Phase II Study of Docetaxel in Combination with Everolimus for Second- or Third-Line Therapy of Advanced Non-Small-Cell Lung Cancer.

Phase II Study of Docetaxel in Combination with Everolimus for Second- or Third-Line Therapy of Advanced Non-Small-Cell Lung Cancer.

J Thorac Oncol. 2013 Mar;8(3):369-72

Authors: Ramalingam SS, Owonikoko TK, Behera M, Subramanian J, Saba NF, Kono SA, Gal AA, Sica G, Harvey RD, Chen Z, Klass CM, Shin DM, Fu H, Sun SY, Govindan R, Khuri FR

Abstract
We conducted a phase II study of docetaxel in combination with everolimus, a mammalian target of rapamycin (mTOR) inhibitor, for salvage therapy of advanced non-small-cell lung cancer (NSCLC) based on promising preclinical and early-phase clinical data. Patients with advanced-stage NSCLC treated with one or two previous systemic therapy regimens were given docetaxel (60 mg/m) and everolimus (5 mg orally once daily on days 1-19) every 3 weeks. Archived tumor specimens were evaluated for markers of mTOR pathway activation (total and phosphorylated mTOR, Akt, S6, eIF4e, and 4EBP1). Twenty-eight patients were enrolled (median age: 62 years; male: 13; Caucasians: 19; adenocarcinoma: 20; performance status 0, 3; performance status 1, 23; 1 previous regimen, 16). A median of 3.5 cycles of therapy was administered. Two patients experienced partial response and 15 had stable disease (clinical benefit rate, 70%). The 6-month progression-free survival rate was 5%, and the median overall survival was 9.6 months. Low pAkt expression correlated with clinical benefit rate (p = 0.01) but not with progression-free survival or overall survival. The combination of everolimus and docetaxel was tolerated well, but the efficacy was relatively modest in an unselected population of patients with NSCLC.

PMID: 23407561 [PubMed - in process]

c-met inhibitors zm-447439 rad001

Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS A? Reduction.

Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS A? Reduction.

ACS Med Chem Lett. 2012 Nov 8;3(11):897-902

Authors: Stamford AW, Scott JD, Li SW, Babu S, Tadesse D, Hunter R, Wu Y, Misiaszek J, Cumming JN, Gilbert EJ, Huang C, McKittrick BA, Hong L, Guo T, Zhu Z, Strickland C, Orth P, Voigt JH, Kennedy ME, Chen X, Kuvelkar R, Hodgson R, Hyde LA, Cox K, Favreau L, Parker EM, Greenlee WJ

Abstract
Inhibition of BACE1 to prevent brain A? peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS A? levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF A?40 levels when administered orally to rats.

PMID: 23412139 [PubMed - as supplied by publisher]

rad001 ecdysone chir-258

Phase II Study of Docetaxel in Combination with Everolimus for Second- or Third-Line Therapy of Advanced Non-Small-Cell Lung Cancer.

Phase II Study of Docetaxel in Combination with Everolimus for Second- or Third-Line Therapy of Advanced Non-Small-Cell Lung Cancer.

J Thorac Oncol. 2013 Mar;8(3):369-72

Authors: Ramalingam SS, Owonikoko TK, Behera M, Subramanian J, Saba NF, Kono SA, Gal AA, Sica G, Harvey RD, Chen Z, Klass CM, Shin DM, Fu H, Sun SY, Govindan R, Khuri FR

Abstract
We conducted a phase II study of docetaxel in combination with everolimus, a mammalian target of rapamycin (mTOR) inhibitor, for salvage therapy of advanced non-small-cell lung cancer (NSCLC) based on promising preclinical and early-phase clinical data. Patients with advanced-stage NSCLC treated with one or two previous systemic therapy regimens were given docetaxel (60 mg/m) and everolimus (5 mg orally once daily on days 1-19) every 3 weeks. Archived tumor specimens were evaluated for markers of mTOR pathway activation (total and phosphorylated mTOR, Akt, S6, eIF4e, and 4EBP1). Twenty-eight patients were enrolled (median age: 62 years; male: 13; Caucasians: 19; adenocarcinoma: 20; performance status 0, 3; performance status 1, 23; 1 previous regimen, 16). A median of 3.5 cycles of therapy was administered. Two patients experienced partial response and 15 had stable disease (clinical benefit rate, 70%). The 6-month progression-free survival rate was 5%, and the median overall survival was 9.6 months. Low pAkt expression correlated with clinical benefit rate (p = 0.01) but not with progression-free survival or overall survival. The combination of everolimus and docetaxel was tolerated well, but the efficacy was relatively modest in an unselected population of patients with NSCLC.

PMID: 23407561 [PubMed - in process]

dovitinib dna-pk coxinhibitors

Rationally Designed Multitarget Agents against Inflammation and Pain.

Rationally Designed Multitarget Agents against Inflammation and Pain.

Curr Med Chem. 2013 Feb 14;

Authors: Hwang SH, Wecksler AT, Wagner K, Hammock BD

Abstract
Arachidonic acid (ARA) undergoes enzyme-mediated oxidative metabolism, resulting in the formation of a number of biologically active metabolites. For over a century, these biochemical transformations have been the target of numerous pharmacological drugs for inflammation and pain. In particular, non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) selective inhibitors (coxibs) are widely used in the treatment of inflammation and pain. However, gastrointestinal (GI) and cardiovascular adverse effects of NSAIDs and coxibs, and recent findings demonstrating there are significant risks from the disruption of oxylipin levels when pharmacologically inhibiting a single ARA cascade metabolic pathway have led to studies involving the simultaneous inhibition of multiple pathways in ARA cascade. These studies suggest that multitarget inhibition represents a new and valuable option to enhance efficacy or reduce side-effects in the treatment of inflammation and pain. This review focuses on the crosstalk within the three pathways of the ARA cascade (cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450)), and summarizes the current and future approaches of multitarget inhibitors for the treatment of eicosanoid driven inflammation and pain.

PMID: 23410172 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer.

Related Articles

A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer.

J Thorac Oncol. 2012 Oct;7(10):1602-8

Authors: Goldberg SB, Supko JG, Neal JW, Muzikansky A, Digumarthy S, Fidias P, Temel JS, Heist RS, Shaw AT, McCarthy PO, Lynch TJ, Sharma S, Settleman JE, Sequist LV

Abstract
INTRODUCTION: This investigator-initiated study explores the safety, maximum tolerated dose, clinical response, and pharmacokinetics of hydroxychloroquine (HCQ) with and without erlotinib in patients with advanced non-small-cell lung cancer.
METHODS: Patients with prior clinical benefit from an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor were randomized to HCQ or HCQ plus erlotinib in a 3 + 3 dose-escalation schema.
RESULTS: Twenty-seven patients were treated, eight with HCQ (arm A) and 19 with HCQ plus erlotinib (arm B). EGFR mutations were detected in 74% of the patients and 85% had received two or more prior therapies. Arm A had no dose-limiting toxicities, but the maximum tolerated dose was not reached as this arm closed early to increase overall study accrual. In arm B, one patient each experienced grade 3 rash, nail changes, skin changes, nausea, dehydration, and neutropenia; one had grade 4 anemia; and one developed fatal pneumonitis, all considered unrelated to HCQ. There were no dose-limiting toxicities, therefore the highest tested dose for HCQ with erlotinib 150 mg was 1000 mg daily. One patient had a partial response to erlotinib/HCQ, for an overall response rate of 5% (95% confidence interval, 1-25). This patient had an EGFR mutation and remained on therapy for 20 months. Administration of HCQ did not alter the pharmacokinetics of erlotinib.
CONCLUSIONS: HCQ with or without erlotinib was safe and well tolerated. The recommended phase 2 dose of HCQ was 1000 mg when given in combination with erlotinib 150 mg.

