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 inhi… Show more
“…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.…”
We demonstrated that the presence of a somatic RET mutation correlates with a worse outcome of MTC patients, not only for the highest probability to have persistence of the disease, but also for a lower survival rate in a long-term follow up. More interestingly, the presence of a somatic RET mutation correlates with the presence of lymph node metastases at diagnosis, which is a known bad prognostic factor for the definitive cure of MTC patients.
“…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.…”
We demonstrated that the presence of a somatic RET mutation correlates with a worse outcome of MTC patients, not only for the highest probability to have persistence of the disease, but also for a lower survival rate in a long-term follow up. More interestingly, the presence of a somatic RET mutation correlates with the presence of lymph node metastases at diagnosis, which is a known bad prognostic factor for the definitive cure of MTC patients.
“…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.…”
Section: Introductionmentioning
confidence: 99%
“…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.…”
Background-HSP90 is a chaperone protein regulating several client proteins involved in thyroid cancer development. The purpose of this study is to mechanisticially evaluate a novel natural-product HSP90 inhibitor in thyroid cancer cell lines for future translational applications.
“…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.…”
Background
Despite development of current targeted therapies for medullary thyroid cancer (MTC), long-term survival remains unchanged. Recently isolated novel withanolide compounds from Solanaceae physalis are highly potent against MTCs. We hypothesize that these withanolides uniquely inhibit RET phosphorylation and the mammalian target of rapamycin (mTOR) pathway in MTC cells as a mechanism of antiproliferation and apoptosis.
Methods
MTC cells were treated with novel withanolides and MTC-targeted drugs. In vitro studies assessed cell viability and proliferation (MTS; trypan blue assays), apoptosis (flow cytometry with Annexin V/PI staining; confirmed by Western blot analysis), long-term cytotoxic effects (clonogenic assay), and suppression of key regulatory proteins such as RET, Akt, and mTOR (by Western blot analysis).
Results
The novel withanolides potently reduced MTC cell viability (half maximal inhibitory concentration [IC50], 270–2,850 nmol/L; 250–1,380 nmol/L for vandetanib; 360–1,640 nmol/L for cabozantinib) with induction of apoptosis at <1,000 nmol/L of drug. Unique from other targeted therapies, withanolides suppressed RET and Akt phosphorylation and protein expression (in a concentration- and time-dependent manner) as well as mTOR activity and translational activity of 4E-BP1 and protein synthesis mediated by p70S6kinase activation at IC50 concentrations.
Conclusion
Novel withanolides from Physalis selectively and potently inhibit MTC cells in vitro. Unlike other MTC-targeted therapies, these compounds uniquely inhibit both RET kinase activity and the Akt/mTOR prosurvival pathway. Further translational studies are warranted to evaluate their clinical potential.
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