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Dive into the research topics where David Segal is active.

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Featured researches published by David Segal.


Leukemia | 2009

Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice

Yaoyu Chen; Yiguo Hu; Shawnya Michaels; David Segal; Dennis M. Brown; Shaoguang Li

Omacetaxine mepesuccinate (formerly homoharringtonine) is a molecule with a mechanism of action that is different from tyrosine kinase inhibitors, and its activity in chronic myeloid leukemia (CML) seems to be independent of the BCR-ABL mutation status. Using BCR-ABL-expressing myelogenous and lymphoid cell lines and mouse models of CML and B-cell acute lymphoblastic leukemia (B-ALL) induced by wild-type BCR-ABL or T315I mutant-BCR-ABL, we evaluated the inhibitory effects of omacetaxine on CML and B-ALL. We showed that more than 90% of the leukemic stem cells were killed after treatment with omacetaxine in vitro. In contrast, less than 9 or 25% of the leukemic stem cells were killed after treating with imatinib or dasatinib, respectively. After 4 days of treatment of CML mice with omacetaxine, Gr-1+myeloid leukemia cells decreased in the peripheral blood of the treated CML mice. In the omacetaxine-treated B-ALL mice, only 0.8% of the B220+leukemia cells were found in peripheral blood, compared with 34% of the B220+leukemia cells in the placebo group. Treatment with omacetaxine decreased the number of leukemia stem cells and prolonged the survival of mice with BCR-ABL-induced CML or B-ALL.


Blood | 2016

The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism

Mary Ann Anderson; Jing Deng; John F. Seymour; Constantine S. Tam; Su Young Kim; Joshua Fein; Lijian Yu; Jennifer R. Brown; David Westerman; Eric G. Si; Ian Majewski; David Segal; Sari H. Enschede; David C. S. Huang; Matthew S. Davids; Anthony Letai; Andrew W. Roberts

BCL2 blunts activation of the mitochondrial pathway to apoptosis, and high-level expression is required for chronic lymphocytic leukemia (CLL) survival. Venetoclax (ABT-199) is a small-molecule selective inhibitor of BCL2 currently in clinical trials for CLL and other malignancies. In conjunction with the phase 1 first-in-human clinical trial of venetoclax in patients with relapsed or refractory CLL (M12-175), we investigated the mechanism of action of venetoclax in vivo, explored whether in vitro sensitivity assays or BH3 profiling correlated with in vivo responses in patients, and determined whether loss of TP53 function affected responses in vitro and in vivo. In all samples tested, venetoclax induced death of CLL cells in vitro at concentrations achievable in vivo, with cell death evident within 4 hours. Apoptotic CLL cells were detected in vivo 6 or 24 hours after a single 20-mg or 50-mg dose in some patients. The extent of mitochondrial depolarization by a BIM BH3 peptide in vitro was correlated with percentage reduction of CLL in the blood and bone marrow in vivo, whereas the half lethal concentration derived from standard cytotoxicity assays was not. CLL cell death in vitro and the depth of clinical responses were independent of deletion of chromosome 17p, TP53 mutation, and TP53 function. These data provide direct evidence that venetoclax kills CLL cells in a TP53-independent fashion by inhibition of BCL2 in patients and support further assessment of BH3 profiling as a predictive biomarker for this drug.


Blood | 2016

Hierarchy for targeting pro-survival BCL2 family proteins in multiple myeloma: pivotal role of MCL1.

Jia-Nan Gong; Tiffany Khong; David Segal; Yuan Yao; Chris D. Riffkin; Jean-Marc Garnier; Seong Lin Khaw; Guillaume Lessene; Andrew Spencer; Marco J. Herold; Andrew W. Roberts; David C. S. Huang

New therapeutic targets are needed to address the poor prognosis of patients with high-risk multiple myeloma. Myeloma cells usually express a range of the prosurvival BCL2 proteins. To define the hierarchy of their relative importance for maintaining the survival of myeloma cells, we targeted each of them in a large panel of cell lines, using pharmacological inhibitors or gene editing or by peptide-based approaches, alone or in combination. The majority of well-established immortalized cell lines (17/25) or low-passage myeloma cell lines (5/7) are readily killed when MCL1 is targeted, even including those cell lines sensitive to BCL2 inhibition. Targeting MCL1 also constrained the growth of myeloma in vivo. We also identified a previously unrecognized subset of myeloma that is highly BCLXL-dependent, and has the potential for cotargeting MCL1 and BCLXL. As MCL1 is pivotal for maintaining survival of most myelomas, it should be prioritized for targeting in the clinic once high-quality, validated inhibitors become available.


