Targeted Therapy in Refractory Thyroid Cancer

Current Achievements and Limitations

Lucia Brilli; Furio Pacini

Disclosures

Future Oncol. 2011;7(5):657-668. 

In This Article

Targeted Therapy & Bone Metastases

A frequent observation with all the TKIs is that, for reasons as yet unknown, they are poorly effective on bone lesions compared with other metastases in parenchymatous organs.

Novel bone-targeting agents are under development and investigation, based on the understanding of the molecular processes and pathways involved in bone metastases. One of the most studied factors is the RANK ligand (RANKL), a member of the tumor necrosis family that binds to RANK on preosteoclasts and mature osteoclasts, and mediates the differentiation, function and survival of osteoclasts. Bone metastases stimulate the expression and production of RANKL by osteoblasts, which, in turn, perpetuate bone destruction and progression of the disease.[47]

Denosumab (AMG-162) is an investigational human monoclonal antibody that specifically binds and inhibits RANKL, thus arresting osteoclast-mediated bone resorption. Recently, this drug has been studied in Phase II trials in patients with bone metastases from several solid cancers.[47,48] Patients treated with denosumab displayed a lower incidence of skeletal-related events and a reduced level of urinary N-telopeptide, a marker of progression of bone metastases correlated with skeletal events.[47]

Another drug currently under investigation, alone or in combination with chemotherapy, in patients with bone metastases from solid tumors is the inhibitor of Src, a nonreceptor TK. Preclinical data suggest that Src is involved in normal bone remodelling and, when overexpressed and activated, may play a role in bone metastases in several human cancers, including thyroid tumors. In vitro studies have shown that FAK, a critical substrate and effector of Src, is phosphorylated at tyrosine residue 861 in a subset of PTC and in ATC, and that it could be inhibited by a novel Src inhibitor (AZD0530).[49] Similar findings have also been demonstrated in MTC.[50] Thus, Src inhibitors may become new effective therapies for bone metastases.

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