New drugs in thyroid cancer

Abstract

This review is focused on "new drugs" that might be developed for thyroid cancer treatment. Thyroid cancer is frequently associated to the activation of specific protein (RET, BRAF) and lipid [PI(3)K] kinases. There is good evidence that these genetic lesions are causative events in thyroid cancer initiation or progression. Therefore, novel compounds able to target these kinases might be useful for thyroid cancer treatment. The power of this approach is witnessed by the examples of BCR-ABL, c-KIT and EGFR inhibitors in the treatment of chronic myelogenous leukemia (CML), gastro-intestinal stromal tumors (GIST) and non-small cell lung carcinoma (NSCLC).

Prognostic Significance of SomaticRETOncogene Mutations in Sporadic Medullary Thyroid Cancer: A 10-Year Follow-Up Study

“…In the era of the development of new targeted therapies, the demonstration that RET mutations are related to a worse outcome also has a direct therapeutic implication. RET positive cases might be treated with tyrosine kinase inhibitors and, in particular, with those having a higher affinity for RET (31). Although tumor RET gene mutation analysis could help to predict patients who will respond to RET-targeted therapies, unfortunately, the genetic test is not commercially available, and, at present, it is performed only in thyroid cancer-dedicated clinical units.…”

A novel HSP90 modulator with selective activity against thyroid cancers in vitro

“…Papillary thyroid cancers (PTC) have been characterized by alterations of one of several kinases including rearrangements of the RET (RET/PTC) receptor tyrosine kinase (13-43% of cases), point mutations in the BRAF serine/threonine kinase (29-69% of cases), rarely rearrangements of the NRTK1 receptor tyrosine kinase (5-13% of cases) or amplification of the catalytic subunit of phosphatidylinositol-3-kinase (up to 12% of cases) 4-9. Follicular thyroid cancers (FTC), which make up approximately 10-15% of all thyroid cancers, are often associated with RAS oncogene mutations in 40-53% of cases or rearrangements between the PAX8 transcription factor and the peroxisome proliferator-activated receptor (PPAR)in 25-63% of cases 9,10. Medullary thyroid cancers (MTC) (5-9% of all thyroid malignancies) are familial in 25% of cases as part of the MEN 2 syndromes or sporadic in 75% of cases 11.…”

“…Almost all familial and over 50% of sporadic MTCs are due to mutations of the transmembrane tyrosine kinase receptor RET proto-oncogene. Recent evidence also points to a high prevalence (up to 50%) of TP53 mutations in MTC 9. Anaplastic thyroid cancers (ATC; 1-5% of all thyroid cancers) carry the worst clinical prognosis with most patients dying of the disease within months of diagnosis.…”

Novel withanolides target medullary thyroid cancer through inhibition of both RET phosphorylation and the mammalian target of rapamycin pathway

“…These TKIs that target RET include drugs such as vandetanib, sorafenib, sunitinib, imatinib, axitinib, motesanib, gefitinib, and cabozantinib (XL184). 7–9 Although these drugs may stabilize disease progression in many patients, they lack durable, long-term responses and carry moderate systemic toxicity for many patients. Opportunities, therefore, remain to identify novel durable therapies for advanced MTC.…”