azd-6244 and Carcinoma--Papillary

A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of selumetinib in iodine-refractory papillary thyroid cancer (IRPTC).. Patients with advanced IRPTC with or without follicular elements and documented disease progression within the preceding 12 months were eligible to receive selumetinib at a dose of 100 mg twice daily. The primary endpoint was objective response rate using Response Evaluation Criteria in Solid Tumors. Secondary endpoints were safety, overall survival, and progression-free survival (PFS). Tumor genotype including mutations in BRAF, NRAS, and HRAS was assessed.. Best responses in 32 evaluable patients out of 39 enrolled were 1 partial response (3%), 21 stable disease (54%), and 11 progressive disease (28%). Disease stability maintenance occurred for 16 weeks in 49%, 24 weeks in 36%. Median PFS was 32 weeks. BRAF V600E mutants (12 of 26 evaluated, 46%) had a longer median PFS compared with patients with BRAF wild-type (WT) tumors (33 versus 11 weeks, respectively, HR = 0.6, not significant, P = 0.3). The most common adverse events and grades 3 to 4 toxicities included rash, fatigue, diarrhea, and peripheral edema. Two pulmonary deaths occurred in the study and were judged unlikely to be related to the study drug.. Selumetinib was well tolerated but the study was negative with regard to the primary outcome. Secondary analyses suggest that future studies of selumetinib and other mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) inhibitors in IRPTC should consider BRAF V600E mutation status in the trial design based on differential trends in outcome.

Topics: Adenocarcinoma, Follicular; Adult; Aged; Aged, 80 and over; Benzimidazoles; Carcinoma; Carcinoma, Papillary; Diarrhea; Exanthema; Fatigue; Female; Genotype; Humans; Iodine Radioisotopes; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Pharmacogenetics; Proto-Oncogene Proteins B-raf; ras Proteins; Thyroid Cancer, Papillary; Thyroid Neoplasms; Treatment Outcome

Redifferentiation therapy with BRAF/MEK inhibitors to facilitate treatment with radioiodine represents a good choice for radioiodine-refractory differentiated thyroid carcinoma, but recent initial clinical outcomes were modest. MAPK rebound caused by BRAF/MEK inhibitors-induced activation of HER2/HER3 is a resistance mechanism, and combination with HER inhibitor to prevent MAPK rebound may sensitize BRAFV600E-mutant thyroid cancer cells to redifferentiation therapy. To evaluate if inhibiting both BRAF/MEK and HER can produce stronger redifferetiation effect, we tested the effects of BRAF/MEK inhibitor dabrafenib/selumetinib alone or in combination with HER inhibitor lapatinib on the expression and function of iodine- and glucose-handling genes in BRAFV600E-positive BCPAP and K1 cells, using BHP 2-7 cells harboring RET/PTC1 rearrangement as control. Herein, we showed that lapatinib prevented MAPK rebound and sensitized BRAFV600E-positive papillary thyroid cancer cells to BRAF/MEK inhibitors. Dabrafenib/selumetinib alone increased iodine-uptake and toxicity and suppressed glucose-metablism in BRAFV600E-positive papillary thyroid cancer cells. When lapatinib was added, more significant effects on iodine- and glucose-handling gene expression, cell membrane location of sodium/iodine symporter as well as radioiodine uptake and toxicity were observed. Thus, combined therapy using HER inhibitor and BRAF/MEK inhibitor presented more significant redifferentiation effect on papillary thyroid cancer cells harboring BRAFV600E than BRAF/MEK inhibitor alone. In vivo and clinical studies assessing such combined targeted redifferentiation strategy were warranted.

Topics: Benzimidazoles; Blotting, Western; Carcinoma, Papillary; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Humans; Imidazoles; Inhibitory Concentration 50; Lapatinib; MAP Kinase Kinase 1; Microscopy, Fluorescence; Mutation, Missense; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Quinazolines; Receptor, ErbB-2; Reverse Transcriptase Polymerase Chain Reaction; Thyroid Neoplasms

The BRAF V600E mutation is commonly observed in papillary thyroid cancer (PTC) and predominantly activates the MAPK pathway. Presence of BRAF V600E predicts increasing risk of recurrence and higher mortality rate, and treatment options for such patients are limited. Vemurafenib, a BRAF V600E inhibitor, is initially effective, but cells inevitably develop alternative mechanisms of pathway activation. Mechanisms of primary resistance have been described in short-term cultures of PTC cells; however, mechanisms of acquired resistance have not. In the present study, we investigated possible adaptive mechanisms of BRAF V600E inhibitor resistance in KTC1 thyroid cancer cells following long-term vemurafenib exposure. We found that a subpopulation of KTC1 cells acquired resistance to vemurafenib following 5 months of treatment with the inhibitor. Resistance coincided with the spontaneous acquisition of a KRAS G12D activating mutation. Increases in activated AKT, ERK1/2, and EGFR were observed in these cells. In addition, the resistant cells were less sensitive to combinations of vemurafenib and MEK1 inhibitor or AKT inhibitor. These results support the KRAS G12D mutation as a genetic mechanism of spontaneously acquired secondary BRAF inhibitor resistance in BRAF V600E thyroid cancer cells.

