Most thyroid cancers can be cured by surgery, 131I internal radiation and thyroid stimulating hormone (TSH) suppression therapy, but there is still a lack of effective treatment for progressive medullary carcinoma, locally advanced radioiodine-refractory thyroid cancer. The use of molecularly targeted drugs for these patients is a major advancement in thyroid cancer treatment in recent years, and has shown good application prospects.
Some of the molecular targeted drugs have been approved by the US Food and Drug Administration and have been included in the 2014 edition of the National Comprehensive Cancer Network (NCCN) and American Thyroid Association (ATA) guidelines for thyroid cancer treatment, becoming the fourth route of thyroid cancer treatment.
1. The basis of thyroid cancer gene therapy
Progress in molecular biology of thyroid cancer is the basis of targeted therapy, among which the genes closely related to the development of thyroid cancer and more representative include ret gene, ras gene, BRAF gene and VEGF gene.
Mutations in ret gene can be found in medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC). Statistics show that about 95% of hereditary MTC and 70% of sporadic MTC are caused by mutations in the ret gene. point mutations in specific sites of the ret gene enhance the conversion of ret proteins, stimulate tyrosine kinase autophosphorylation, and induce hyperproliferation of parafollicular thyroid cells leading to MTC formation. ret gene breakage fuses with different heterologous genes to form the fusion gene ret/ PTC.
This type of rearrangement causes a change in the promoter of the ret gene, which activates the gene. Depending on the heterologous gene, at least 13 types of ret/PTC genes have been identified, and statistics show that rearrangement mutations in the ret/PTC gene can be detected in 30% to 40% of PTC patients. ret/PTC gene rearrangements are the most common genetic event in PTC.
The ras gene encodes the production of a GTP-binding protein. In thyroid cancer, ras gene mutations produce active transactivator proteins and are considered to be an important early event in tumorigenesis, with N-ras and H-ras gene mutations accounting for 10% to 20% of these events.
BRAF genes belong to the RAF gene family, which are downstream signaling molecules of ret and ras and encode B-type mitogen-activated protein kinase-dependent kinases involved in signaling of the RAS-RAF-MAPK/ERK pathway, which can be continuously activated to regulate cell growth and development and eventually lead to tumorigenesis. BRAF gene mutations occur in approximately 44% of PTC and approximately 24% of undifferentiated thyroid cancers, and BRAFV600E mutations are closely associated with thyroid cancer TNM stage, aggressiveness, and lymph node metastasis status.
VEGF genes are associated with tumor cell bloodstream metastasis, and VEGF-A, vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2 are overexpressed in >90,0% of MTC patients.
Point mutations, gene translocations or abnormal gene methylation of these genes activate intracellular RAS/MAPK/ERK and PI3K/Akt signaling pathways to promote the development of thyroid cancer. These important findings have laid the theoretical foundation for molecularly targeted thyroid cancer therapy and made it possible to scientifically apply thyroid cancer biotherapy.
2.The main targets of protein tyrosine kinase inhibitors
With the gradual elucidation of the basic process of signal transduction pathway changes in tumor cells. With the gradual elucidation of the basic process of signal transduction pathway changes in tumor cells, it has become one of the effective ways of anti-tumor drug research to find new targeted drugs with high efficiency, low toxicity and high specificity by using some key kinases in cellular signal transduction pathways as drug screening targets. Currently, up to 75% of the targets in the field of antitumor are protein kinases, and most of the small molecule tumor target inhibitors currently on the market are tyrosine protein kinase inhibitors (TKI).
In May 2001, Imatinib, as the first TKI approved by FDA, has very good efficacy in the treatment of chronic myeloid leukemia, and its success is a milestone, opening a new era of molecular targeted therapy for tumors.
Protein tyrosine kinases can be divided into receptor-type and non-receptor-type. Non-receptor tyrosine kinases have been clearly associated with the development of malignant tumors mainly include SRC, ABL, JAK and FAK families. The receptor tyrosine kinases that are most closely associated with the development of thyroid tumors are the following families, respectively.