Blood | 2013

Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription

Daniel Thomas; Jason A. Powell; François Vergez; David Segal; Nhu-Y Nguyen; Adele Baker; Tse-Chieh Teh; Emma F Barry; Jean-Emmanuel Sarry; Erwin M. Lee; Tracy L. Nero; Anissa M. Jabbour; Giovanna Pomilio; Benjamin D Green; Stéphane Manenti; Stefan P. Glaser; Michael W. Parker; Angel F. Lopez; Paul G. Ekert; Richard B. Lock; David C. S. Huang; Susan K. Nilsson; Christian Recher; Andrew Wei; Mark A. Guthridge

Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). A screen for compounds that downregulate Mcl-1 identified the kinase inhibitor, PIK-75, which demonstrates marked proapoptotic activity against a panel of cytogenetically diverse primary human AML patient samples. We show that PIK-75 transiently blocks Cdk7/9, leading to transcriptional suppression of MCL-1, rapid loss of Mcl-1 protein, and alleviation of its inhibition of proapoptotic Bak. PIK-75 also targets the p110α isoform of PI3K, which leads to a loss of association between Bcl-xL and Bak. The simultaneous loss of Mcl-1 and Bcl-xL association with Bak leads to rapid apoptosis of AML cells. Concordantly, low Bak expression in AML confers resistance to PIK-75-mediated killing. On the other hand, the induction of apoptosis by PIK-75 did not require the expression of the BH3 proteins Bim, Bid, Bad, Noxa, or Puma. PIK-75 significantly reduced leukemia burden and increased the survival of mice engrafted with human AML without inducing overt toxicity. Future efforts to cotarget PI3K and Cdk9 with drugs such as PIK-75 in AML are warranted.


Blood | 2012

E6AP ubiquitin ligase regulates PML-induced senescence in Myc-driven lymphomagenesis

Kamil Wolyniec; Jake Shortt; Elisa de Stanchina; Yaara Levav-Cohen; Osnat Alsheich-Bartok; Igal Louria-Hayon; Vincent Corneille; Beena Kumar; Simone J. Woods; Stephen Opat; Ricky W. Johnstone; Clare L. Scott; David Segal; Pier Paolo Pandolfi; Stephen B. Fox; Andreas Strasser; Yong-hui Jiang; Scott W. Lowe; Sue Haupt; Ygal Haupt

Neoplastic transformation requires the elimination of key tumor suppressors, which may result from E3 ligase-mediated proteasomal degradation. We previously demonstrated a key role for the E3 ubiquitin ligase E6AP in the regulation of promyelocytic leukemia protein (PML) stability and formation of PML nuclear bodies. Here, we report the involvement of the E6AP-PML axis in B-cell lymphoma development. A partial loss of E6AP attenuated Myc-induced B-cell lymphomagenesis. This tumor suppressive action was achieved by the induction of cellular senescence. B-cell lymphomas deficient for E6AP expressed elevated levels of PML and PML-nuclear bodies with a concomitant increase in markers of cellular senescence, including p21, H3K9me3, and p16. Consistently, PML deficiency accelerated the rate of Myc-induced B-cell lymphomagenesis. Importantly, E6AP expression was elevated in ∼ 60% of human Burkitt lymphomas, and down-regulation of E6AP in B-lymphoma cells restored PML expression with a concurrent induction of cellular senescence in these cells. Our findings demonstrate that E6AP-mediated down-regulation of PML-induced senescence is essential for B-cell lymphoma progression. This provides a molecular explanation for the down-regulation of PML observed in non-Hodgkin lymphomas, thereby suggesting a novel therapeutic approach for restoration of tumor suppression in B-cell lymphoma.