Topics: Aged; Antineoplastic Agents; Benzimidazoles; Carcinoma, Papillary; Cell Line, Tumor; Drug Resistance, Neoplasm; Enzyme Inhibitors; ErbB Receptors; Female; Gain of Function Mutation; Gene Knockdown Techniques; Heterocyclic Compounds, 3-Ring; Humans; Indoles; Male; MAP Kinase Kinase 1; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidines; RNA Interference; RNA, Small Interfering; Sulfonamides; Thyroid Cancer, Papillary; Thyroid Neoplasms; Vemurafenib

To evaluate MHC class I expression on papillary thyroid cancer (PTC) and analyze changes in MHC expression and associated immune activation with current and experimental treatments for thyroid cancer using in vitro PTC cell lines.. MHC class I expression and assessment of tumor-infiltrating leukocyte populations were evaluated by immunohistochemistry. PTC cell lines were analyzed for HLA-ABC expression by flow cytometry following tyrosine kinase inhibitor, IFNα or IFNγ, or radiation treatment. Functional changes in antigenicity were assessed by coculture of allogeneic donor peripheral blood leukocytes (PBL) with pretreated or untreated PTC cell lines and measurement of T-cell activation and cytokine production.. Both MHC class I and β2-microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor-infiltrating immune cells, including effector (CD3(+), CD8(+), CD16(+)) and suppressor (FoxP3(+)) populations. Treatment of PTC cell lines with the MEK1/2 inhibitor selumetinib or IFN increased HLA-ABC expression. This phenotypic change was associated with increased T-cell activation (%CD25(+) of CD3(+)) and IL2 production by PBL cocultured with treated PTC cell lines. Additive effects were seen with combination selumetinib and IFN treatment.. MHC class I expression loss is frequent in human PTC specimens and represents a significant mechanism of immune escape. Increased antigenicity following selumetinib and IFN treatment warrants further study for immunotherapy of progressive PTC.

Topics: Adult; Aged; Benzimidazoles; Biomarkers; Carcinoma; Carcinoma, Papillary; Cell Line, Tumor; Drug Synergism; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Histocompatibility Antigens Class I; Humans; Immunohistochemistry; Interferons; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Thyroid Cancer, Papillary; Thyroid Neoplasms; Tumor Escape; Young Adult

Although a wide spectrum of inhibitors of the MEK/ERK and PI3K/AKT pathways have been discovered and entered clinical trials, the effects of their individual use in thyroid cancer were often disappointing. We hypothesized that dual targeting of these two pathways would be a safe and effective strategy against aggressive thyroid cancers.. We examined the antiproliferative effects of the MEK/ERK inhibitor AZD6244 and the PI3K/AKT inhibitor GDC0941, individually or in combination, on thyroid cancer cells harboring both the BRAF(V600E) and PIK3CA mutations. The effects of drug exposure on both total and phosphorylated (p-) forms of AKT and ERK were monitored by Western blotting analysis. Effects of these inhibitors on cell-cycle progression and apoptosis were measured by flow cytometry and DNA-fragmentation analyses, respectively.. We observed significant toxicities to viability of cells with low concentrations of AZD6244 or GDC0941, which were synergistic when the two inhibitors were used in combination (P < 0.01). AZD6244 abrogated p-ERK and GDC0941 abrogated p-AKT levels, confirming their expected target effects. Unexpectedly, monotherapy with AZD6244 resulted in activation of the PI3K signaling pathway in some cancer cell lines and co-exposure to AZD6244 and GDC0941 was necessary to suppress both pathways. Flow cytometry showed G1 arrest. DNA fragmentation analysis showed an increased apoptosis of cells dually treated with the two inhibitors.. Concomitant suppression of MEK/ERK and PI3K/AKT pathways by AZD6244 and GDC0941 abrogates compensatory mechanisms of tumor survival and causes synergistic cytotoxicity in thyroid cancer cells.

Topics: Antineoplastic Agents; Apoptosis; Benzimidazoles; Carcinoma; Carcinoma, Papillary; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; Humans; Indazoles; Mitogen-Activated Protein Kinase Kinases; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Sulfonamides; Thyroid Cancer, Papillary; Thyroid Neoplasms

Over the past 5 years, patients with progressive radioactive iodine-refractory thyroid cancer have responded to "targeted" multikinase inhibitors, which inhibit angiogenesis and not the tumor cell. Here, selumetinib targets the mitogen-activated protein kinase pathway in papillary thyroid carcinoma and shows limited single-agent activity in the patients with tumors that harbor the (V600E)BRAF mutation.

Topics: Adenocarcinoma, Follicular; Benzimidazoles; Carcinoma; Carcinoma, Papillary; Female; Humans; Male; Pharmacogenetics; Thyroid Cancer, Papillary; Thyroid Neoplasms

Topics: Aged; Benzimidazoles; Carcinoma, Papillary; Drug Eruptions; Humans; Male; MAP Kinase Kinase Kinases; Thyroid Neoplasms