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Current status of clinical trials for glioblastoma.

Glioblastoma, the most highly aggressive and lethal form of brain cancer, has been a particular challenge to treat in terms of improving a patient's quality of life and outcome. Each of the current treatment options is limited due to factors intrinsic to the tumor's biology and the special microenvironment of its location within the brain. Surgical resection is limited by the non-circumscribed borders that can be detected. Radiation therapy has to contend with neurotoxicity to adjacent normal tissues. Chemotherapy is constrained by the blood-brain barrier, which is a very real constraint of sy

Effect of epidermal growth factor receptor tyrosine kinase inhibition on epithelial proliferation in normal and premalignant breast.

The factors controlling epithelial proliferation in ductal carcinoma in situ (DCIS) are unclear. Antiestrogens are effective in the prevention of the majority of estrogen receptor-positive, but not estrogen receptor (ER)-negative breast cancers, which suggests that other factor(s) are promoting proliferation in ER-negative DCIS. Mutated or overexpressed tyrosine kinases are frequently associated with tumor development. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is involved with mitogenesis and is expressed in ER-negative DCIS. We hypothesized that EGFR is centra

Targeting Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer by Inducing Epidermal Growth Factor Receptor Degradation via Methionine 790 Oxidation.

AIMS: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat non-small cell lung cancer (NSCLC) patients with EGFR mutation, but TKI resistance is common. Almost half of the acquired resistance patients are due to additional T790M mutation on EGFR (EGFR(T790M)), thus overcoming TKI resistance is important. In this study, we aim to investigate the role of reactive oxygen species (ROS) in TKI resistance as well as the molecular and biological effects of EGFR(T790M) after redox manipulation. RESULTS: The basal ROS levels in EGFR(T790M)-containing T

MicroRNA-133b inhibits the growth of non-small-cell lung cancer by targeting the epidermal growth factor receptor.

Both the deregulation of microRNAs and epidermal growth factor receptor (EGFR) are emerging as important factors in non-small-cell lung cancer (NSCLC). Here, miR-133b was found to be associated with tumor stage, the extent of regional lymph node involvement, stage, visceral pleura or vessel invasion and EGFR mRNA expression in Chinese patients with NSCLC. Bioinformatic analysis and luciferase reporter assay revealed that miR-133b can interact specifically with the 3'-UTR of EGFR mRNA. Functionally, miR-133b transfection showed regulatory activity in translationally repressing EGFR mRNA. Moreov

The effects of ZD1839 (Iressa), a highly selective EGFR tyrosine kinase inhibitor, as a radiosensitiser in bile duct carcinoma cell lines.

The signaling pathway that is initiated by binding of epidermal growth factor receptor (EGFR) and results in sustained signaling through PI3K plays an important role in a tumor's response to ionizing radiation. The current in vitro study explored both the effects of ZD1839 (Iressa), a highly selective EGFR tyrosine kinase inhibitor, as a radiosensitiser for bile duct carcinoma cell lines and ZD1839's general effects on cell growth in the same two lines. Secondly, we ensured suppression of radiation-induced phosphorylation of EGFR by ZD1839 using an immunoprecipitation technique. Furthermore, w

Oral administration of a novel taxane, an antisense oligonucleotide targeting protein kinase A, and the epidermal growth factor receptor inhibitor Iressa causes cooperative antitumor and antiangiogenic activity.

PURPOSE: Protein kinase A type I (PKAI) and the epidermal growth factor receptor (EGFR) play a role in neoplastic transformation and interact with each other in transducing mitogenic signals. We developed different PKAI and EGFR inhibitors, demonstrating their cooperation with cytotoxic drugs and the therapeutic potential of the combined blockade of PKAI and EGFR. In this study, we investigated the effect of orally active PKAI and EGFR inhibitors in combination with a novel taxane. EXPERIMENTAL DESIGN: We combined a hybrid PKAI antisense oligonucleotide sequence (AS-PKAI), the EGFR inhibitor

Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial.

