Detection of BRAF mutations in the tumour and serum of patients enrolled in the AZD6244 (ARRY-142886) advanced melanoma phase II study

Board, Ruth; Ellison, Gillian; Orr, Maria; Kemsley, Karin; McWalter, Gael; Blockley, Laura; Dearden, Simon; Morris, Clive; Ranson, Malcolm R; Cantarini, Mireille; Dive, Caroline; Hughes, Andrew

doi:10.1038/sj.bjc.6605371

Cited by 89 publications

(63 citation statements)

References 16 publications

(27 reference statements)

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“…[18][19][20][21][22][23] Further, AZD6244 is a noncompetitive MEK inhibitor with preclinical antitumor activity in solid tumor models including hepatocellular, colon, myeloma, thyroid, pancreatic, melanoma, and breast cancers 19,20,41 and tested clinically in phase 1 24 and phase 2 trials of advanced, refractory colorectal, melanoma, and lung cancer. [25][26][27] AZD6244 has been examined in leukemia and myeloma models, [42][43][44] however to our knowledge, has never been tested in lymphoma.…”

Section: Discussionmentioning

confidence: 99%

“…[18][19][20][21][22][23] Furthermore, phase 1 and phase 2 solid tumor clinical trials have shown this agent to be well-tolerated and have encouraging clinical efficacy. [24][25][26][27] To our knowledge, minimal data are available on newer generation MEK inhibitors in lymphoma and moreover, this anti-MEK agent has never been examined in lymphoma. We sought to examine the mechanisms of action and cytotoxic effect of the novel 2nd generation MEK small molecule antagonist, AZD6244, in lymphoma cell lines, primary cells, and an in vivo human DLBCL xenograft model.…”

Section: Introductionmentioning

confidence: 99%

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The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma

Bhalla

Evens

Dai

et al. 2011

Blood

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IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults accounting for nearly 35% of all non-Hodgkin lymphomas (NHL). Significant advances have been in the treatment of DLBCL, particularly with immunochemotherapy, however approximately 30%-40% of patients still die from this malignancy. In addition, short-and long-term toxicities of chemotherapy, including secondary malignancies and leukemias, continue to adversely impact the long-term prognosis of patients. Continued investigations of novel targeted therapeutic agents in DLBCL are warranted.The RAS/RAF/mitogen-activated protein kinase 1/2 (MEK1/2)/ extracellular signal-regulated kinase 1/2 (ERK1/2) plays a prominent role in cancer biology, including hematologic malignancies, in part through the regulation of cell growth and proliferation. [1][2][3][4][5] Activating mutations in RAS and RAF lead to aberrant activation of their downstream target, MEK1/2. Directly downstream of MEK1/2, ERK1 and ERK2 are intimately involved in transducing signals from growth factor receptors and cytokine receptors after ligand binding. 2 Furthermore, ERK is the only known catalytic substrate of MEK. 6 We and others have shown that the MEK/ERK signaling pathway is constitutively active in a large number of cancers, including hematologic malignancies. 3,4,[7][8][9] Moreover, the MEK/ERK signal transduction cascade has been shown to be susceptible to pharmacologic intervention. Thus, MEK has emerged as an attractive therapeutic target in cancer.The majority of preclinical, and especially clinical trial data studying MEK inhibitors to date have emerged largely from solid tumor studies. [10][11][12][13][14] We recently showed in preclinical studies that inhibition of ERK1/2 phosphorylation by 1st generation MEK and ERK inhibitors correlated with significant cell death in a lymphoma tumor model, 15 while others showed that sublethal concentrations of a 1st generation MEK antagonist potentiated the effect of sorafemib in lymphoma cells. 16 Furthermore, we recently demonstrated that MCT-1, an oncogene directly downstream of MEK/ ERK, is over-expressed in the majority of primary DLBCLs. 15 MCT-1 is known to colocalize with ERK1/2, while phosphorylation of MCT-1 protein by ERK is critical for stabilization of MCT-1 protein and for its functional ability to promote cell proliferation. 15,17 ARRY-142886 (AZD6244, selumetinib; Astra Zeneca) is a selective nonATP-competitive 2nd generation oral MEK inhibitor studied primarily in solid tumor studies with reported nanomolar activity against purified MEK1 enzyme. [18][19][20][21][22][23] Furthermore, phase 1 and phase 2 solid tumor clinical trials have shown this agent to be well-tolerated and have encouraging clinical efficacy. [24][25][26][27] To our knowledge, minimal data are available on newer generation MEK inhibitors in lymphoma and moreover, this anti-MEK agent has never been examined in lymphoma. We sought to examine the mechanisms of action and cytotoxic effect of the novel 2nd generation MEK sma...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma

Bhalla

Evens

Dai

et al. 2011

Blood

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“…Our group investigated the clinical utility of cfDNA from serum as an alternative source of BRAF mutation testing in 126 metastatic melanoma patients who participated in a phase II study testing the efficacy of AZD6244, a specific MEK1/2 inhibitor (Board et al 2009). Responses to AZD6244 were observed only in patients whose tumours harboured BRAF mutations.…”

Section: Cutaneous Melanomamentioning

confidence: 99%

“…Recent advances in PCR based technology have now allowed the analysis of point mutations in EGFR, KRAS, BRAF and PIK3CA genes from cfDNA isolated from patients' plasma or serum (Kimura et al 2007;Hodgson et al 2010;Board et al 2009Board et al , 2010. These genes are of particular importance in determining response to a variety of novel agents in clinical use and in development for the treatment of cancer.…”

Section: Introductionmentioning

confidence: 99%

Current status and future potential of somatic mutation testing from circulating free DNA in patients with solid tumours

Aung

Board

Ellison

et al. 2010

HUGO J

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Genetic alterations can determine the natural history of cancer and its treatment response. With further advances in DNA sequencing technology, multiple novel genetic alterations will be discovered which could be exploited as prognostic, predictive and pharmacodynamic biomarkers in the development and use of cancer therapeutics. As such, the importance in clinical practice of efficient and robust somatic mutation testing in solid tumours cannot be overemphasized in the current era of personalized medicine. However, significant challenges remain regarding the testing of genetic biomarkers in clinical practice. Reliance on archived formalin fixed, paraffin embedded tumour, obtained from diagnostic biopsies, for testing somatic genetic alterations could restrict the scientific community in asking relevant questions about a patient's cancer biology. Problems inherent with using formalin fixed, archival tissue are well recognized and difficult to resolve. It could be argued that to achieve rapid and efficient incorporation of genetic biomarkers into clinical practice, somatic mutation testing in cancer patients should be simpler, less invasive using a readily available clinical sample, whilst maintaining robustness and reproducibility. In this regard, use of circulating free DNA (cfDNA) from plasma or serum as an alternative and/or additional source of DNA to test cancer specific genetic alterations is an attractive proposition. In light of encouraging results from recent studies, this mini review will discuss the current role and future potential of somatic mutation testing from circulating or cell free DNA derived from the blood of patients with solid tumours.

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“…The results have revealed that among the 53 patients evaluable for all study end points, 22 (42%) were chemosensitive and 31 (58%) chemoresistant patients and the chemosensitive patients showed an increased overall survival of 14.6 months compared with 7.4 mo in chemoresistant patients [90] . In the same way, the results from a recent study have also indicated the possibility to establish the B-Raf E600V mutation status in the tissue biopsies and circulating free DNA samples from melanoma patients to assess the patients that could be susceptible to respond to the pharmacological agents targeting oncogenic B-Raf E600V mutant [91] . In addition, it has also been noted that the serum concentrations of diverse angiogenic factors such as VEGF, basic fibroblast factor (bFGF) and IL-8 were increased in melanoma patients relative to healthy individuals and associated with advanced stages and poor overall and progression-free survival of melanoma patients [18,23] .…”

Section: Patientsmentioning

confidence: 97%

Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas

Mimeault

Batra²

2012

WJCO

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Cutaneous malignant melanoma is the most aggressive form of skin cancer with an extremely poor survival rate for the patients diagnosed with locally invasive and metastatic disease states. Intensive research has led in last few years to an improvement of the early detection and curative treatment of primary cutaneous melanomas that are confined to the skin by tumor surgical resection. However, locally advanced and disseminated melanomas are generally resistant to conventional treatments, including ionizing radiation, systemic chemotherapy, immunotherapy and/or adjuvant stem cellbased therapies, and result in the death of patients. The rapid progression of primary melanomas to locally invasive and/or metastatic disease states remains a major obstacle for an early effective diagnosis and a curative therapeutic intervention for melanoma patients. Importantly, recent advances in the melanoma research have led to the identification of different gene products that are often implicated in the malignant transformation of melanocytic cells into melanoma cells, including melanoma stem/progenitor cells, during melanoma initiation and progression to locally advanced and metastatic disease states. The frequent deregulated genes products encompass the oncogenic B-RafV600E and N-RasQ61R mutants, different receptor tyrosine kinases and developmental pathways such as epidermal growth factor receptor (EGFR), stem cell-like factor (SCF) receptor KIT, hedgehog, Wnt/β-catenin, Notch, stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) and vascular endothelial growth factor (VEGF)/ VEGFR receptor. These growth factors can cooperate to activate distinct tumorigenic downstream signaling elements and epithelial-mesenchymal transition (EMT)-associated molecules, including phosphatidylinositol 3'-kinase (PI3K)/Akt/ molecular target of rapamycin (mTOR), nuclear factor-kappaB (NF-κB), macrophage inhibitory cytokine-1 (MIC-1), vimentin, snail and twist. Of therapeutic relevance, these deregulated signal transduction components constitute new potential biomarkers and therapeutic targets of great clinical interest for improving the efficacy of current diagnostic and prognostic methods and management of patients diagnosed with locally advanced, metastatic and/or relapsed melanomas.

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Detection of BRAF mutations in the tumour and serum of patients enrolled in the AZD6244 (ARRY-142886) advanced melanoma phase II study

Cited by 89 publications

References 16 publications

The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma

The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma

Current status and future potential of somatic mutation testing from circulating free DNA in patients with solid tumours

Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas

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