New Targeted Therapies for Anaplastic Thyroid Cancer

Abstract

Anaplastic thyroid cancer (ATC) is often incurable because it doesn't respond to radioiodine, radiotherapy or chemotherapy, and new therapeutic approaches are needed. Peroxisome proliferator-activated receptor-gamma (PPARg) gene and protein are present in ATC cells, and PPARg ligands inhibit cell proliferation, induce apoptosis, and also down regulate the invasive potential of ATC cells. Also, inhibitors of the Aurora serine/threonine kinases have antineoplastic effect on ATC cells in vitro and on ATC xenografts. Tyrosine kinases inhibitors are actually under evaluation for the treatment of ATC, for example imanitib or sorafenib. Other studies have focused on evaluating antiangiogenic agents for treatment of ATC. These agents include: combretastatin A4 phosphate, aplidin, PTK787/ZK222584, and human VEGF monoclonal antibodies (bevacizumab, cetuximab). Small-molecule adenosine triphosphate (ATP) competitive inhibitors directed intracellularly at epidermal growth factor receptor (EGFR)'s tyrosine kinase, such as erlotinib, or gefitinib are also under evaluation. The development of drugs that have multiple therapeutic targets and the utilization of multiple cancer-targeting agents are both emerging strategies for ATC treatment. For example, a preclinical study evaluated the activity of a dual inhibitor of EGFR and vascular endothelial growth factor (VEGF), NVP-AEE788, alone and in combination with paclitaxel for the treatment of ATC. Even if new therapeutic approaches against ATC are under development, more research is needed to finally identify therapies able to control and to cure this disease. The possibility of testing the sensitivity of primary ATC cells from each subject to different drugs could increase the effectiveness of the treatment in the next future.

Normal human thyroid cells, BCPAP, and TPC-1 thyroid tumor cell lines display different profile in both basal and TNF-α-induced CXCL8 secretion

“…In addition, besides type I and Type II interferons which were previously shown to inhibit the secretion of CXCL8 [13,15], other potentially interesting molecules to be tested for their CXCL8 inhibiting effects could include PPAR-c agonists. This appears to be supported by the evidences provided by Antonelli et al who reported that PPAR-c agonists display antineoplastic activity [25,26] and inhibit the secretion of several chemokines in primary cultures of thyroid cancer cells [27,28]. With specific regards to CXCL8, pioglitazone (a potent PPAR-c agonist) was demonstrated to inhibit the TNF-a induced CXCL8 secretion in endometriotic stromal cells [29] and to suppress CXCL8 mRNA expression in pancreatic cancer cell lines [30].…”

Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma

“…In light of its rapid growth rate, it is somewhat surprising that ATC is not sensitive to any current systemic therapies, including radiation or chemotherapy. Although several promising targeted therapies (2)(3)(4)(5) and multimodal treatment strategies (6,7) have been explored, to date no therapy has been definitively proven to prolong survival in these patients. Clearly, novel treatments are desperately needed.…”

Inhibition of Foxp3 in cancer cells induces apoptosis of thyroid cancer cells

“…It binds to peroxisome proliferator responsive element (PPRE) as a heterodimer with the retinoid X receptor. The activity or/and expression of PPARγ is downregulated in thyroid cancer (Aldred et al, 2003;Antonelli et al, 2012;Espadinha et al, 2009), suggesting that the defect in PPARγ may contribute to the development of thyroid cancer. Indeed, in a mouse model PPARγ insufficiency results in the activation of the nuclear factor-kappaB (NF-κB) signaling pathway, leading to thyroid carcinogenesis (Kato et al, 2006).…”