PMID: 22878749 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

Regulation of Drosophila metamorphosis by xenobiotic response regulators.

Regulation of Drosophila metamorphosis by xenobiotic response regulators.

PLoS Genet. 2013 Feb;9(2):e1003263

Authors: Deng H, Kerppola TK

Abstract
Mammalian Nrf2-Keap1 and the homologous Drosophila CncC-dKeap1 protein complexes regulate both transcriptional responses to xenobiotic compounds as well as native cellular and developmental processes. The relationships between the functions of these proteins in xenobiotic responses and in development were unknown. We investigated the genes regulated by CncC and dKeap1 during development and the signal transduction pathways that modulate their functions. CncC and dKeap1 were enriched within the nuclei in many tissues, in contrast to the reported cytoplasmic localization of Keap1 and Nrf2 in cultured mammalian cells. CncC and dKeap1 occupied ecdysone-regulated early puffs on polytene chromosomes. Depletion of either CncC or dKeap1 in salivary glands selectively reduced early puff gene transcription. CncC and dKeap1 depletion in the prothoracic gland as well as cncC(K6/K6) and dKeap1(EY5/EY5) loss of function mutations in embryos reduced ecdysone-biosynthetic gene transcription. In contrast, dKeap1 depletion and the dKeap1(EY5/EY5) loss of function mutation enhanced xenobiotic response gene transcription in larvae and embryos, respectively. Depletion of CncC or dKeap1 in the prothoracic gland delayed pupation by decreasing larval ecdysteroid levels. CncC depletion suppressed the premature pupation and developmental arrest caused by constitutive Ras signaling in the prothoracic gland; conversely, constitutive Ras signaling altered the loci occupied by CncC on polytene chromosomes and activated transcription of genes at these loci. The effects of CncC and dKeap1 on both ecdysone-biosynthetic and ecdysone-regulated gene transcription, and the roles of CncC in Ras signaling in the prothoracic gland, establish the functions of these proteins in the neuroendocrine axis that coordinates insect metamorphosis.

PMID: 23408904 [PubMed - in process]

c-met inhibitors zm-447439 rad001

Everolimus in colorectal cancer.

Everolimus in colorectal cancer.

Expert Opin Pharmacother. 2013 Feb 13;

Authors: Altomare I, Hurwitz H

Abstract
Introduction: There has been a strong preclinical rationale for studying mammalian target of rapamycin (mTOR) inhibitors as single agents or in combination, in multiple malignancies and colorectal cancer in particular. Areas covered: The authors summarize the complete clinical experience to date of all trials, both published and in abstract form, of everolimus in colorectal cancer. While initial Phase I trials showed promise, further studies have confirmed that single agent everolimus is not active in advanced metastatic colorectal carcinoma with trials showing single agent tolerability, but without significant hints of efficacy in terms of either objective tumor responses or prolonged stable disease. Combination regimens, including combinations with cytotoxic chemotherapy, and inhibitors of VEGF, EGFR and HDAC have been tested specifically in the colorectal setting in Phase I and Phase II clinical trials. The authors discuss the potential reasons for mixed results and suggest future directions for the development of everolimus in colorectal malignancies. Expert opinion: Studies demonstrate limited clinical activity of everolimus for the treatment of advanced colorectal cancer and have been complicated by increases in toxicity. However, the central role of the PI3K/mTOR pathway in cancer biology suggests that other drug combinations with mTOR inhibition may still merit evaluation.

PMID: 23406528 [PubMed - as supplied by publisher]

dovitinib dna-pk coxinhibitors

A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer.

Related Articles

A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer.

J Thorac Oncol. 2012 Oct;7(10):1602-8

Authors: Goldberg SB, Supko JG, Neal JW, Muzikansky A, Digumarthy S, Fidias P, Temel JS, Heist RS, Shaw AT, McCarthy PO, Lynch TJ, Sharma S, Settleman JE, Sequist LV

Abstract
INTRODUCTION: This investigator-initiated study explores the safety, maximum tolerated dose, clinical response, and pharmacokinetics of hydroxychloroquine (HCQ) with and without erlotinib in patients with advanced non-small-cell lung cancer.
METHODS: Patients with prior clinical benefit from an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor were randomized to HCQ or HCQ plus erlotinib in a 3 + 3 dose-escalation schema.
RESULTS: Twenty-seven patients were treated, eight with HCQ (arm A) and 19 with HCQ plus erlotinib (arm B). EGFR mutations were detected in 74% of the patients and 85% had received two or more prior therapies. Arm A had no dose-limiting toxicities, but the maximum tolerated dose was not reached as this arm closed early to increase overall study accrual. In arm B, one patient each experienced grade 3 rash, nail changes, skin changes, nausea, dehydration, and neutropenia; one had grade 4 anemia; and one developed fatal pneumonitis, all considered unrelated to HCQ. There were no dose-limiting toxicities, therefore the highest tested dose for HCQ with erlotinib 150 mg was 1000 mg daily. One patient had a partial response to erlotinib/HCQ, for an overall response rate of 5% (95% confidence interval, 1-25). This patient had an EGFR mutation and remained on therapy for 20 months. Administration of HCQ did not alter the pharmacokinetics of erlotinib.
CONCLUSIONS: HCQ with or without erlotinib was safe and well tolerated. The recommended phase 2 dose of HCQ was 1000 mg when given in combination with erlotinib 150 mg.

PMID: 22878749 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer.

Related Articles

A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer.

J Thorac Oncol. 2012 Oct;7(10):1602-8

Authors: Goldberg SB, Supko JG, Neal JW, Muzikansky A, Digumarthy S, Fidias P, Temel JS, Heist RS, Shaw AT, McCarthy PO, Lynch TJ, Sharma S, Settleman JE, Sequist LV

Abstract
INTRODUCTION: This investigator-initiated study explores the safety, maximum tolerated dose, clinical response, and pharmacokinetics of hydroxychloroquine (HCQ) with and without erlotinib in patients with advanced non-small-cell lung cancer.
METHODS: Patients with prior clinical benefit from an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor were randomized to HCQ or HCQ plus erlotinib in a 3 + 3 dose-escalation schema.
RESULTS: Twenty-seven patients were treated, eight with HCQ (arm A) and 19 with HCQ plus erlotinib (arm B). EGFR mutations were detected in 74% of the patients and 85% had received two or more prior therapies. Arm A had no dose-limiting toxicities, but the maximum tolerated dose was not reached as this arm closed early to increase overall study accrual. In arm B, one patient each experienced grade 3 rash, nail changes, skin changes, nausea, dehydration, and neutropenia; one had grade 4 anemia; and one developed fatal pneumonitis, all considered unrelated to HCQ. There were no dose-limiting toxicities, therefore the highest tested dose for HCQ with erlotinib 150 mg was 1000 mg daily. One patient had a partial response to erlotinib/HCQ, for an overall response rate of 5% (95% confidence interval, 1-25). This patient had an EGFR mutation and remained on therapy for 20 months. Administration of HCQ did not alter the pharmacokinetics of erlotinib.
CONCLUSIONS: HCQ with or without erlotinib was safe and well tolerated. The recommended phase 2 dose of HCQ was 1000 mg when given in combination with erlotinib 150 mg.

PMID: 22878749 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Association of integrin beta1 and c-MET in mediating EGFR TKI gefitinib resistance in non-small cell lung cancer.

Association of integrin beta1 and c-MET in mediating EGFR TKI gefitinib resistance in non-small cell lung cancer.