BACKGROUND: Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. METHODS: In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and h…

Heat shock protein 90-sheltered overexpression of insulin-like growth factor 1 receptor contributes to malignancy of thymic epithelial tumors.

PURPOSE: The underlying molecular mechanisms of thymic epithelial malignancies (TEMs) are poorly understood. Consequently, there is a lack of efficacious targeted therapies and patient prognosis remains dismal, particularly for advanced TEMs. We sought to investigate protumorigenic mechanism relevant to this understudied cancer. EXPERIMENTAL DESIGN: Recently established cell lines derived from thymic epithelial tumors were used as a model system. The antitumor activity of specific heat shock protein 90 (Hsp90) inhibitors was investigated by an analysis of cell viability, cell cycle, and apopt

One patient with metastastic colorectal cancer successfully treated by combination of targeted agents after failure of chemotherapy.

Either cetuximab or bevacizumab can improve the survival of patients with metastastic colorectal cancer (mCRC) if administered combided with cytotoxic agents. However, the effect of two or more target agents in combination is uncertain in these patients. Here, we reported a patient with mCRC successfully treated by a combination of target agents after the failure of chemotherapy. The patient received palliative resection of primary tumor followed by 9 cycles of postoperative XELOX regimen, cytokine-induced killer cell (CIK)-based biotherapy, traditional Chinese medicine, particle implantation

The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses c-Src and Pak1 pathways and invasiveness of human cancer cells.

PURPOSE: Abnormalities in the expression and signaling pathways downstream of the epidermal growth factor receptor (EGFR) contribute to the progression, invasion, and maintenance of the malignant phenotype in human cancers, including those of the head and neck and breast. Accordingly, agents such as the EGFR tyrosine kinase inhibitor (EGFR-TKI) ZD1839 (Iressa) are promising, biologically based treatments that are in various stages of preclinical and clinical development. The process of tumor progression requires, among other steps, increased transformation, directional migration, and enhanced

Chemotherapeutic agents and the skin: An update.

UNLABELLED: Chemotherapeutic agents give rise to numerous well described adverse effects that may affect the skin, hair, mucous membranes, or nails. The mucocutaneous effects of longstanding agents have been extensively studied and reviewed. Over the last 2 decades, a number of new molecular entities for the treatment of cancer have been approved by the United States Food and Drug Administration (FDA). This article reviews the cutaneous toxicity patterns of these agents. It also reviews one drug that has not received FDA approval but is in use outside the United States and is important dermato

Early (Days 1-4) post-treatment serum hCG level changes predict single-dose methotrexate treatment success in tubal ectopic pregnancy.

STUDY QUESTION: What is the capacity of the change between Day 1 and Day 4 post-treatment serum human chorionic gonadotropin (hCG) levels fo … rexate. The data were derived from a UK multicentre randomized controlled trial of methotrexate and gefitinib versus methotrexate and placebo for treatment of tubal ectopic pregnancy (GEM3). For this analysis, we include data from both treatment arms. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were categorized according to single-dose methotrex …

Tumor growth inhibition by simultaneously blocking epidermal growth factor receptor and cyclooxygenase-2 in a xenograft model.

PURPOSE: Our previous study revealed that simultaneously targeting epidermal growth factor receptor (EGFR) tyrosine kinase and cyclooxygenase-2 (COX-2) additively or synergistically inhibited growth of squamous cell carcinoma of the head and neck (SCCHN) in vitro. However, an in vivo efficacy of this combined treatment in SCCHN has not been studied. EXPERIMENTAL DESIGN: Nude mice were pretreated with control (1% Tween 80), ZD1839 (50 mg/kg) alone, celecoxib (50 mg/kg) alone, or a combination of ZD1839 and celecoxib at the same dosages for 7 days before injection of a human SCCHN cell line Tu2

Data-Driven Computational Modeling Identifies Determinants of Glioblastoma Response to SHP2 Inhibition.

