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]

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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]

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