Cancer Cell Int. 2013 Feb 13;13(1):15

Authors: Ju L, Zhou C

Abstract
ABSTRACT: Although some patients are initially sensitive to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), resistance invariably develops. Therefore, it's very important to study the molecular mechanism of this resistance. In our previous study we found that integrin beta1 can induce EGFR TKIs resistance in non-small cell lung cancer (NSCLC) cells. Here we analyzed the association of integrin beta1 and c-MET that is a recognized mechanism of EGFR TKIs resistance in NSCLC to demonstrate the mechanism of integrin beta1 related EGFR TKIs resistance. We found that the ligands of integrin beta1 and c-MET could synergistically promote cell proliferation and their inhibitors could synergistically improve the sensitivity to gfitinib, increase apoptosis, and inhibit the downstream signal transduction: focal adhesion kinase (FAK) and AKT. On the other hand, ligand-dependent activation of integrin beta1 could induce EGFR TKIs resistance through activating c-MET and its downstream signals. Thus, it can be concluded that there is crosstalk between integrin beta1 and c-MET and integrin beta1 mediates EGFR TKI resistance associating with c-MET signaling pathway in non-small cell lung cancer.

PMID: 23402326 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2.

Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2.

Breast Cancer. 2013 Feb 13;

Authors: Noguchi S, Masuda N, Iwata H, Mukai H, Horiguchi J, Puttawibul P, Srimuninnimit V, Tokuda Y, Kuroi K, Iwase H, Inaji H, Ohsumi S, Noh WC, Nakayama T, Ohno S, Rai Y, Park BW, Panneerselvam A, El-Hashimy M, Taran T, Sahmoud T, Ito Y

Abstract
BACKGROUND: The addition of mTOR inhibitor everolimus (EVE) to exemestane (EXE) was evaluated in an international, phase 3 study (BOLERO-2) in patients with hormone-receptor-positive (HR(+)) breast cancer refractory to letrozole or anastrozole. The safety and efficacy of anticancer treatments may be influenced by ethnicity (Sekine et al. in Br J Cancer 99:1757-62, 2008). Safety and efficacy results from Asian versus non-Asian patients in BOLERO-2 are reported. METHODS: Patients were randomized (2:1) to 10�mg/day EVE�+�EXE or placebo (PBO)�+�EXE. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, clinical benefit rate, and safety. RESULTS: Of 143 Asian patients, 98 received EVE�+�EXE and 45 received PBO�+�EXE. Treatment with EVE�+�EXE significantly improved median PFS versus PBO�+�EXE among Asian patients by 38�% (HR�=�0.62; 95�% CI, 0.41-0.94). Median PFS was also improved among non-Asian patients by 59�% (HR�=�0.41; 95�% CI, 0.33-0.50). Median PFS duration among EVE-treated Asian patients was 8.48 versus 4.14�months for PBO�+�EXE, and 7.33 versus 2.83�months, respectively, in non-Asian patients. The most common grade 3/4 adverse events (stomatitis, anemia, elevated liver enzymes, hyperglycemia, and dyspnea) occurred at similar frequencies in Asian and non-Asian patients. Grade 1/2 interstitial lung disease occurred more frequently in Asian patients. Quality of life was similar between treatment arms in Asian patients. CONCLUSION: Adding EVE to EXE provided substantial clinical benefit in both Asian and non-Asian patients with similar safety profiles. This combination represents an improvement in the management of postmenopausal women with HR(+)/HER2(-) advanced breast cancer progressing on nonsteroidal aromatase inhibitors, regardless of ethnicity.

PMID: 23404211 [PubMed - as supplied by publisher]

dna-pk coxinhibitors c-met inhibitors

Population pharmacokinetic/pharmacodynamic modeling to assist dosing schedule selection for dovitinib.

Related Articles

Population pharmacokinetic/pharmacodynamic modeling to assist dosing schedule selection for dovitinib.

J Clin Pharmacol. 2013 Jan;53(1):14-20

Authors: Wang X, Kay A, Anak O, Angevin E, Escudier B, Zhou W, Feng Y, Dugan M, Schran H

Abstract
Dovitinib is an oral multitargeted kinase inhibitor with potent activity against receptors for vascular endothelial growth factor, platelet-derived growth factor, and basic fibroblast growth factor. Initial phase 1 to 2 studies of dovitinib using a continuous daily dosing schedule has shown that dovitinib exhibits a prolonged and overproportional increase in dose and exposure relationship above 400 mg/d. To address this, intermittent dosing schedules were explored using a model-based approach. A semi-mechanistic population pharmcokinetic/pharmacodynamic (PD) model was developed from 4 dovitinib phase 1 studies with daily dosing schedules. Autoinduction of cytochrome P450 1A (CYP1A) responsible for dovitinib metabolism was described using an indirect response model. Simulation of dovitinib plasma concentration profiles following 4 intermittent dosing schedules suggested that intermittent dosing could prevent prolonged drug accumulation. Based on the simulated plasma profiles, PD response, and patient compliance, a 5-days-on/2-days-off intermittent dosing schedule was selected for a phase 1 to 2 clinical study. The observed dovitinib plasma concentrations in this study confirmed the model predictions. Furthermore, dovitinib was well tolerated, and antitumor activity was observed as well in this new study. The 5-days-on/2-days-off dosing schedule is currently used in a dovitinib registration trial and other clinical trials.

PMID: 23400739 [PubMed - in process]

c-met inhibitors zm-447439 rad001

Association of integrin beta1 and c-MET in mediating EGFR TKI gefitinib resistance in non-small cell lung cancer.

Association of integrin beta1 and c-MET in mediating EGFR TKI gefitinib resistance in non-small cell lung cancer.

Cancer Cell Int. 2013 Feb 13;13(1):15

Authors: Ju L, Zhou C

Abstract
ABSTRACT: Although some patients are initially sensitive to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), resistance invariably develops. Therefore, it's very important to study the molecular mechanism of this resistance. In our previous study we found that integrin beta1 can induce EGFR TKIs resistance in non-small cell lung cancer (NSCLC) cells. Here we analyzed the association of integrin beta1 and c-MET that is a recognized mechanism of EGFR TKIs resistance in NSCLC to demonstrate the mechanism of integrin beta1 related EGFR TKIs resistance. We found that the ligands of integrin beta1 and c-MET could synergistically promote cell proliferation and their inhibitors could synergistically improve the sensitivity to gfitinib, increase apoptosis, and inhibit the downstream signal transduction: focal adhesion kinase (FAK) and AKT. On the other hand, ligand-dependent activation of integrin beta1 could induce EGFR TKIs resistance through activating c-MET and its downstream signals. Thus, it can be concluded that there is crosstalk between integrin beta1 and c-MET and integrin beta1 mediates EGFR TKI resistance associating with c-MET signaling pathway in non-small cell lung cancer.

PMID: 23402326 [PubMed - as supplied by publisher]

rad001 ecdysone chir-258

Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2.

Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2.