Oncogenic protein tyrosine phosphatases have long been viewed as drug targets of interest, and recently developed allosteric inhibitors of SH2 domain-containing phosphatase-2 (SHP2) have entered clinical trials. However, the ability of phosphatases to regulate many targets directly or indirectly and to both promote and antagonize oncogenic signaling may make the efficacy of phosphatase inhibition challenging to predict. Here we explore the consequences of antagonizing SHP2 in glioblastoma, a recalcitrant cancer where SHP2 has been proposed as a useful drug target. Measuring protein phosphoryla

Novel molecular targeted therapies for refractory thyroid cancer.

The incidence of thyroid cancer continues to increase and this neoplasia remains the most common endocrine malignancy. No effective systemic treatment currently exists for iodine-refractory differentiated or medullary thyroid carcinoma, but recent advances in the pathogenesis of these diseases have revealed key targets that are now being evaluated in the clinical setting. RET (rearranged during transfection)/PTC (papillary thyroid carcinoma) gene rearrangements, B-Raf gene mutations, and vascular endothelial growth factor receptor 2 (VEGFR-2) angiogenesis pathways are some of the known genetic

Genetic variations in ABC transporter genes as a predictive biomarker for toxicity in North Indian lung cancer patients undergoing platinum-based doublet chemotherapy.

ATP-binding cassette (ABC) transporters are expressed in various human tissues and play a vital role in the efflux of various chemotherapeutic drugs. The current study has assessed genetic variants of ABCB1, ABCC1, ABCC2, and ABCG2 genes in 407 lung cancer patients undergoing platinum-based doublet chemotherapy. The association of ABCB1 (C1236 T, C3435 T, and G2677 T/A), ABCC1 (G3173 A and G2168 A),ABCC2 (G4544 A), and ABCG2 (C421 A) polymorphisms with chemotherapy-induced adverse events were assessed, and statistical analysis was conducted. Our data showed that patients harboring heterozygous

Long Term Therapeutic Plan for Patients with Non-Small Cell Lung Cancer Harboring EGFR Mutation.

Non-small cell lung cancer harboring epidermal growth factor receptor (EGFR) sensitizing mutations has a distinct disease entity. Patients with this cancer have better prognosis, and frequently achieve long-term survival. EGFR-tyrosine kinase inhibitor (TKI) is the drug of choice for this cancer; but the disease inevitably progresses, after durable response. The tumor is a mixture of EGFR-TKI sensitive clones and resistant clones, regardless of their molecular mechanisms. EGFR-TKI sensitive clones are very susceptible to this drug, but rarely eradicated; so, withdrawal of the drug permits rapi

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… Jackman et al. 34 reported a case with local failure in central nervous system (CNS) controlled by high dose gefitinib. The patient with NSCLC harboring EGFR exon 19 deletion responded to gefitinib at the usual dose of 250 mg/day. … response to gefitinib Oncology 2010 79 423 429 21474967 10.1159/000326488 28 Riely GJ Kris MG Zhao B Akhurst T Milton DT Moore E Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition …

Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance.

One of the greatest obstacles to current cancer treatment efforts is the development of drug resistance by tumors. Despite recent advances in diagnostic practices and surgical interventions, many neoplasms demonstrate poor response to adjuvant or neoadjuvant radiation and chemotherapy. As a result, the prognosis for many patients afflicted with these aggressive cancers remains bleak. The insulin-like growth factor (IGF) signaling axis has been shown to play critical role in the development and progression of various tumors. Many basic science and translational studies have shown that IGF pathw

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… That is, cell lines that were already resistant to gefitinib were found to have increased total-IGF-1R and phosphorylated-IGF-1R expression, but overexpression of IGF-1R did not confer resistance to gefitinib-sensitive cells. 52 Another study looking at IGF-1R expression using immunohistochemistry did … AG1024, which prevents autophosphorylation of IGF-1R, synergizes with gefitinib to produce pro-apoptotic and anti-proliferative effects in vitro in previously gefitinib-resistant NSCLC cells. 59 In mutant KRAS lung adenocarcinoma, IGF's downstream PI3K/AKT signaling is thought to be involved with both …