Ammoun S, Schmid MC, Triner J, Manley P, Hanemann CO. "Neuro Oncol. 2011 Jul"
Loss of the tumor suppressor merlin is really a trigger of frequent tumors in the anxious method, including schwannomas, meningiomas, and ependymomas, which occur spontaneously or as part of neurofibromatosis kind 2 (NF2). Due to the fact there's health care want for drug therapies for these tumors, our purpose would be to find therapeutic targets.
We have studied the pathobiology of schwannomas, since they are the most widespread merlin-deficient tumors and so are a product for all merlin-deficient tumors. With use of a human schwannoma in vitro design, we beforehand described strong overexpression/activation of platelet-derived growth aspect receptor-β(PDGFR-β) leading to powerful, long-lasting activation of extracellular-signal-regulated kinase (ERK1/2) and AKT and increased schwannoma growth, which we effectively inhibited making use of the PDGFR/Raf inhibitor sorafenib. Even so, the benign character of schwannomas might demand long-term therapy; thus, drug tolerability is definitely an issue.
With using Western blotting, proliferation assays, viability assays, as well as a main human schwannoma cell in vitro model, we examined the PDGFR/c-KIT inhibitors imatinib (Glivec(;) Novartis) and nilotinib (Tasigna(;) Novartis). Imatinib and nilotinib inhibited PDGF-DD-mediated ERK1/2 activation, basal and PDGF-DD-mediated activation of PDGFR-β and AKT, and schwannoma proliferation. Nilotinib is more potent than imatinib, exerting its maximal inhibitory effect at concentrations decrease than steady-state trough plasma levels. Additionally, nilotinib mixed using the MEK1/2 inhibitor selumetinib (AZD6244) at reduced concentrations displayed more powerful efficiency towards tumor development inhibition, in comparison with nilotinib alone.
We recommend that therapy with nilotinib or combinational treatment that simultaneously inhibits PDGFR and the downstream Raf/MEK1/2/ERK1/2 pathway could stand for an effective treatment for schwannomas and other merlin-deficient tumors.
2011年10月31日星期一
2011年10月30日星期日
Function of the novel anti-MEK small molecule ARRY-142886 on large B-cell lymphoma.
Bhalla S, Evens AM, Dai B, Prachand S, Gordon LI, Gartenhaus RB. "Blood. 2011 Jul"
The RAS/RAF/MEK/ERK signaling pathway has become mostly unexplored like a possible therapeutic goal in lymphoma. The novel 2nd generation anti-MEK little molecule, ARRY-142886, down-regulated its direct downstream goal, phospho-ERK (pERK) in germinal center and nongerminal center diffuse significant B-cell lymphoma (DLBCL) cell lines and primary cells.
Similar diminished pERK levels had been famous regardless of constitutive activation (CA) of MEK. Consequently, numerous lymphoma-related ERK substrates were down-regulated by ARRY-142886 such as MCT-1, c-Myc, Bcl-2, Mcl-1, and CDK1/2. ARRY-142886 induced time- and dose-dependent antiproliferation and apoptosis in all DLBCL cell lines and fresh/primary cells (IC50 100nM-300nM). Moreover, ARRY-142886 resulted in drastically much less tumor compared with manage in an in vivo DLBCL SCID xenograft model.
Cell demise was related with cleaved PARP, caspases-8, -9, and -3, and apoptosis was caspase-dependent. In addition, there was stabilization of FoxO3a, activation of BIM and PUMA, plus a considerable decrease in c-Myc transcripts. In addition, siRNA knockdown of BIM abrogated selumetinib-related apoptosis inhibitor, although shRNA knockdown of ERK minimally sensitized cells. Lastly, manipulation of AKT with transfection of OCI-LY3 cells with CA-AKT or via chemical inhibition (LY294002) had minimum effect on ARRY-142886-induced cell loss of life.
Altogether, these findings show that the novel anti-MEK agent, ARRY-142886, induced apoptosis in DLBCL and that cell demise was BIM-dependent.
2011年10月27日星期四
Genotype-dependent sensitivity of uveal melanoma cell lines to inhibition of B-Raf, MEK, and Akt kinases.
Mitsiades N, Chew SA, He B, Riechardt AI, Karadedou T, Kotoula V, Poulaki V. "Invest Ophthalmol Vis Sci. 2011 Sep"
PURPOSE:
Inhibitors of B-Raf and MEK kinases maintain promise for your administration of cutaneous melanomas harboring BRAF mutations. BRAF mutations are uncommon in uveal melanomas (UMs), but somatic mutations inside the G protein α subunits Gαq and Gα11 (encoded by GNAQ and GNA11, respectively) happen within a mutually exclusive pattern in ～80% of UMs. The effect of B-Raf and MEK inhibitors on Gα-mutant UMs remains unidentified.