Breast Cancer. 2013 Feb 13;

Authors: Noguchi S, Masuda N, Iwata H, Mukai H, Horiguchi J, Puttawibul P, Srimuninnimit V, Tokuda Y, Kuroi K, Iwase H, Inaji H, Ohsumi S, Noh WC, Nakayama T, Ohno S, Rai Y, Park BW, Panneerselvam A, El-Hashimy M, Taran T, Sahmoud T, Ito Y

Abstract
BACKGROUND: The addition of mTOR inhibitor everolimus (EVE) to exemestane (EXE) was evaluated in an international, phase 3 study (BOLERO-2) in patients with hormone-receptor-positive (HR(+)) breast cancer refractory to letrozole or anastrozole. The safety and efficacy of anticancer treatments may be influenced by ethnicity (Sekine et al. in Br J Cancer 99:1757-62, 2008). Safety and efficacy results from Asian versus non-Asian patients in BOLERO-2 are reported. METHODS: Patients were randomized (2:1) to 10�mg/day EVE�+�EXE or placebo (PBO)�+�EXE. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, clinical benefit rate, and safety. RESULTS: Of 143 Asian patients, 98 received EVE�+�EXE and 45 received PBO�+�EXE. Treatment with EVE�+�EXE significantly improved median PFS versus PBO�+�EXE among Asian patients by 38�% (HR�=�0.62; 95�% CI, 0.41-0.94). Median PFS was also improved among non-Asian patients by 59�% (HR�=�0.41; 95�% CI, 0.33-0.50). Median PFS duration among EVE-treated Asian patients was 8.48 versus 4.14�months for PBO�+�EXE, and 7.33 versus 2.83�months, respectively, in non-Asian patients. The most common grade 3/4 adverse events (stomatitis, anemia, elevated liver enzymes, hyperglycemia, and dyspnea) occurred at similar frequencies in Asian and non-Asian patients. Grade 1/2 interstitial lung disease occurred more frequently in Asian patients. Quality of life was similar between treatment arms in Asian patients. CONCLUSION: Adding EVE to EXE provided substantial clinical benefit in both Asian and non-Asian patients with similar safety profiles. This combination represents an improvement in the management of postmenopausal women with HR(+)/HER2(-) advanced breast cancer progressing on nonsteroidal aromatase inhibitors, regardless of ethnicity.

PMID: 23404211 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

Accessory gland as a site for prothoracicotropic hormone controlled ecdysone synthesis in adult male insects.

Accessory gland as a site for prothoracicotropic hormone controlled ecdysone synthesis in adult male insects.

PLoS One. 2013;8(2):e55131

Authors: Hentze JL, Moeller ME, J�rgensen AF, Bengtsson MS, Bordoy AM, Warren JT, Gilbert LI, Andersen O, Rewitz KF

Abstract
Insect steroid hormones (ecdysteroids) are important for female reproduction in many insect species and are required for the initiation and coordination of vital developmental processes. Ecdysteroids are also important for adult male physiology and behavior, but their exact function and site of synthesis remains unclear, although previous studies suggest that the reproductive system may be their source. We have examined expression profiles of the ecdysteroidogenic Halloween genes, during development and in adults of the flour beetle Tribolium castaneum. Genes required for the biosynthesis of ecdysone (E), the precursor of the molting hormone 20-hydroxyecdysone (20E), are expressed in the tubular accessory glands (TAGs) of adult males. In contrast, expression of the gene encoding the enzyme mediating 20E synthesis was detected in the ovaries of females. Further, Spookiest (Spot), an enzyme presumably required for endowing tissues with competence to produce ecdysteroids, is male specific and predominantly expressed in the TAGs. We also show that prothoracicotropic hormone (PTTH), a regulator of E synthesis during larval development, regulates ecdysteroid levels in the adult stage in Drosophila melanogaster and the gene for its receptor Torso seems to be expressed specifically in the accessory glands of males. The composite results suggest strongly that the accessory glands of adult male insects are the main source of E, but not 20E. The finding of a possible male-specific source of E raises the possibility that E and 20E have sex-specific roles analogous to the vertebrate sex steroids, where males produce primarily testosterone, the precursor of estradiol. Furthermore this study provides the first evidence that PTTH regulates ecdysteroid synthesis in the adult stage and could explain the original finding that some adult insects are a rich source of PTTH.

PMID: 23383307 [PubMed - in process]

coxinhibitors c-met inhibitors zm-447439

[Results of targeted therapies for m1 renal cell carcinoma: our experience].

Related Articles

[Results of targeted therapies for m1 renal cell carcinoma: our experience].

Urologia. 2012;79 Suppl 19:e72-5

Authors: Legramanti S, Antonelli A, Ferrari V, Arrighi N, Corti S, Zanotelli T, Ozzoli A, Cosciani Cunico S, Simeone C

Abstract
Introduction: Since a few years ago no effective medical therapies were available to cure metastatic renal cell carcinoma (RCC). Nowadays, encouraging preliminary results support some new therapeutic agents, collectively named as targeted therapies (TT). ?This paper reviews our experience with the use of TT in the setting of RCC with metastasis at the diagnosis.?Material and Methods: Retrospective evaluation of the data of 24 patients (7 females, 17 males, median age: 59aa) affected by clear cell RCC with distant metastatis at diagnosis, treated with TT from 2005 to 2012.20 of the 24 patients (83,3%) underwent preliminary cytoreductive nephrectomy, whereas for the others a percutaneous biopsy of the renal tumor was obtained. 5 (20.8%) patients received an immunotherapy with IL-2 or IFN and then a TT due to a progression. Schedules were applied following heterogeneous regimens along the period of data collection (randomized clinical trial, expanded access, standard indication). Response has been evaluated by RECIST criteria. ?Results: As first-line therapy of TT 18 patients received Sunitinib, 4 Sorafenib, 2 Temsirolimus; 11 received a second-line (8 Sorafenib, 2 Sunitinib, 1 Everolimus); 6 received also a third-line (5 Everolimus, 1 Tensirolimus). At last available control, after a mean follow up time of 13,7 months (1-29) a progressive disease was present in 12 cases (50%), a stable disease in 6 (25%), a reduction of the disease in 4 (16.5%); 7 patients (29.5%) died; overall mean survival of the entire group was 14,7 months. ?Even if the study suffers from the limitations related to the small number of cases and the retrospective design, seems that no factors played a role in determining the response to theraphy. ?Conclusions: The results of TT in clinical practice resemble the ones from randomised clinical trials. It's extremely hard to predict the response to treatment.

PMID: 23371277 [PubMed - in process]

rad001 ecdysone chir-258

[Results of targeted therapies for m1 renal cell carcinoma: our experience].

Related Articles

[Results of targeted therapies for m1 renal cell carcinoma: our experience].

Urologia. 2012;79 Suppl 19:e72-5

Authors: Legramanti S, Antonelli A, Ferrari V, Arrighi N, Corti S, Zanotelli T, Ozzoli A, Cosciani Cunico S, Simeone C

Abstract
Introduction: Since a few years ago no effective medical therapies were available to cure metastatic renal cell carcinoma (RCC). Nowadays, encouraging preliminary results support some new therapeutic agents, collectively named as targeted therapies (TT). ?This paper reviews our experience with the use of TT in the setting of RCC with metastasis at the diagnosis.?Material and Methods: Retrospective evaluation of the data of 24 patients (7 females, 17 males, median age: 59aa) affected by clear cell RCC with distant metastatis at diagnosis, treated with TT from 2005 to 2012.20 of the 24 patients (83,3%) underwent preliminary cytoreductive nephrectomy, whereas for the others a percutaneous biopsy of the renal tumor was obtained. 5 (20.8%) patients received an immunotherapy with IL-2 or IFN and then a TT due to a progression. Schedules were applied following heterogeneous regimens along the period of data collection (randomized clinical trial, expanded access, standard indication). Response has been evaluated by RECIST criteria. ?Results: As first-line therapy of TT 18 patients received Sunitinib, 4 Sorafenib, 2 Temsirolimus; 11 received a second-line (8 Sorafenib, 2 Sunitinib, 1 Everolimus); 6 received also a third-line (5 Everolimus, 1 Tensirolimus). At last available control, after a mean follow up time of 13,7 months (1-29) a progressive disease was present in 12 cases (50%), a stable disease in 6 (25%), a reduction of the disease in 4 (16.5%); 7 patients (29.5%) died; overall mean survival of the entire group was 14,7 months. ?Even if the study suffers from the limitations related to the small number of cases and the retrospective design, seems that no factors played a role in determining the response to theraphy. ?Conclusions: The results of TT in clinical practice resemble the ones from randomised clinical trials. It's extremely hard to predict the response to treatment.