(1) Epidermal growth factor receptor (EGFR) family: including HER1 (ErbB1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4);
(2) Insulin receptor family members: including insulin receptor (IR), insulin-like growth factor-1 receptor (IGF-1R), and insulin-related receptor (IRR);
(3) Platelet-derived growth factor receptor (PDGFR) family: including PDGFR-α, PDGFR-β, colony-stimulating factor 1 receptor (CSF-1R), and stem cell growth factor receptor (c-KIT);
(4) Vascular endothelial growth factor receptor (VEGFR) family: including VEGFR-1 (FLT-1), VEGFR-2 (KDR/FLK1) and VEGFR-3 (FLT-4);
(5) Fibroblast growth factor receptor (FGFR) family: members are FGFR1, FGFR2, FGFR3 and FGFR4.
Tumor is a multifactorial and multiple signaling influenced disease, and cancer cells are prone to resistance to highly selective inhibitors, so multi-target kinase inhibitors that can block multiple signaling pathways for cell growth often achieve better therapeutic results in clinical practice and become a new trend in tumor treatment and new drug development.
Currently, most protein tyrosine kinase inhibitors have partially overlapping biological effects and are multi-targeted kinase inhibitors (MKIs). The main drugs and their targets are shown in Table 1.
3.Progress of research on thyroid cancer-related small molecule multi-targeted tyrosine kinase inhibitors
3,1,1 Vandetanib inhibits RET, EFGFR and EGFR. in a phase II study, 30 patients with MTC treated with vandetanib had partialresponse (PR) in 20% of patients and stable disease (SD) in 53% of patients for >24 weeks. Serum calcitonin levels decreased to less than 50% of baseline in 80% of patients and were maintained for at least >4 weeks.
The subsequent phase III trial (ZETA) was randomized, double-blinded, and had a placebo control group with 331 patients with unresectable locally advanced MTC or metastatic MTC. The results showed that progression-free survival (PFS) was prolonged in the vandetanib group compared with the placebo group (30 months versus 19 months), and the risk of disease progression was reduced by 54% compared with the placebo group (HR=0,46; 95% CI0,31-0,69; P<0,001);
In addition, the objective remission rate (objectiveresponserate, ORR) of 45% (P<0, 0001), disease control rate (diseaseecontrolrate, DCR) (P=0, 001), calcitonin level (P<0, 001), and carcinoembryonic antigen level in the vandetanib group compared with the placebo group (P<0, It was approved by the FDA in 2011 for use in patients with symptomatic or progressive MTC.
Because of its cardiotoxicity, vandetanib requires rigorous risk assessment and mitigation measures (REMS) with ambulatory monitoring of ECG and electrolyte (potassium, calcium and magnesium) levels at 2-4 weeks, 8-12 weeks and every 3 months after 12 weeks of treatment initiation. Therefore, the NCCN recommends using it only in patients with relapsed and progressive MTC.
Common adverse reactions include diarrhea, rash, nausea, hypertension, headache, and prolonged QTc interval. These adverse reactions can usually be controlled by the appropriate medication or by reducing the dose of vandetanib. Other serious adverse reactions such as polymorphic ventricular tachycardia and sudden cardiac death have been classified as black box warnings by the US Food and Drug Administration (FDA). Therefore, careful consideration is still needed for asymptomatic or slowly progressing MTC. It is contraindicated in patients with long QT syndrome.
QT prolongation is an adverse event unique to vandetanib and may be associated with its unique inhibition of the epidermal growth factor receptor (EGFR). In post-marketing clinical evaluations, the serious adverse events of vandetanib again raised clinical concerns. Meta-analysis showed that 2,188 oncology patients treated with vandetanib 300 mg monotherapy developed varying degrees of QTc prolongation in 16, 4% of patients and QTc >500 ms in 3, 7% of patients.
3,1,2 Cabozantinib, which has a stronger affinity for ret than vandetanib, and effectively inhibits the expression of VEGFR-2 and MET genes.
In a phase III clinical trial on progressive MTC (EXAM). 330 patients with metastatic MTC were randomized to treatment with cabozantinib (219) or placebo (111), with tumor evaluation every 12 weeks until tumor progression or toxicity was determined to be intolerable. The results showed that patients in the cabozantinib group had a PFS of 11,2 months compared to 4,0 months in the placebo control group, and the cabozantinib group was prolonged by 7 months compared to the placebo control group.