Science Translational Medicine | 2017

Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer

Delphine Mérino; James R. Whittle; François Vaillant; Antonin Serrano; Jia-Nan Gong; Göknur Giner; Ana Leticia Maragno; Maïa Chanrion; Emilie Schneider; Bhupinder Pal; Xiang Li; Grant Dewson; Julius Gräsel; Kevin H. Liu; Najoua Lalaoui; David Segal; Marco J. Herold; David C. S. Huang; Gordon K. Smyth; Guillaume Lessene; Jane E. Visvader; Geoffrey J. Lindeman

The MCL-1 inhibitor S63845 is effective in combination with conventional therapy for targeting triple-negative and HER2-amplified breast cancer. Cutting off another tumor lifeline BH3 mimetics are drugs that inhibit the BCL-2 family of prosurvival proteins in cancer cells and thereby promote cancer cell death. Unfortunately, MCL-1, a member of this prosurvival family, can interfere with treatment because it is not sensitive to currently available BH3 mimetics. The MCL-1 inhibitor S63845 was developed to overcome this mechanism of treatment resistance, and Merino et al. examined the effectiveness of this drug in cell lines and xenografts derived from breast cancer patients. The authors demonstrated the drug’s efficacy in combination with several drugs that are already in clinical use and also identified a protein that can promote treatment resistance, which may help predict which patients are more likely to benefit from the new treatment. The development of BH3 mimetics, which antagonize prosurvival proteins of the BCL-2 family, represents a potential breakthrough in cancer therapy. Targeting the prosurvival member MCL-1 has been an area of intense interest because it is frequently deregulated in cancer. In breast cancer, MCL-1 is often amplified, and high expression predicts poor patient outcome. We tested the MCL-1 inhibitor S63845 in breast cancer cell lines and patient-derived xenografts with high expression of MCL-1. S63845 displayed synergistic activity with docetaxel in triple-negative breast cancer and with trastuzumab or lapatinib in HER2-amplified breast cancer. Using S63845-resistant cells combined with CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 (CRISPR-associated 9) technology, we identified deletion of BAK and up-regulation of prosurvival proteins as potential mechanisms that confer resistance to S63845 in breast cancer. Collectively, our findings provide a strong rationale for the clinical evaluation of MCL-1 inhibitors in breast cancer.


Bioorganic & Medicinal Chemistry | 2015

Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9

Louisa Phillipson; David Segal; Tracy L. Nero; Michael W. Parker; Soo San Wan; Melanie de Silva; Mark A. Guthridge; Andrew Wei; Christopher J. Burns

The serine-threonine kinase CDK9 is a target of emerging interest for the development of anti-cancer drugs. There are multiple lines of evidence linking CDK9 activity to cancer, including the essential role this kinase plays in transcriptional regulation through phosphorylation of the C-terminal domain (CTD) of RNA polymerase II. Indeed, inhibition of CDK9 has been shown to result in a reduction of short-lived proteins such as the pro-survival protein Mcl-1 in malignant cells leading to the induction of apoptosis. In this work we report our initial studies towards the discovery of selective CDK9 inhibitors, starting from the known multi-kinase inhibitor PIK-75 which possesses potent CDK9 activity. Our series is based on a pyrazolo[1,5-a]pyrimidine nucleus and, importantly, the resultant lead compound 18b is devoid of the structural liabilities present in PIK-75 and possesses greater selectivity.


Cell Death & Differentiation | 2017

Anti-apoptotic proteins BCL-2, MCL-1 and A1 summate collectively to maintain survival of immune cell populations both in vitro and in vivo

Emma M. Carrington; Yifan Zhan; Jamie L. Brady; Jian Guo Zhang; Robyn M. Sutherland; Natasha S Anstee; Robyn L. Schenk; Ingela Vikstrom; Rebecca B. Delconte; David Segal; Nicholas D. Huntington; David M. Tarlinton; David C. S. Huang; Andreas Strasser; Suzanne Cory; Marco J. Herold; Andrew M. Lew