METHODS:
The effect with the B-Raf inhibitor PLX4720, the MEK inhibitor AZD6244, as well as the Akt inhibitors MK2206 on UM cell lines was assessed with the utilization of cell viability, proliferation, and apoptosis assays and immunoblot evaluation.
RESULTS:
BRAF-mutant UM cells were sensitive to each PLX4720 and AZD6244, undergoing cell cycle arrest although not apoptosis. UM cells having a Gα-protein mutation (GNAQ or GNA11) had been mildly delicate to AZD6244 but completely resistant to PLX4720. In reality, PLX4720 paradoxically increased ERK phosphorylation in Gα-mutant UM cells. The combination of AZD6244 with PLX4720 had synergistic anticancer exercise in BRAF-mutant cells although not in Gα-mutant cells. The Akt inhibitor MK2206 sensitized BRAF-mutant cells to both PLX4720 and AZD6244 and sensitized Gα-mutant cells to AZD6244 but didn't overcome the resistance from the Gα-mutant cells to PLX4720.
CONCLUSIONS:
The response of UM cells to inhibition of B-Raf, MEK, and Akt depends on their genotype. Future use of such targeted therapies in medical trials of UM individuals will demand careful style and individual choice based on genotype to provide personalised and powerful therapy.
PURPOSE:
Inhibitors of B-Raf and MEK kinases maintain promise for your administration of cutaneous melanomas harboring BRAF mutations. BRAF mutations are uncommon in uveal melanomas (UMs), but somatic mutations inside the G protein α subunits Gαq and Gα11 (encoded by GNAQ and GNA11, respectively) happen within a mutually exclusive pattern in ～80% of UMs. The effect of B-Raf and MEK inhibitors on Gα-mutant UMs remains unidentified.
METHODS:
The effect with the B-Raf inhibitor PLX4720, the MEK inhibitor AZD6244, as well as the Akt inhibitors MK2206 on UM cell lines was assessed with the utilization of cell viability, proliferation, and apoptosis assays and immunoblot evaluation.
RESULTS:
BRAF-mutant UM cells were sensitive to each PLX4720 and AZD6244, undergoing cell cycle arrest although not apoptosis. UM cells having a Gα-protein mutation (GNAQ or GNA11) had been mildly delicate to AZD6244 but completely resistant to PLX4720. In reality, PLX4720 paradoxically increased ERK phosphorylation in Gα-mutant UM cells. The combination of AZD6244 with PLX4720 had synergistic anticancer exercise in BRAF-mutant cells although not in Gα-mutant cells. The Akt inhibitor MK2206 sensitized BRAF-mutant cells to both PLX4720 and AZD6244 and sensitized Gα-mutant cells to AZD6244 but didn't overcome the resistance from the Gα-mutant cells to PLX4720.
CONCLUSIONS:
The response of UM cells to inhibition of B-Raf, MEK, and Akt depends on their genotype. Future use of such targeted therapies in medical trials of UM individuals will demand careful style and individual choice based on genotype to provide personalised and powerful therapy.
2011年10月26日星期三
Activation and involvement of Ral GTPases in colorectal cancer.
Martin TD, Samuel JC, Routh ED, Der CJ, Yeh JJ. "Cancer Res. 2011 Jan"
Current approaches to block KRAS oncogene purpose concentrate on inhibition of K-Ras downstream effector signaling. We evaluated the antitumor action of selumetinib (AZD6244, ARRY-142886), a powerful and selective MEK1/2 inhibitor, on the panel of colorectal carcinoma (CRC) cells and identified no inhibition of KRAS mutant CRC cell anchorage-independent development.
Although AKT action was elevated in KRAS mutant cells, and PI3K inhibition did impair the growth of MEK inhibitor-insensitive CRC cell lines, concurrent therapy with selumetinib didn't give further antitumor exercise. Consequently, we speculated that inhibition in the Ral guanine exchange aspect (RalGEF) effector pathway may possibly be a far more efficient strategy for blocking CRC growth.