PMID: 23371277 [PubMed - in process]

dna-pk coxinhibitors c-met inhibitors

Structure-activity relationship of fenamates as Slo2.1 channel activators.

Related Articles

Structure-activity relationship of fenamates as Slo2.1 channel activators.

Mol Pharmacol. 2012 Nov;82(5):795-802

Authors: Garg P, Sanguinetti MC

Abstract
Niflumic acid, 2-{[3-(trifluoromethyl)phenyl]amino}pyridine-3-carboxylic acid (NFA), a nonsteroidal anti-inflammatory drug that blocks cyclooxygenase (COX), was shown previously to activate [Na(+)](i)-regulated Slo2.1 channels. In this study, we report that other fenamates, including flufenamic acid, mefenamic acid, tolfenamic acid, meclofenamic acid, and a phenyl acetic acid derivative, diclofenac, also are low-potency (EC(50) = 80 ?M to 2.1 mM), partial agonists of human Slo2.1 channels heterologously expressed in Xenopus oocytes. Substituent analysis determined that N-phenylanthranilic acid was the minimal pharmacophore for fenamate activation of Slo2.1 channels. The effects of fenamates were biphasic, with an initial rapid activation phase followed by a slow phase of current inhibition. Ibuprofen, a structurally dissimilar COX inhibitor, did not activate Slo2.1. Preincubation of oocytes with ibuprofen did not significantly alter the effects of NFA, suggesting that neither channel activation nor inhibition is associated with COX activity. A point mutation (A278R) in the pore-lining S6 segment of Slo2.1 increased the sensitivity to activation and reduced the inhibition induced by NFA. Together, our results suggest that fenamates bind to two sites on Slo2.1 channels: an extracellular accessible site to activate and a cytoplasmic accessible site in the pore to inhibit currents.

PMID: 22851714 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

[Advances of molecular subtype and targeted therapy of lung cancer].

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[Advances of molecular subtype and targeted therapy of lung cancer].

Zhongguo Fei Ai Za Zhi. 2012 Sep 20;15(9):545-52

Authors: Shao L, Song Z, Zhang Y, Su D

Abstract
The discovery of multiple molecular mechanisms underlying the development, progression, and prognosis of lung cancer, has created new opportunities for targeted therapy. Each subtype is associated with molecular tests that define the subtype and drugs that may have potential therapeutic effect on lung cancer. In 2004, mutations in the epidermal growth factor receptor (epidermal growth factor receptor, EGFR) gene were discovered in non-small cell lung cancers (NSCLC), especially in adenocarcinomas. And they are strongly associated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Moreover, in 2007 the existence of the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene was discovered in NSCLC, and the same as EGFR-TKIs, ALK inhibitors are being found to be highly effective in lung cancers. At present, multiple molecular subtype of lung cancer and relevant targeted drugs are undering study. Here, we review the remarkable progress in molecular subtype of lung cancer and the related targeted therapy.

PMID: 22989458 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

Effectiveness of Statin Prescribing on Reducing Mortality in South Asian, Chinese, and White Patients With Diabetes.

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Effectiveness of Statin Prescribing on Reducing Mortality in South Asian, Chinese, and White Patients With Diabetes.

Can J Cardiol. 2013 Feb 5;

Authors: Brunner NW, Ramanathan K, Wang H, Quan H, Khan NA

Abstract
BACKGROUND: Clinical trials have shown that 3-hydroxy-3-methylgutaryl coenzyme A reductase inhibitors (statins) reduce mortality in patients with diabetes. However, as these trials were conducted in largely white populations, it is unknown whether the benefits of statins can be extended to other ethnic populations in which the incidence of diabetes is rising sharply. We investigated associations between statin prescription and outcomes in a multiethnic population with diabetes. METHODS: We identified all patients with newly diagnosed diabetes in British Columbia, Canada (1993-2006), using administrative data. Validated surname analysis was used to identify South Asian and Chinese patients. Statin prescribing was defined as any prescription filled within 1 year of diabetes diagnosis according to a provincial pharmacy database. Median length of follow-up was 4 years. Cox proportional hazards models were constructed for each ethnic group to determine the association of statin prescribing with time to death, adjusting for covariates including age, sex, socioeconomic status, and comorbid conditions. RESULTS: There were 143,630 white, 9529 South Asian, and 14,084 Chinese persons with newly diagnosed diabetes. White patients were older and had more comorbidity than the other groups. Statin prescribing was associated with lower mortality compared with no prescribing within each ethnic group: South Asian (Hazard Ratio [HR], 0.69; 95% confidence interval [CI], 0.55-0.86; P�= 0.001), Chinese (HR, 0.60; 95% CI, 0.49-0.72; P < 0.0001), and white (HR, 0.65; 95% CI, 0.63-0.67; P < 0.0001). CONCLUSIONS: Statin prescribing is associated with lower mortality in white, Chinese, and South Asian patients with newly diagnosed diabetes, confirming the benefits of statins across these ethnic groups.

PMID: 23395514 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

Norisoboldine alleviates joint destruction in rats with adjuvant-induced arthritis by reducing RANKL, IL-6, PGE(2), and MMP-13 expression.

Related Articles

Norisoboldine alleviates joint destruction in rats with adjuvant-induced arthritis by reducing RANKL, IL-6, PGE(2), and MMP-13 expression.

Acta Pharmacol Sin. 2013 Feb 11;

Authors: Wei ZF, Jiao XL, Wang T, Lu Q, Xia YF, Wang ZT, Guo QL, Chou GX, Dai Y

Abstract
Aim:To explore the effects of norisoboldine (NOR), a major isoquinoline alkaloid in Radix Linderae, on joint destruction in rats with adjuvant-induced arthritis (AIA) and its underlying mechanisms.Methods:AIA was induced in adult male SD rats by intradermal injection of Mycobacterium butyricum in Freund's complete adjuvant at the base of the right hind paw and tail. From d 14 after immunization, the rats were orally given NOR (7.5, 15, or 30 mg/kg) or dexamethasone (0.5 mg/kg) daily for 10 consecutive days. Joint destruction was evaluated with radiological scanning and H&E staining. Fibroblast-like synoviocytes (FLS) were prepared from fresh synovial tissues in the AIA rats. The expression of related proteins and mRNAs were detected by ELISA, Western blotting and RT-PCR.Results:In AIA rats, NOR (15 and 30 mg/kg) significantly decreased the swelling of paws and arthritis index scores, and elevated the mean body weight. NOR (30 mg/kg) prevented both the infiltration of inflammatory cells and destruction of bone and cartilage in joints. However, NOR (15 mg/kg) only suppressed the destruction of bone and cartilage, but did not obviously ameliorate synovial inflammation. NOR (15 and 30 mg/kg) significantly decreased the serum levels of receptor activator of nuclear factor ?B ligand (RANKL), IL-6, PGE(2), and MMP-13, but not the osteoprotegerin and MMP-1 levels. The mRNA levels of RANKL, IL-6, COX-2, and MMP-13 in synovium were also suppressed. Dexamethasone produced similar effects in AIA rats as NOR did, but without elevating the mean body weight. In the cultured FLS, treatment with NOR (10 and 30 mmol/L) significantly decreased the secretion of RANKL, IL-6, PGE(2), and MMP-13 proteins. Furthermore, the treatment selectively prevented the activation of MAPKs, AKT and transcription factor AP-1 component c-Jun, but not the recruitment of TRAF6 or the activation of JAK2/STAT3. Treatment of the cultured FLS with the specific inhibitors of p38, ERK, AKT, and AP-1 significantly decreased the secretion of RANKL, IL-6, PGE(2), and MMP-13 proteins.Conclusion:NOR can alleviate joint destruction in AIA rats by reducing RANKL, IL-6, PGE(2), and MMP-13 expression via the p38/ERK/AKT/AP-1 pathway.