The rate of MTC progression was 20% in the cabozantinib group and 60% in the placebo group, respectively. Serum calcitonin levels decreased by 45% relative to baseline values in the cabozantinib group after 12 weeks of treatment initiation, whereas they increased by 57% in the placebo group (P<0.001), indicating tumor progression in the placebo group, but data on overall survival (overallsurvival, OS) were not available for analysis, and the data that have been collected show that cabozantinib has no statistically significant improvement in OS compared with placebo. The difference in improvement from placebo was not statistically significant.
Cabozantinib was approved by the FDA in 2012 for the treatment of non-surgically resectable malignant locally advanced MTC or metastatic MTC [18-21]. Rare adverse events include severe bleeding and gastrointestinal perforation (3%) or fistula (1%), which must be discontinued if they occur; severe bleeding is a contraindication to the use of cabozantinib. Compared to vandetanib, cabozantinib has good clinical efficacy against MTC with relatively mild adverse effects, no reported QTc prolongation, and better patient tolerability.
3,1,3 Sorafenib (Sorafenib) is the only VEGFR-like inhibitor class that inhibits raf kinase. By inhibiting c-Raf kinase and downstream signaling, it impedes the phosphorylation process of MEK and ERK, reduces the level of pERK, and plays an anti-proliferative role; it also inhibits the activity of various tyrosine kinases such as VEGFR-2, VEGFR-3 and PDGFR-β, and plays an anti-angiogenic role. It also inhibits the phosphorylation process of eIF4E and down-regulates the level of anti-apoptotic protein Mcl-1 in vivo, which has a pro-apoptotic effect.
In a phase II clinical trial, a total of 30 patients with radioiodinated differentiated thyroid cancer (RR-DTC) were enrolled and given oral treatment with sorafenib. According to responseevaluationcriteriainsolidtumors (RECIST), partial remission was observed in 7 of 30 patients with CT results lasting 18 to 84 weeks, 53% of patients had stable disease for at least 14 to 89 weeks, and 95% of patients had a decrease in thyroglobulin levels of 70 percent.
However, sorafenib was less effective in patients with bone metastases. In the phase III clinical trial, 417 patients were enrolled (207 in the sorafenib group and 210 in the placebo group), with a median PFS of 10 or 8 months in the sorafenib group and only 5 or 8 months in the placebo group.
The main adverse reactions were hand-foot syndrome (76, 3%), diarrhea (68, 6%), rash (50, 2%), and alopecia (67, 1%). Most adverse reactions are grade 1 to 2 and can be alleviated by reducing the drug dosage or discontinuing it [26]. approved by the FDA in 2014 for the treatment of RR-DTC and progressive thyroid cancer, it improves progression-free survival in patients with progressive thyroid cancer but does not improve overall survival.
3,1,4Lenvatinib acts primarily on VEGFR2 (KDR)/VEGFR3 (Flt-4) and slightly less on VEGFR1/Flt-1.
The results of the Phase III clinical trial (SELECT) of levatinib for advanced progressive and RR-DTC showed that levatinib significantly prolonged PFS in patients with RR-DTC compared to the placebo group (18, 3 months vs, 3, 6 months). Moreover, there were 4 cases (4%) of complete remission (CR) and 165 cases (63, 2%) of PR in the levatinib use group compared to 0 and 2 (1, 5%) in the placebo group.
In another study, 64 patients with metastatic, radioiodine-refractory differentiated thyroid cancer entered the study. 35 patients in the first group, treated with the first-line drug sorafenib, had a PFS of 7,4 months; 17 patients in the second group of 25 patients failed sorafenib treatment, and these patients continued with second-line drugs such as levatinib, and their PFS was extended to 11,4 months.
Therefore, although these drugs have similar mechanisms of action, other targeted drugs can serve as effective remedies after sorafenib treatment failure. 2015 FDA approved levatinib for the treatment of metastatic thyroid cancer and RR-DTC.
