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

Other (Non-TK Receptor) Target Therapies Under Investigation

Several non-TKI drugs are currently under investigation but their efficacy or safety profiles are not yet available. These include the following drugs discussed below.

Fosbretabulin (Combretastatin-A4 Phosphate)

This drug demonstrated efficacy in one patient with ATC, who was enrolled in a Phase I trial, with multiple solid malignancies. Subsequently, an open-label, Phase II trial has been conducted in 26 patients with advanced or metastatic ATC at a dose of 45 mg/m2, intravenously.[51] Their median survival was 4.7 months and 34% of the patient survival ≥6.

A Phase II/III trial is ongoing to evaluate the safety and efficacy of fosbretabulin in combination with paclitaxel and carboplatin compared with paclitaxel and carboplatin in ATC.[105]

Everolimus

Everolimus and its analogues are inhibitors of PI3K–AKT–mTOR pathway, which is aberrantly activated in most cancers and leads to increased growth and resistance to apoptosis. The PI3K–AKT–mTOR pathway is activated through several mechanisms; including genetic alterations activating the PI3K–AKT–mTOR pathway as reported in 81% of ATC.[52] Everolimus is now undergoing investigation in patients with advanced thyroid cancer (studies currently recruiting participants.[106,107,108]

Bortezomib

Bortezomib is the first of a new class of drug termed proteasome inhibitors. The ubiquitin-proteasome pathway is a major pathway for degradation of intracellular proteins. This class of drug blocks the action of proteasome–cellular complexes that break down proteins to prevent cancer growth. Bortezomib demonstrated an antitumor effect in in vitro studies in medullary and anaplastic cancer cells.[53] Based on these results, Phase I studies have been conducted in patients with advanced thyroid cancer. Preliminary results indicated that bortezomib associated with sunitinib could synergically enhance the individual antitumor activity: three out of five evaluable patients achieved biochemical response, two out of six (33%) achieved PR and four out of six (77%) stable disease with a mPFS of 12 months.[54]

Thalidomide & Lenalidomide

These drugs are immunomodulatory compounds acting on angiogenesis through mechanisms that are still unknown. Thalidomide was used in a Phase II trial in patients with metastatic, progressive, radioiodine refractory thyroid carcinomas. Among 28 evaluable patients, five (18%) achieved a PR and nine (32%) a stable disease but at the expense of a high rate of adverse events such as peripheral neuropathy, fatigue and infections.[55]

Lenalidomide has similar benefit compared with thalidomide but with better tolerability.[56]

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