PMID: 23396374 [PubMed - as supplied by publisher]

rad001 ecdysone chir-258

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

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Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Transfusion. 2012 Nov;52(11):2406-13

Authors: Avanzi MP, Chen A, He W, Mitchell WB

Abstract
BACKGROUND: Large-scale in vitro production of platelets (PLTs) from cord blood stem cells is one goal of stem cell research. One step toward this goal will be to produce polyploid megakaryocytes capable of releasing high numbers of PLTs. Megakaryocyte polyploidization requires distinct cytoskeletal and cellular mechanisms, including actin polymerization, myosin activation, microtubule formation, and increased DNA production. In this study we variably combined inhibition of these principal mechanisms of cytokinesis with the goal of driving polyploidization in megakaryocytes.
STUDY DESIGN AND METHODS: Megakaryocytes were derived from umbilical cord blood and cultured with reagents that inhibit distinct mechanisms of cytokinesis: Rho-Rock inhibitor (RRI), Src inhibitor (SI), nicotinamide (NIC), aurora B inhibitor (ABI), and myosin light chain kinase inhibitor (MLCKI). Combinations of reagents were used to determine their interactions and to maximize megakaryocyte ploidy.
RESULTS: Treatment with RRI, NIC, SI, and ABI, but not with MLCKI, increased the final ploidy and RRI was the most effective single reagent. RRI and MLCKI, both inhibitors of MLC activation, resulted in opposite ploidy outcomes. Combinations of reagents also increased ploidy and the use of NIC, SI, and ABI was as effective as RRI alone. Addition of MLCKI to NIC, SI, and ABI reached the highest level of polyploidization.
CONCLUSION: Megakaryocyte polyploidization results from modulation of a combination of distinct cytokinesis pathways. Reagents targeting distinct cytoskeletal pathways produced additive effects in final megakaryocyte ploidy. The RRI, however, showed no additive effect but produced a high final ploidy due to overlapping inhibition of multiple cytokinesis pathways.

PMID: 22612069 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors c-met inhibitors

Image-based high-throughput screening for inhibitors of angiogenesis.

Related Articles

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

Abstract
Automated multicolor fluorescence microscopy facilitates high-throughput quantitation of cellular parameters of complex, organotypic systems. In vitro co-cultured vascular cells form capillary-like networks that model facets of angiogenesis, making it an attractive alternative for anti-angiogenic drug discovery. We have adapted this angiogenesis assay system to a high-throughput format to enable automated image-based high-throughput screening of live primary human vascular cell co-cultures with chemical libraries for anti-angiogenic drug discovery. Protocols are described for setup of a fluorescence-based co-culture assay, live cell image acquisition, image analysis of morphological parameters, and screening data handling.

PMID: 23027002 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

Systemic therapy for advanced pancreatic neuroendocrine tumors.

Systemic therapy for advanced pancreatic neuroendocrine tumors.

Semin Oncol. 2013 Feb;40(1):75-83

Authors: Kulke MH

Abstract
Neuroendocrine tumors (NETs) occur throughout the body, and share similar histologic characteristics. However, it has become increasingly evident that pancreatic NETs tend to respond differently to therapeutic agents than do other NET subtypes. In most cases, systemic therapy has been more effective in NETs of pancreatic origin than in NETs arising from other locations. Traditional systemic treatment options for pancreatic NETs include somatostatin analogs or cytotoxic chemotherapy. Recently, the biologically targeted agents everolimus and sunitinib were approved for use in patients with metastatic disease. Novel agents, as well as novel drug combinations, are currently under investigation.

PMID: 23391115 [PubMed - in process]

dna-pk coxinhibitors c-met inhibitors

The genetics of neuroendocrine tumors.

The genetics of neuroendocrine tumors.

Semin Oncol. 2013 Feb;40(1):37-44

Authors: Oberg K

Abstract
Neuroendocrine tumors (NETs) present a wide spectrum of malignant diseases from rather benign to very malignant variants. The majority of these tumors are sporadic, but there are several familial (inherited) syndromes to consider, such as multiple endocrine neoplasia type 1 and type 2 (MEN-1 and MEN-2), von Hippel-Lindau syndrome (VHL), tuberosclerosis, and neurofibromatosis syndromes. The MEN-1 gene is mutated not only in MEN-1 families, but a recent study shows that more than 40% of sporadic pancreatic NETs (PNETs) harbor MEN-1 gene mutations. The same study reported that ATRX/DAXX genes are mutated in a significant number of tumors, as are genes encoding components of the mammalian target of rapamycin (mTOR) signal transduction pathway. These findings have implications for the new therapies that have been approved for the treatment of PNETs, such as the tyrosine kinase inhibitor sunitinib, as well the mTOR inhibitor everolimus. Small intestinal NETs show a less varied mutational pattern in that the majority of genetic alterations are found on chromosome 18. There seem to be no differences between the sporadic and the familiar type of small intestinal NETs (carcinoids). A wide range of genetic alterations have been described for the different subtypes of NETs, but the mechanisms underlying tumor development are essentially unknown except for MEN-2, in which an activating mutation of the RET proto-oncogene drives tumor progression and affords a direct genotype/phenotype correlation. Genome-wide screening of different types of NETs can now be performed for a reasonable price and is likely to generate new insights into the tumor biology and carcinogenesis in various subtypes of NETs.

PMID: 23391111 [PubMed - in process]

coxinhibitors c-met inhibitors zm-447439

Evaluation of Below-the-Knee Drug-Eluting Stents With Frequency-Domain Optical Coherence Tomography:.

Evaluation of Below-the-Knee Drug-Eluting Stents With Frequency-Domain Optical Coherence Tomography:.

J Endovasc Ther. 2013 Feb;20(1):80-93

Authors: Paraskevopoulos I, Spiliopoulos S, Davlouros P, Karnabatidis D, Katsanos K, Alexopoulos D, Siablis D

Abstract
Purpose : To report the use of intravascular frequency-domain optical coherence tomography (FD-OCT) to detect and characterize in-stent neointimal tissue following infrapopliteal drug-eluting stent (DES) placement in patients suffering from critical limb ischemia. Methods : This prospective study included 12 patients (7 men; mean age 72.8�7.2 years) who had previously received 21 infrapopliteal sirolimus- or everolimus-eluting stents. The patients returned for regular angiographic follow-up or presented with clinical relapse of symptoms over a mean follow-up of 13.5�7.3 months (range 6-33), at which time FD-OCT imaging was performed. Study endpoints were technical imaging success, defined as successful FD-OCT acquisition and visualization of the arterial lumen and complete vessel wall, and the detection and characterization of in-stent neointimal hyperplasia according to widely accepted OCT criteria. Results : OCT imaging was successfully completed in 19 of the 21 stents. Binary in-stent restenosis (ISR>50%) was detected in 10/19 stents. Percent restenosis was higher after longer follow-up (60.6%�19.8% ?1 year vs. 35.3%�20.6% <1 year, p=0.03) and in symptomatic vs. asymptomatic patients (61.5%�20.4% vs. 37.2%�19.3%, p=0.04). Neoatherosclerosis findings included lipid-laden neointima (16/19), neointimal neovascularization (13/19), neointimal calcifications (6/19), and thrombus (5/19); no cases of thin-cap fibroatheroma were identified. Neointimal calcifications were more frequent after ?12 months of follow-up compared to <12 months (46.6% vs. 0%, p=0.02). Conclusion : FD-OCT of the infrapopliteal arteries following DES placement is safe and feasible and may demonstrate features of developing neointimal neoatherosclerosis. The latter might play a key role as a mechanism of below-the-knee ISR and warrants further investigation.