RalGEFs are activators from the associated RalA and RalB modest GTPases and we identified activation of each in CRC cell lines and affected individual tumors. Interfering RNA steady suppression of RalA expression lowered CRC tumor cell anchorage-independent development, but remarkably, secure suppression of RalB greatly improved soft agar colony measurement and formation frequency. Regardless of their opposing actions, each RalA and RalB regulation of anchorage-independent growth needed interaction with RalBP1/RLIP76 and components from the exocyst complex.
Interestingly, RalA interaction using the Exo84 but not Sec5 exocyst component was essential for supporting anchorage-independent development, while RalB interaction with Sec5 although not Exo84 was essential for inhibition of anchorage-independent growth. We suggest that anti-RalA-selective therapies could provide an powerful strategy for KRAS mutant colorectal carcinoma (CRC).
Current approaches to block KRAS oncogene purpose concentrate on inhibition of K-Ras downstream effector signaling. We evaluated the antitumor action of selumetinib (AZD6244, ARRY-142886), a powerful and selective MEK1/2 inhibitor, on the panel of colorectal carcinoma (CRC) cells and identified no inhibition of KRAS mutant CRC cell anchorage-independent development.
Although AKT action was elevated in KRAS mutant cells, and PI3K inhibition did impair the growth of MEK inhibitor-insensitive CRC cell lines, concurrent therapy with selumetinib didn't give further antitumor exercise. Consequently, we speculated that inhibition in the Ral guanine exchange aspect (RalGEF) effector pathway may possibly be a far more efficient strategy for blocking CRC growth.
RalGEFs are activators from the associated RalA and RalB modest GTPases and we identified activation of each in CRC cell lines and affected individual tumors. Interfering RNA steady suppression of RalA expression lowered CRC tumor cell anchorage-independent development, but remarkably, secure suppression of RalB greatly improved soft agar colony measurement and formation frequency. Regardless of their opposing actions, each RalA and RalB regulation of anchorage-independent growth needed interaction with RalBP1/RLIP76 and components from the exocyst complex.
Interestingly, RalA interaction using the Exo84 but not Sec5 exocyst component was essential for supporting anchorage-independent development, while RalB interaction with Sec5 although not Exo84 was essential for inhibition of anchorage-independent growth. We suggest that anti-RalA-selective therapies could provide an powerful strategy for KRAS mutant colorectal carcinoma (CRC).
2011年10月25日星期二
Biological and Medical Action of AV-951 in Patients With Advanced Solid Tumors.
Eskens FA, de Jonge MJ, Bhargava P, Isoe T, Cotreau MM, Esteves B, Hayashi K, Burger H, Thomeer M, van Doorn L, Verweij J. "Clin Cancer Res. 2011 Oct"
PURPOSE:
To assess the maximum tolerated dose (MTD)/dose-limiting toxicities (DLTs), safety, pharmacokinetics, and pharmacodynamics of AV-951, a potent and selective oral VEGFR tyrosine kinase inhibitor.
EXPERIMENTAL Design:
Dose ranges of 1.0, 1.5, and 2.0 mg/day AV-951 for 28 days followed by 14 days off medicine had been explored in sufferers with sophisticated sound tumors.
RESULTS:
Forty-one sufferers had been enrolled. Animal data incorrectly predicted toxicity, leading to DLTs in the beginning dose (2.0 mg) consisting of grade three proteinuria and hypertension and grade 3 ataxia. At 1.0 mg, no DLT was observed; At an intermediate dose (1.5 mg), one individual experienced DLT consisting of quality 3 hypertension. This dose was determined as the MTD Of 10 further individuals handled at 1.5 mg, 1 patient every single knowledgeable grade three hypertension and grade 3 tiredness, and two patients skilled grade three and four transaminase elevation. In 12 additional sufferers handled at 1.0 mg, no DLT was observed. Pharmacokinetics shown lengthy absorption time, dose proportional publicity, plus a half-life of 4.7 days. Plasma ranges of VEGF-A and sVEGFR-2 showed dose-dependent increases and decreases, respectively. Dynamic contrast-enhanced magnetic resonance imaging indicated reduction in tumor perfusion. Clinical activity was observed in renal cell cancer, colorectal most cancers, as well as other tumors.
CONCLUSIONS:
AV-951 was well tolerated with manageable unwanted effects. The pharmacokinetics profile uncovered that AV-951 was suitable for as soon as every day dosing. Encouraging and tough medical activity was observed. The suggested day-to-day dose of AV-951 in a 4 week on 2 week off dosing program is 1.5 mg.
PURPOSE:
To assess the maximum tolerated dose (MTD)/dose-limiting toxicities (DLTs), safety, pharmacokinetics, and pharmacodynamics of AV-951, a potent and selective oral VEGFR tyrosine kinase inhibitor.