3,2 Targeted thyroid cancer therapeutics in clinical trials Many commercially available targeted therapeutics are currently in clinical trials. Some of the drugs have been used in kidney cancer, non-small cell lung cancer and gastrointestinal mesenchymal tumor, but clinical trials are underway for thyroid cancer applications. The progress of their clinical studies is shown in Table 2. The other most anticipated drugs are the BRAFV600E-specific inhibitor vimofenib and the ras-specific inhibitor tipifarnib, but these two drugs have just completed phase I clinical trials.
3,2,2 Vemurafenib (Vemurafenib) inhibits BRAFV600E, C-Raf, and wild-type BRAF. BRAFV600E mutations are associated with the aggressiveness of thyroid cancer, and in 2013, three patients with metastatic PTC with BRAFV600E mutations were enrolled in a phase I clinical trial.
Treatment with vimofenib, evaluated according to RECIST after 8 weeks, confirmed partial remission of lung lesions in one patient with a PFS of 11, 7 months; the other two patients had stable disease with a progression-free survival of 11, 4 months and 13, 2 months, respectively. Phase II clinical trials of this drug are expected [10]. It is currently FDA approved for the treatment of advanced (metastatic) or unresectable melanoma.
3,2,3 Tipifarnib, a specific farnesyltransferase (FTase) inhibitor, acts on H-ras or N-ras mutant cells and has the most significant anti-proliferative effect. Combined application of sorafenib can inhibit B-Raf, ret, VEGF, H-ras, and N-ras simultaneously.
Simultaneous inhibition of Ras/Raf/MAPKkinase/ERK and ret signaling to pathways from each target, the results of the clinical trial in phase I in 2015, 35 thyroid cancer patients treated with sorafenib combined with tipifarnib, including 22 cases of DTC, PR4, 5% SD6 months; 13 cases of MTC, PR38% SD6 months; PFS was 18 months.
3, 3NCCN thyroid cancer guidelines for the treatment of small molecule kinase inhibitors recommended NCCN guidelines 2014V2 edition for the treatment of small molecule kinase inhibitors put forward the following 4 principles.
(1) Oral small molecule kinase inhibitors can be used for unresectable locally recurrent lesions or metastatic MTC, and radioiodine-refractory differentiated thyroid cancer.
(2) The following 3 aspects need to be considered for patients considering the use of small molecule kinase inhibitors.
(i) Small molecule kinase inhibitors are associated with patient’s PFS rather than cure rate;
(2) The known side effects of small molecule kinase inhibitors may seriously affect the patient’s quality of life;
(3) The natural course of MTC and DTC progression varies in each patient, ranging from a few months to several years.
(3) The rate of disease progression is a factor that must be considered for treatment; for asymptomatic, slowly progressing patients small molecule kinase inhibitors may not be appropriate, especially when serious side effects occur; for rapidly progressing patients patients may still benefit from them even if complications arise.
(4) The dose and side effects of small molecule kinase inhibitors must be managed optimally, requiring comprehensive consideration of skin, blood pressure, and gastrointestinal side effects and timely dose adjustment.
For patients with unresectable locally recurrent lesions, iodine-refractory differentiated thyroid cancer, especially those who have invaded vital organs and cannot be treated with external irradiation, small molecule kinase inhibitors may be used for treatment. Sorafenib is preferred and those who are ineffective may try clinical trials with axitinib, pazopanib, sunitinib or vandetanib with recommendation level 2A.
For symptomatic recurrent or metastatic medullary carcinoma, vandetanib or cabozantinib is recommended, and sorafenib or sunitinib is recommended in cases where the first two drugs are not suitable.
4. Conclusion
With the development of clinical trials, molecularly targeted therapeutic agents for thyroid cancer are gradually approved by FDA and formally used in the clinic. In recent years, targeted therapy for thyroid cancer has gradually shifted from inhibition of tumor neovascularization to treatment of thyroid cancer-specific gene mutations and combination of drugs, and the results are encouraging. Molecular targeted drugs have many advantages such as high specificity, reliable efficacy and less damage, which have great potential and broad prospect in the treatment of thyroid cancer.