PMID: 23391087 [PubMed - in process]

ecdysone chir-258 dovitinib

Accessory gland as a site for prothoracicotropic hormone controlled ecdysone synthesis in adult male insects.

Accessory gland as a site for prothoracicotropic hormone controlled ecdysone synthesis in adult male insects.

PLoS One. 2013;8(2):e55131

Authors: Hentze JL, Moeller ME, J�rgensen AF, Bengtsson MS, Bordoy AM, Warren JT, Gilbert LI, Andersen O, Rewitz KF

Abstract
Insect steroid hormones (ecdysteroids) are important for female reproduction in many insect species and are required for the initiation and coordination of vital developmental processes. Ecdysteroids are also important for adult male physiology and behavior, but their exact function and site of synthesis remains unclear, although previous studies suggest that the reproductive system may be their source. We have examined expression profiles of the ecdysteroidogenic Halloween genes, during development and in adults of the flour beetle Tribolium castaneum. Genes required for the biosynthesis of ecdysone (E), the precursor of the molting hormone 20-hydroxyecdysone (20E), are expressed in the tubular accessory glands (TAGs) of adult males. In contrast, expression of the gene encoding the enzyme mediating 20E synthesis was detected in the ovaries of females. Further, Spookiest (Spot), an enzyme presumably required for endowing tissues with competence to produce ecdysteroids, is male specific and predominantly expressed in the TAGs. We also show that prothoracicotropic hormone (PTTH), a regulator of E synthesis during larval development, regulates ecdysteroid levels in the adult stage in Drosophila melanogaster and the gene for its receptor Torso seems to be expressed specifically in the accessory glands of males. The composite results suggest strongly that the accessory glands of adult male insects are the main source of E, but not 20E. The finding of a possible male-specific source of E raises the possibility that E and 20E have sex-specific roles analogous to the vertebrate sex steroids, where males produce primarily testosterone, the precursor of estradiol. Furthermore this study provides the first evidence that PTTH regulates ecdysteroid synthesis in the adult stage and could explain the original finding that some adult insects are a rich source of PTTH.

PMID: 23383307 [PubMed - in process]

chir-258 dovitinib dna-pk

Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma.

Related Articles

Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma.

BJU Int. 2012 Dec;110(11):1747-53

Authors: Iacovelli R, Lanoy E, Albiges L, Escudier B

Abstract
UNLABELLED: Study Type--Prognosis (cohort series) Level of Evidence 2b. What's known on the subject? and What does the study add? In the literature, few studies have evaluated the role of tumour burden (TB) in metastatic real cell carcinoma (mRCC), even though it has been considered as important in localized tumours. In metastatic patients the role of TB is uncertain because it was analyzed in chemotherapy treated patients or using a partial evaluation of TB. This study, first reports the independent prognostic and predictive role of TB in mRCC patients treated with targeted agents in prospective clinical trials. TB is able to predict prognosis independently to localization of metastases and prognostic class defined by MSKCC criteria, moreover it is strictly related to patient's performance status.
OBJECTIVE: ? To investigate the possible prognostic role of baseline tumour burden (TB) in terms of progression-free survival (PFS) and overall survival (OS), in patients with metastatic renal cell carcinoma (mRCC).
PATIENTS AND METHODS: ? A homogenous group of patients with mRCC enrolled in second-line trials post-cytokine treatment were selected for the present analysis. ? The Response Evaluation Criteria in Solid Tumors (the sum of the longest unidimensional diameter of each target lesion) were used to assess TB. ? The PFS and OS rates were estimated using the Kaplan-Meier method and compared across the groups using the log-rank test. ? The association between TB and PFS or OS was evaluated using a Cox proportional hazards model. Multivariable analyses were adjusted for other prognostic variables: the Memorial Sloan Kettering Cancer Centre (MSKCC) risk class and treatment.
RESULTS: ? A total of 124 patients were included in the final analysis. Of these, 66% received sorafenib or sunitinib and 34% received placebo. The median follow-up was 80.1 month. ? TB was directly related to PFS and OS and these associations remained significant after adjusting for modified MSKCC risk class and treatment,. ? Each 1-cm increase in TB increased the risk of progression by 4.5% (hazard ratio [HR]: 1.05; 95% confidence interval [CI] 1.02-1.07; P < 0.001) and the risk of death by 5% (HR: 1.05; 95% CI 1.03-1.08; P < 0.001).
CONCLUSIONS: ? TB is easy to calculate from standard computed tomography and significantly relates to OS in patients with mRCC. ? We report for the first time the independent prognostic role of baseline TB in multivariate analysis. ?? We believe that this information could be translated into clinical practice.

PMID: 23106948 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

Protein kinase A antagonist inhibits ?-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+) mice.

Related Articles

Protein kinase A antagonist inhibits ?-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+) mice.

Mol Cancer. 2011;10:149

Authors: Brudvik KW, Paulsen JE, Aandahl EM, Roald B, Task�n K

Abstract
BACKGROUND: The adenomatous polyposis coli (APC) protein is part of the destruction complex controlling proteosomal degradation of ?-catenin and limiting its nuclear translocation, which is thought to play a gate-keeping role in colorectal cancer. The destruction complex is inhibited by Wnt-Frz and prostaglandin E(2) (PGE(2)) - PI-3 kinase pathways. Recent reports show that PGE(2)-induced phosphorylation of ?-catenin by protein kinase A (PKA) increases nuclear translocation indicating two mechanisms of action of PGE(2) on ?-catenin homeostasis.
FINDINGS: Treatment of Apc(Min/+) mice that spontaneously develop intestinal adenomas with a PKA antagonist (Rp-8-Br-cAMPS) selectively targeting only the latter pathway reduced tumor load, but not the number of adenomas. Immunohistochemical characterization of intestines from treated and control animals revealed that expression of ?-catenin, ?-catenin nuclear translocation and expression of the ?-catenin target genes c-Myc and COX-2 were significantly down-regulated upon Rp-8-Br-cAMPS treatment. Parallel experiments in a human colon cancer cell line (HCT116) revealed that Rp-8-Br-cAMPS blocked PGE(2)-induced ?-catenin phosphorylation and c-Myc upregulation.
CONCLUSION: Based on our findings we suggest that PGE(2) act through PKA to promote ?-catenin nuclear translocation and tumor development in Apc(Min/+) mice in vivo, indicating that the direct regulatory effect of PKA on ?-catenin nuclear translocation is operative in intestinal cancer.

PMID: 22168384 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Accessory gland as a site for prothoracicotropic hormone controlled ecdysone synthesis in adult male insects.

Accessory gland as a site for prothoracicotropic hormone controlled ecdysone synthesis in adult male insects.