EXPERIMENTAL Design:
Dose ranges of 1.0, 1.5, and 2.0 mg/day AV-951 for 28 days followed by 14 days off medicine had been explored in sufferers with sophisticated sound tumors.
RESULTS:
Forty-one sufferers had been enrolled. Animal data incorrectly predicted toxicity, leading to DLTs in the beginning dose (2.0 mg) consisting of grade three proteinuria and hypertension and grade 3 ataxia. At 1.0 mg, no DLT was observed; At an intermediate dose (1.5 mg), one individual experienced DLT consisting of quality 3 hypertension. This dose was determined as the MTD Of 10 further individuals handled at 1.5 mg, 1 patient every single knowledgeable grade three hypertension and grade 3 tiredness, and two patients skilled grade three and four transaminase elevation. In 12 additional sufferers handled at 1.0 mg, no DLT was observed. Pharmacokinetics shown lengthy absorption time, dose proportional publicity, plus a half-life of 4.7 days. Plasma ranges of VEGF-A and sVEGFR-2 showed dose-dependent increases and decreases, respectively. Dynamic contrast-enhanced magnetic resonance imaging indicated reduction in tumor perfusion. Clinical activity was observed in renal cell cancer, colorectal most cancers, as well as other tumors.
CONCLUSIONS:
AV-951 was well tolerated with manageable unwanted effects. The pharmacokinetics profile uncovered that AV-951 was suitable for as soon as every day dosing. Encouraging and tough medical activity was observed. The suggested day-to-day dose of AV-951 in a 4 week on 2 week off dosing program is 1.5 mg.
Molecular Focused Therapy of Sophisticated Hepatocelluar Carcinoma
Sorafenib (Bayer43-9006; Nexavar) can be a novel, modest molecular specific numerous tyrosine protein kinase inhibitors (VEGFR and PDGFR) and RAF/MEK/ERK cascade inhibitor with IC50 values of 6, 22, 38 nM for Raf-1, wt BRAF and V599E mutant BRAF. Nexavar (Bayer43-9006; Nexavar) stops the proliferation of tumor by focusing on the Raf/MAPK/ERK signaling transduction pathway; in addition, it has distinguished anti-angiogenic activities attained by way of inhibiting the tyrosine kinase VEGR-2 and VEGFR-3 as well as PDGF receptor beta.
Recently, two important stage II clinical randomized, placebo-controlled trials are carried out in the West and Asia-pacific area. The outcomes from this two studies have obviously exhibited the survival benefit in making use of single-agent Nexavar in dealing with individuals with sophisticated hepatocellular carcinoma (HCC). The patients randomized to sorafenib arm had a median time to progression (TTP) of five level 5 months and general survival (OS) of ten stage 7 months inside the Western research, whilst time to progression (TTP) and overall survival (OS) had been two stage eight months and 6 point five months within the eastern trial, respectively.
Notably, the survival information through the patients enrolled within the Western trial virtually doubled these within the Eastern investigation. Even in the individuals treated with placebo, the overall survival of patients in the Western trial (for seven position 9 months) was still way far better than the individuals within the Eastern trial (lasting for four stage two months). What is the cause that produced the variations? This may attribute towards the reality that Asia centers generally attempt to enroll sufferers with poorer prognosis.[1]
References:
[1] Most cancers Res. 2004 Oct 1;64(19):7099-109.
Recently, two important stage II clinical randomized, placebo-controlled trials are carried out in the West and Asia-pacific area. The outcomes from this two studies have obviously exhibited the survival benefit in making use of single-agent Nexavar in dealing with individuals with sophisticated hepatocellular carcinoma (HCC). The patients randomized to sorafenib arm had a median time to progression (TTP) of five level 5 months and general survival (OS) of ten stage 7 months inside the Western research, whilst time to progression (TTP) and overall survival (OS) had been two stage eight months and 6 point five months within the eastern trial, respectively.
Notably, the survival information through the patients enrolled within the Western trial virtually doubled these within the Eastern investigation. Even in the individuals treated with placebo, the overall survival of patients in the Western trial (for seven position 9 months) was still way far better than the individuals within the Eastern trial (lasting for four stage two months). What is the cause that produced the variations? This may attribute towards the reality that Asia centers generally attempt to enroll sufferers with poorer prognosis.[1]
References:
[1] Most cancers Res. 2004 Oct 1;64(19):7099-109.
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