Dataset Information

Selective use of vandetanib in the treatment of thyroid cancer.

ABSTRACT: Vandetanib is a once-daily orally available tyrosine kinase inhibitor that works by blocking RET (REarranged during Transfection), vascular endothelial growth factor receptor (VEGFR-2, VEGFR-3), and epidermal growth factor receptor and to a lesser extent VEGFR-1, which are important targets in thyroid cancer (TC). It is emerging as a potentially effective option in the treatment of advanced medullary thyroid cancer (MTC) and in dedifferentiated papillary thyroid cancer not responsive to radioiodine. The most important effect of vandetanib in aggressive MTC is a prolongation of progression-free survival and a stabilization of the disease. Significant side effects have been observed with the vandetanib therapy (as fatigue, hypertension, QTc prolongation, cutaneous rash, hand-and-foot syndrome, diarrhea, etc), and severe side effects can require the suspension of the drug. Several studies are currently under way to evaluate the long-term efficacy and tolerability of vandetanib in MTC and in dedifferentiated papillary TC. The efficacy of vandetanib in patients with MTC in long-term treatments could be overcome by the resistance to the drug. However, the effectiveness of the treatment could be ameliorated by the molecular characterization of the tumor and by the possibility to test the sensitivity of primary TC cells from each subject to different tyrosine kinase inhibitor. Association studies are evaluating the effect of the association of vandetanib with other antineoplastic agents (such as irinotecan, bortezomib, etc). Further research is needed to determine the ideal therapy to obtain the best response in terms of survival and quality of life.

SUBMITTER: Fallahi P

PROVIDER: S-EPMC4498730 | biostudies-other | 2015

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Selective use of vandetanib in the treatment of thyroid cancer.

Fallahi Poupak P Di Bari Flavia F Ferrari Silvia Martina SM Spisni Roberto R Materazzi Gabriele G Miccoli Paolo P Benvenga Salvatore S Antonelli Alessandro A

Drug design, development and therapy 20150703

Vandetanib is a once-daily orally available tyrosine kinase inhibitor that works by blocking RET (REarranged during Transfection), vascular endothelial growth factor receptor (VEGFR-2, VEGFR-3), and epidermal growth factor receptor and to a lesser extent VEGFR-1, which are important targets in thyroid cancer (TC). It is emerging as a potentially effective option in the treatment of advanced medullary thyroid cancer (MTC) and in dedifferentiated papillary thyroid cancer not responsive to radioiod ...[more]

PMID: 26170630

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Project description:BackgroundAlthough the incidence of anaplastic thyroid carcinoma (ATC) is low (2.5% of thyroid cancer cases), this cancer has a very poor prognosis (survival rates < 5 months) and accounts for 14-39% of deaths. Conventional therapies based on surgery in combination with radiotherapy or chemotherapy showed limited effectiveness primarily due to the robust and protective DNA damage response in thyroid cancer cells.MethodsWe used single-cell transcriptomic data from patients with different subtypes of thyroid cancer to study expression of genes involved in homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. Then, we investigated the mechanisms of DNA damage and repair in anaplastic (C643 and Hth74) and papillary (TPC-1) thyroid cancer cell lines. The effect of caffeine (inhibitor of ATM and ATR) and UCN-01 (CHK1 inhibitor) was evaluated in cell cycle progression of thyroid cancer cells after γ-radiation or doxorubicin treatment. The DNA damage response was monitored after staining of phosphorylated γ-H2AX and 53BP1. Reporter plasmids were used to determine the efficacy of double-strand DNA breaks (DSBs) repair by HR and NHEJ in thyroid cancer cells. We evaluated the combination of selective inhibition of the DNA ligase IV by SCR7 and doxorubicin on cellular apoptosis and tumor growth in xenograft murine models of anaplastic thyroid cancer.ResultsSingle-cell RNA-Seq showed that NHEJ- and HR-related genes are expressed in ATC and PTC patients. We showed that ATC cells undergo mitosis in the presence of unrepaired DNA damage caused by γ-radiation and doxorubicin treatment. To proliferate and survive, these cells efficiently repair DNA lesions using homologous recombination (HR) and non-homologous end joining (NHEJ). The combination of SCR7 with doxorubicin, significantly increased apoptosis and impaired ATC tumor growth in a xenograft mouse model compared to doxorubicin monotherapy.ConclusionThis study shows the therapeutic value of the combination of a DNA ligase IV inhibitor and DNA-damaging agents (doxorubicin and/or γ-radiation) for the treatment of anaplastic thyroid cancer.

Project description:BackgroundAnaplastic thyroid cancer (ATC) is rare, accounting for 1-2% of thyroid malignancies. Median survival is only 3-10 months, and the optimal therapeutic approach has not been established. This study aimed to evaluate outcomes in ATC based on treatment modality.MethodsRetrospective review was performed for patients treated at a single institution between 1990 and 2015. Demographic and clinical covariates were extracted from the medical record. Overall survival (OS) was modeled using Kaplan Meier curves for different treatment modalities. Univariate and multivariate analyses were conducted to assess the relationships between treatment and disease characteristics and OS.Results28 patients with ATC were identified (n = 16 female, n = 12 male; n = 22 Caucasian, n = 6 African-American; median age 70.9). Majority presented as Stage IVB (71.4%). Most patients received multimodality therapy. 19 patients underwent local surgical resection. 21 patients received locoregional external beam radiotherapy (EBRT) with a median cumulative dose of 3,000 cGy and median number of fractions of 16. 14 patients received systemic therapy (n = 11 concurrent with EBRT), most commonly doxorubicin (n = 9). 16 patients were never disease free, 11 patients had disease recurrence, and 1 patient had no evidence of disease progression. Median OS was 4 months with 1-year survival of 17.9%. Regression analysis showed that EBRT (HR: 0.174; 95% CI: 0.050-0.613; p=0.007) and surgical resection (HR: 0.198; 95% CI: 0.065-0.598; p=0.004) were associated with improved OS. Administration of chemotherapy was not associated with OS.ConclusionsAnaplastic thyroid cancer patients receiving EBRT to the thyroid area/neck and/or surgical resection had better OS than patients without these therapies, though selection bias likely contributed to improved outcomes since patients who can undergo these therapies tend to have better performance status. Prognosis remains poor overall, and new therapeutic approaches are needed to improve outcomes.

Dataset Information

Selective use of vandetanib in the treatment of thyroid cancer.

Publications

Selective use of vandetanib in the treatment of thyroid cancer.

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets