Nikolas Haass

Publications (37) View all

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  Available from: Nikolas Haass

  Article: Meeting report from the 7th International Melanoma Congress, Sydney, November, 2010.

  P Hersey, K S M Smalley, A Weeraratna, M Bosenberg, X D Zhang, N K Haass, E Paton, G Mann, R A Scolyer, T Tüting
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  ABSTRACT: The 2010 7th International Melanoma Congress sponsored by the Society for Melanoma Research and held in Sydney, Australia, was held together with the International Melanoma and Skin Cancer Centers group and the International Melanoma Pathology Study Group. As a consequence, there were over 900 registrants that included a wide range of clinicians (surgeons, medical oncologists, dermatologists) specialising in the management of melanoma as well as scientists and students carrying out laboratory-based research in melanoma. There was a general consensus that this grouping of clinicians, pathologists and scientists was mutually advantageous and plans are afoot to continue this grouping in future meetings. The meeting was dominated by the advances being made in treatment of melanoma with selective BRAF inhibitors but interest in epithelial mesenchymal transition and phenotypic changes in melanoma was apparent in many of the talks. The authors have attempted to capture many of the new developments in melanoma research but apologize to those speakers and poster presenters who had equally important findings not captured in these summaries.
  Pigment Cell & Melanoma Research 02/2011; 24(1):e1-15. · 5.06 Impact Factor
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  Article: The BH3 mimetic ABT-737 sensitises human melanoma cells to apoptosis induced by selective BRAF inhibitors but does not reverse acquired resistance.

  David Wroblewski, Branka Mijatov, Nethia Mohana-Kumaran, Fritz Lai, Stuart J Gallagher, Nikolas K Haass, Xu Dong Zhang, Peter Hersey
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  ABSTRACT: Although the introduction of selective BRAF inhibitors has been a major advance in treatment of metastatic melanoma, approximately 50% of patients have limited responses including stabilisation of disease or no response at all. The present study aims to identify a novel means of overcoming resistance of melanoma to killing by BRAF inhibitors. We examined the influence of the BH3 mimetic ABT-737 on induction of apoptosis by the selective BRAF inhibitor PLX4720 in melanoma cells with or without BRAF V600E mutation. Included were cell lines established from four patients before and during treatment with selective BRAF inhibitors and 3D spheroids derived from these cell lines. Cell lines with no or low sensitivity to PLX4720 underwent synergistic increases and increased rates of apoptosis when combined with ABT-737. This degree of synergism was not seen in cell lines without BRAF V600E mutations. Apoptosis was mediated through the mitochondrial pathway and was due in part to upregulation of Bim as shown by inhibition of apoptosis following siRNA knockdown of Bim. Similar effects were seen in cell lines established from patients prior to treatment but not in lines from patients clinically resistant to the selective BRAF inhibitors and in 3D spheroids derived from these cell lines. These results suggest that combination of selective BRAF inhibitors with ABT-737 or the related orally available compound ABT-263 may increase the degree and rate of responses in previously untreated patients with V600E melanoma but not in those with acquired resistance to these agents.
  Carcinogenesis 10/2012; · 5.70 Impact Factor
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  Article: Modulation of NOXA and MCL-1 as a strategy for sensitizing melanoma cells to the BH3-mimetic ABT-737.

  Keryn M Lucas, Nethia Mohana-Kumaran, Diana Lau, Xu Dong Zhang, Peter Hersey, David C Huang, Wolfgang Weninger, Nikolas K Haass, John D Allen
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  ABSTRACT: Drug resistance in melanoma is commonly attributed to ineffective apoptotic pathways. Inhibiting antiapoptotic BCL-2 and its relatives is an attractive strategy for sensitizing lymphoid malignancies to drugs but it has been largely unsuccessful for melanoma and other solid tumors. ABT-737, a small-molecule BH3-mimetic, selectively inhibits BCL-2, BCL-XL, and BCL-w and shows promise for treating leukemia, lymphoma, and small-cell lung cancer. Melanoma cells are insensitive to ABT-737, but MCL-1 inhibition reportedly increases the sensitivity of other tumors to the compound. The efficacy of MCL-1 and BFL-1 inhibition for sensitizing melanoma cells to ABT-737 was investigated by short hairpin RNA-mediated knockdown or overexpression of their antagonist NOXA in two-dimensional cell culture, a three-dimensional organotypic spheroid model, and an in vivo model. MCL-1 downregulation or NOXA overexpression strongly sensitized melanoma cells to ABT-737 in vitro. NOXA-inducing cytotoxic drugs also strongly sensitized melanomas to ABT-737 but, surprisingly, not vice versa. The drugs most suitable are not necessarily those normally used to treat melanoma. Resistance to ABT-737 occurred quickly in three-dimensional melanoma spheroids through reduced NOXA expression, although experiments with both xenografts and three-dimensional spheroids suggest that penetration of ABT-737 into tumor masses may be the principal limitation, which may be obviated through use of more diffusible BH3-mimetics. Sensitization of tumors to BH3-mimetics by cytotoxic drugs that induce NOXA is a therapeutic strategy worth exploring for the treatment of melanoma and other solid cancers.
  Clinical Cancer Research 12/2011; 18(3):783-95. · 7.74 Impact Factor
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  Available from: Nikolas Haass

  Article: Meeting report from the 2011 International Melanoma Congress, Tampa, Florida.

  Keiran S M Smalley, Andrew E Aplin, Keith T Flaherty, Christoph Hoeller, Anja K Bosserhoff, Nikolas K Haass, Marcus Bosenberg, Antoni Ribas, Raymond Barnhill, Ragini Kudchadkar, Jane L Messina
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  ABSTRACT: The 2011, 8(th) International Congress of the Society for Melanoma Research was held in conjunction with the 5(th) Meeting of the Interdisciplinary Melanoma/Skin Cancer Centres, the 2(nd) Melanoma update for Primary Care Physicians, Surgeons, Oncologists and Dermatologists and the 4(th) Melanoma Pathology Symposium of the International Melanoma Pathology Working Group in Tampa, Florida, USA. The four meetings attracted over 685 attendees and covered the breadth of basic melanoma biology all the way through to the clinical management of melanoma and other skin cancers. The major focus of discussions this year was upon the resistance of melanoma patients to BRAF inhibitors and novel strategies for the preclinical and clinical management of therapeutic escape. Overall, it was felt that the meeting captured the current levels of enthusiasm and optimism that now permeate the melanoma field.
  Pigment Cell & Melanoma Research 11/2011; 25(1):E1-11. · 5.06 Impact Factor
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  Available from: Nikolas Haass

  Article: Evaluation of cell cycle arrest in estrogen responsive MCF-7 breast cancer cells: pitfalls of the MTS assay.

  Eileen M McGowan, Nikki Alling, Elise A Jackson, Daniel Yagoub, Nikolas K Haass, John D Allen, Rosetta Martinello-Wilks
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  ABSTRACT: Endocrine resistance is a major problem with anti-estrogen treatments and how to overcome resistance is a major concern in the clinic. Reliable measurement of cell viability, proliferation, growth inhibition and death is important in screening for drug treatment efficacy in vitro. This report describes and compares commonly used proliferation assays for induced estrogen-responsive MCF-7 breast cancer cell cycle arrest including: determination of cell number by direct counting of viable cells; or fluorescence SYBR®Green (SYBR) DNA labeling; determination of mitochondrial metabolic activity by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay; assessment of newly synthesized DNA using 5-ethynyl-2'-deoxyuridine (EdU) nucleoside analog binding and Alexa Fluor® azide visualization by fluorescence microscopy; cell-cycle phase measurement by flow cytometry. Treatment of MCF-7 cells with ICI 182780 (Faslodex), FTY720, serum deprivation or induction of the tumor suppressor p14ARF showed inhibition of cell proliferation determined by the Trypan Blue exclusion assay and SYBR DNA labeling assay. In contrast, the effects of treatment with ICI 182780 or p14ARF-induction were not confirmed using the MTS assay. Cell cycle inhibition by ICI 182780 and p14ARF-induction was further confirmed by flow cytometric analysis and EdU-DNA incorporation. To explore this discrepancy further, we showed that ICI 182780 and p14ARF-induction increased MCF-7 cell mitochondrial activity by MTS assay in individual cells compared to control cells thereby providing a misleading proliferation readout. Interrogation of p14ARF-induction on MCF-7 metabolic activity using TMRE assays and high content image analysis showed that increased mitochondrial activity was concomitant with increased mitochondrial biomass with no loss of mitochondrial membrane potential, or cell death. We conclude that, whilst p14ARF and ICI 182780 stop cell cycle progression, the cells are still viable and potential treatments utilizing these pathways may contribute to drug resistant cells. These experiments demonstrate how the combined measurement of metabolic activity and DNA labeling provides a more reliable interpretation of cancer cell response to treatment regimens.
  PLoS ONE 01/2011; 6(6):e20623. · 4.09 Impact Factor