further, in vitro results confirmed these findings and suggested that p70S6K/pS6 is a likely molecular target for metformin. Of course, these data should be confirmed by a prospective randomized controlled clinical trial. Nonetheless, these data are consonant with previous studies and are exciting.
However, there are limitations to the present study. A retrospective study is always subject to multiple issues related to the veracity of the data and bias in inclusion and exclusion selection criteria. Further, cell culture studies with several cell lines may not mimic the pathogenesis of thyroid cancer in vivo.
Several additional factors are of interest. Metformin appears to decrease serum thyroid-stimulating hormone levels, and it is possible that this is a mechanism of action in its antineoplastic effects. Metformin did not influence iodine trapping by differentiated thyroid cancer cells in vitro. However, metformin did enhance hydrogen peroxide-inducible activation of AMPK, and overactivation of AMPK was associated with complete inhibition of p70S6K/pS6. These findings suggest that metformin may increase responsiveness to radiation therapy.
In summary, metformin appears to have clinical and in vitro beneficial effects on differentiated thyroid cancer. Additional agents (eg, nelfinavir) may be repositioned for possible use in various cancers, including medullary thyroid cancer. Further clinical and laboratory studies are warranted.
Disclaimer: Dr. Burman is a coauthor of the article discussed.
Abstract
Viewpoint
The prevalence of differentiated thyroid cancer (papillary and follicular) and the mortality rate in older men are increasing at an alarming rate. Current modalities of treatment for differentiated thyroid cancer include thyroidectomy and iodine-131 therapy. In select cases, additional therapies such as external radiation and multikinase inhibitor (MKI) therapy may be considered in patients with progressive metastatic disease. MKI therapy is not approved by the US Food and Drug Administration (FDA) for use in differentiated thyroid cancer and is used off-label. The standard therapies are usually relatively effective in patients with stage 1 or 2 disease but are less frequently effective in patients with more aggressive disease (stage 3 and 4 disease). Unfortunately, despite therapy, about 20%-30% of patients will have evidence of persistent or recurrent disease, most often related to cervical nodal disease. Therefore, it is evident that many patients with differentiated thyroid cancer would also benefit from newer and novel therapies.
Targeted therapy refers to the use of agents that inhibit cellular pathways known or suspected to be active in the development or progression of tumor growth. MKI therapy is considered to represent potentially useful targeted agents. However, a separate but potentially beneficial approach is to explore the use of repositioned agents; that is, medications that are presently available and FDA-approved for use in other conditions. These agents have several potential benefits. In general, their cellular mechanism of action, side-effect profile, and pharmacokinetics are well-known, and these medications are available for use. One such agent is metformin. It has been suggested that metformin users have a lower risk of developing a variety of cancers compared with matched individuals who have not used metformin. Metformin may also increase sensitization to standard chemotherapy in breast cancer patients. Clinical trials are presently exploring the use of metformin as an antineoplastic agent in multiple diseases, including breast, endometrial, and pancreatic cancers.
It is with this background that the study by Klubo-Gwiezdzinska and colleagueswas performed. Using a clinical review of patient charts, the researchers showed that the use of metformin improved thyroid cancer parameters. Further, in vitro results confirmed these findings and suggested that p70S6K/pS6 is a likely molecular target for metformin. Of course, these data should be confirmed by a prospective randomized controlled clinical trial. Nonetheless, these data are consonant with previous studies and are exciting.
However, there are limitations to the present study. A retrospective study is always subject to multiple issues related to the veracity of the data and bias in inclusion and exclusion selection criteria. Further, cell culture studies with several cell lines may not mimic the pathogenesis of thyroid cancer in vivo.
Several additional factors are of interest. Metformin appears to decrease serum thyroid-stimulating hormone levels, and it is possible that this is a mechanism of action in its antineoplastic effects. Metformin did not influence iodine trapping by differentiated thyroid cancer cells in vitro. However, metformin did enhance hydrogen peroxide-inducible activation of AMPK, and overactivation of AMPK was associated with complete inhibition of p70S6K/pS6. These findings suggest that metformin may increase responsiveness to radiation therapy.
In summary, metformin appears to have clinical and in vitro beneficial effects on differentiated thyroid cancer. Additional agents (eg, nelfinavir) may be repositioned for possible use in various cancers, including medullary thyroid cancer. Further clinical and laboratory studies are warranted.
Disclaimer: Dr. Burman is a coauthor of the article discussed.
Abstract
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