Survival of various immune cell populations has been proposed to preferentially rely on a particular anti-apoptotic BCL-2 family member, for example, naive T cells require BCL-2, while regulatory T cells require MCL-1. Here we examined the survival requirements of multiple immune cell subsets in vitro and in vivo, using both genetic and pharmacological approaches. Our findings support a model in which survival is determined by quantitative participation of multiple anti-apoptotic proteins rather than by a single anti-apoptotic protein. This model provides both an insight into how the sum of relative levels of anti-apoptotic proteins BCL-2, MCL-1 and A1 influence survival of T cells, B cells and dendritic cells, and a framework for ascertaining how these different immune cells can be optimally targeted in treatment of immunopathology, transplantation rejection or hematological cancers.


Leukemia | 2018

Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1

Tse-Chieh Teh; Nhu Y.N. Nguyen; Donia M. Moujalled; David Segal; Giovanna Pomilio; Sewa Rijal; Anissa M. Jabbour; K. D. Cummins; Kurt Lackovic; P. Blombery; E. Thompson; Paul G. Ekert; Guillaume Lessene; Stefan P. Glaser; David C. S. Huang; Andrew W. Roberts; Mark A. Guthridge; Andrew Wei

Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response. Targeting the B-cell lymphoma 2 (BCL-2) family of proteins is an attractive option to combat chemoresistance in leukemia. Preclinical and clinical studies indicate modest single-agent activity with selective BCL-2 inhibitors (for example, venetoclax). We show that venetoclax synergizes with cytarabine and idarubicin to increase antileukemic efficacy in a TP53-dependent manner. Although TP53 deficiency impaired sensitivity to combined venetoclax and chemotherapy, higher-dose idarubicin was able to suppress MCL1 and induce cell death independently of TP53. Consistent with an MCL1-specific effect, cell death from high-dose idarubicin was dependent on pro-apoptotic Bak. Combining higher-dose idarubicin with venetoclax was able to partially overcome resistance in Bak-deficient cells. Using inducible vectors and venetoclax to differentially target anti-apoptotic BCL-2 family members, BCL-2 and MCL1 emerged as critical and complementary proteins regulating cell survival in acute myeloid leukemia. Dual targeting of BCL-2 and MCL1, but not either alone, prolonged survival of leukemia-bearing mice. In conclusion, our findings support the further investigation of venetoclax in combination with standard chemotherapy, including intensified doses of idarubicin. Venetoclax should also be investigated in combination with direct inhibitors of MCL1 as a chemotherapy-free approach in the future.


ChemMedChem | 2014

Simplified silvestrol analogues with potent cytotoxic activity.

Bill C. Hawkins; Lisa Lindqvist; Duong Nhu; Phillip P Sharp; David Segal; Andrew Powell; Michael Campbell; Eileen Ryan; Jennifer M. Chambers; Jonathan M. White; Mark A. Rizzacasa; Guillaume Lessene; David C. S. Huang; Christopher J. Burns

The complex natural products silvestrol (1) and episilvestrol (2) are inhibitors of translation initiation through binding to the DEAD‐box helicase eukaryotic initiation factoru20054A (eIF4A). Both compounds are potently cytotoxic to cancer cells in vitro, and 1 has demonstrated efficacy in vivo in several xenograft cancer models. Here we show that 2 has limited plasma membrane permeability and is metabolized in liver microsomes in a manner consistent with that reported for 1. In addition, we have prepared a series of analogues of these compounds where the complex pseudo‐sugar at C6 has been replaced with chemically simpler moieties to improve drug‐likeness. Selected compounds from this work possess excellent activity in biochemical and cellular translation assays with potent activity against leukemia cell lines.

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David C. S. Huang

Walter and Eliza Hall Institute of Medical Research

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Christopher J. Burns

Walter and Eliza Hall Institute of Medical Research

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Guillaume Lessene

Walter and Eliza Hall Institute of Medical Research

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Jia-Nan Gong

Walter and Eliza Hall Institute of Medical Research

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Marco J. Herold

Walter and Eliza Hall Institute of Medical Research

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Nicholas D. Huntington

Walter and Eliza Hall Institute of Medical Research

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Yuan Yao

Walter and Eliza Hall Institute of Medical Research

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