PLoS One. 2013;8(2):e55131

Authors: Hentze JL, Moeller ME, J�rgensen AF, Bengtsson MS, Bordoy AM, Warren JT, Gilbert LI, Andersen O, Rewitz KF

Abstract
Insect steroid hormones (ecdysteroids) are important for female reproduction in many insect species and are required for the initiation and coordination of vital developmental processes. Ecdysteroids are also important for adult male physiology and behavior, but their exact function and site of synthesis remains unclear, although previous studies suggest that the reproductive system may be their source. We have examined expression profiles of the ecdysteroidogenic Halloween genes, during development and in adults of the flour beetle Tribolium castaneum. Genes required for the biosynthesis of ecdysone (E), the precursor of the molting hormone 20-hydroxyecdysone (20E), are expressed in the tubular accessory glands (TAGs) of adult males. In contrast, expression of the gene encoding the enzyme mediating 20E synthesis was detected in the ovaries of females. Further, Spookiest (Spot), an enzyme presumably required for endowing tissues with competence to produce ecdysteroids, is male specific and predominantly expressed in the TAGs. We also show that prothoracicotropic hormone (PTTH), a regulator of E synthesis during larval development, regulates ecdysteroid levels in the adult stage in Drosophila melanogaster and the gene for its receptor Torso seems to be expressed specifically in the accessory glands of males. The composite results suggest strongly that the accessory glands of adult male insects are the main source of E, but not 20E. The finding of a possible male-specific source of E raises the possibility that E and 20E have sex-specific roles analogous to the vertebrate sex steroids, where males produce primarily testosterone, the precursor of estradiol. Furthermore this study provides the first evidence that PTTH regulates ecdysteroid synthesis in the adult stage and could explain the original finding that some adult insects are a rich source of PTTH.

PMID: 23383307 [PubMed - in process]

chir-258 dovitinib dna-pk

Cyclin D1 overexpression perturbs DNA replication and induces replication-associated DNA double-strand breaks in acquired radioresistant cells.

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Cyclin D1 overexpression perturbs DNA replication and induces replication-associated DNA double-strand breaks in acquired radioresistant cells.

Cell Cycle. 2013 Feb 6;12(5)

Authors: Shimura T, Ochiai Y, Noma N, Oikawa T, Sano Y, Fukumoto M

Abstract
Fractionated radiotherapy (RT) is widely used in cancer treatment, because it preserves normal tissues. However, repopulation of radioresistant tumors during fractionated RT limits the efficacy of RT. We recently demonstrated that a moderate level of long-term fractionated radiation confers acquired radioresistance to tumor cells, which is caused by DNA-PK/AKT/GSK3?-mediated cyclin D1 overexpression. The resulting cyclin D1 overexpression leads to forced progression of the cell cycle to S-phase, concomitant with induction of DNA double-strand breaks (DSBs). In this study, we investigated the molecular mechanisms underlying cyclin D1 overexpression-induced DSBs during DNA replication in acquired radioresistant cells. DNA fiber data demonstrated that replication forks progressed slowly in acquired radioresistant cells compared with corresponding parental cells in HepG2 and HeLa cell lines. Slowly progressing replication forks were also observed in HepG2 and HeLa cells that overexpressed a nondegradable cyclin D1 mutant. We also found that knockdown of Mus81endonuclease, which is responsible for resolving aberrant replication forks, suppressed DSB formation in acquired radioresistant cells. Consequently, Mus81 created DSBs to remove aberrant replication forks in response to replication perturbation triggered by cyclin D1 overexpression. After treating cells with a specific inhibitor for DNA-PK or ATM, apoptosis rates increased in acquired radioresistant cells but not in parental cells by inhibiting the DNA damage response to cyclin D1-mediated DSBs. This suggested that these inhibitors might eradicate acquired radioresistant cells and improve fractionated RT outcomes.

PMID: 23388457 [PubMed - as supplied by publisher]

zm-447439 rad001 ecdysone

Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma.

Related Articles

Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma.

BJU Int. 2012 Dec;110(11):1747-53

Authors: Iacovelli R, Lanoy E, Albiges L, Escudier B

Abstract
UNLABELLED: Study Type--Prognosis (cohort series) Level of Evidence 2b. What's known on the subject? and What does the study add? In the literature, few studies have evaluated the role of tumour burden (TB) in metastatic real cell carcinoma (mRCC), even though it has been considered as important in localized tumours. In metastatic patients the role of TB is uncertain because it was analyzed in chemotherapy treated patients or using a partial evaluation of TB. This study, first reports the independent prognostic and predictive role of TB in mRCC patients treated with targeted agents in prospective clinical trials. TB is able to predict prognosis independently to localization of metastases and prognostic class defined by MSKCC criteria, moreover it is strictly related to patient's performance status.
OBJECTIVE: ? To investigate the possible prognostic role of baseline tumour burden (TB) in terms of progression-free survival (PFS) and overall survival (OS), in patients with metastatic renal cell carcinoma (mRCC).
PATIENTS AND METHODS: ? A homogenous group of patients with mRCC enrolled in second-line trials post-cytokine treatment were selected for the present analysis. ? The Response Evaluation Criteria in Solid Tumors (the sum of the longest unidimensional diameter of each target lesion) were used to assess TB. ? The PFS and OS rates were estimated using the Kaplan-Meier method and compared across the groups using the log-rank test. ? The association between TB and PFS or OS was evaluated using a Cox proportional hazards model. Multivariable analyses were adjusted for other prognostic variables: the Memorial Sloan Kettering Cancer Centre (MSKCC) risk class and treatment.
RESULTS: ? A total of 124 patients were included in the final analysis. Of these, 66% received sorafenib or sunitinib and 34% received placebo. The median follow-up was 80.1 month. ? TB was directly related to PFS and OS and these associations remained significant after adjusting for modified MSKCC risk class and treatment,. ? Each 1-cm increase in TB increased the risk of progression by 4.5% (hazard ratio [HR]: 1.05; 95% confidence interval [CI] 1.02-1.07; P < 0.001) and the risk of death by 5% (HR: 1.05; 95% CI 1.03-1.08; P < 0.001).
CONCLUSIONS: ? TB is easy to calculate from standard computed tomography and significantly relates to OS in patients with mRCC. ? We report for the first time the independent prognostic role of baseline TB in multivariate analysis. ?? We believe that this information could be translated into clinical practice.

PMID: 23106948 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

Efficacy of Everolimus in Patients with Metastatic Insulinoma and Refractory Hypoglycemia.

Efficacy of Everolimus in Patients with Metastatic Insulinoma and Refractory Hypoglycemia.

Eur J Endocrinol. 2013 Feb 7;

Authors: Bernard V, Lombard-Bohas C, Taquet MC, Caroli-Bosc FX, Ruszniewski P, Niccoli-Sire P, Guimbaud R, Chougnet CN, Goichot B, Rohmer V, Borson-Chazot F, Baudin E

Abstract
BACKGROUND: Refractory hypoglycemia in patients with metastatic insulinoma is an important cause of morbidity and mortality. Everolimus could be a new therapeutic option. METHODS: Within the French Group, we conducted a retrospective, multicentric study of endocrine tumors to evaluate the time to first recurrence of symptomatic hypoglycemia, after everolimus initiation, in patients with metastatic insulinoma and refractory hypoglycemia. Ongoing hyperglycemic medical options, tumor response, and safety information were recorded. RESULTS: Twelve patients with metastatic insulinoma and refractory hypoglycemia treated with everolimus between May 2007 and June 2011 were reviewed. Everolimus (starting dose, 10 mg/d, except in 1 patient, 5 mg/d) was given after a median of 4 previous therapeutic lines. Clinical benefit was observed in 11 patients, allowing withdrawal of hyperglycemic therapy in 6 patients. After a median duration of 6.5 months (range, 1 to 35+ months), median time to first recurrence of symptomatic hypoglycemia was 6.5 months (range, 0 to 35+ months). Three patients discontinued everolimus because of cardiac and/or pulmonary adverse events at 1, 1.5, and 7 months after initiation, which led to 2 deaths. Three patients discontinued everolimus because of tumor progression at 2, 3, and 10 months after initiation, without recurrence of hypoglycemia. CONCLUSION: Everolimus appears to be a new effective treatment for patients with metastatic insulinoma and refractory hypoglycemia. Tolerance should be carefully monitored.

PMID: 23392213 [PubMed - as supplied by publisher]

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