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https://www.readbyqxmd.com/read/27905446/genomic-evolution-and-chemoresistance-in-germ-cell-tumours
#1
Amaro Taylor-Weiner, Travis Zack, Elizabeth O'Donnell, Jennifer L Guerriero, Brandon Bernard, Anita Reddy, G Celine Han, Saud AlDubayan, Ali Amin-Mansour, Steven E Schumacher, Kevin Litchfield, Clare Turnbull, Stacey Gabriel, Rameen Beroukhim, Gad Getz, Scott L Carter, Michelle S Hirsch, Anthony Letai, Christopher Sweeney, Eliezer M Van Allen
Germ-cell tumours (GCTs) are derived from germ cells and occur most frequently in the testes. GCTs are histologically heterogeneous and distinctly curable with chemotherapy. Gains of chromosome arm 12p and aneuploidy are nearly universal in GCTs, but specific somatic genomic features driving tumour initiation, chemosensitivity and progression are incompletely characterized. Here, using clinical whole-exome and transcriptome sequencing of precursor, primary (testicular and mediastinal) and chemoresistant metastatic human GCTs, we show that the primary somatic feature of GCTs is highly recurrent chromosome arm level amplifications and reciprocal deletions (reciprocal loss of heterozygosity), variations that are significantly enriched in GCTs compared to 19 other cancer types...
November 30, 2016: Nature
https://www.readbyqxmd.com/read/27852038/transcriptomic-metabolomic-reprogramming-in-egfr-mutant-nsclc-early-adaptive-drug-escape-linking-tgf%C3%AE-2-bioenergetics-mitochondrial-priming
#2
Praveena S Thiagarajan, Xiaoliang Wu, Wei Zhang, Ivy Shi, Rakesh Bagai, Patrick Leahy, Yan Feng, Martina Veigl, Daniel Lindner, David Danielpour, Lihong Yin, Rafael Rosell, Trever G Bivona, Zhenfeng Zhang, Patrick C Ma
The impact of EGFR-mutant NSCLC precision therapy is limited by acquired resistance despite initial excellent response. Classic studies of EGFR-mutant clinical resistance to precision therapy were based on tumor rebiopsies late during clinical tumor progression on therapy. Here, we characterized a novel non-mutational early adaptive drug-escape in EGFR-mutant lung tumor cells only days after therapy initiation, that is MET-independent. The drug-escape cell states were analyzed by integrated transcriptomic and metabolomics profiling uncovering a central role for autocrine TGFβ2 in mediating cellular plasticity through profound cellular adaptive Omics reprogramming, with common mechanistic link to prosurvival mitochondrial priming...
November 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27811212/to-prime-or-not-to-prime-that-is-the-question
#3
Danielle S Potter, Anthony Letai
Mitochondrial priming is regulated by the B-cell lymphoma 2 (BCL-2) family of proteins and determines a cell's "readiness" for apoptosis. A highly primed cell will undergo apoptosis more easily than an unprimed cell in response to apoptotic stimuli via the intrinsic apoptotic pathway. Priming can be measured via BH3 profiling, which uses BH3 peptides derived from the BH3 domain of pro-apoptotic BH3-only BCL-2 family members to provoke a response from viable mitochondria. BH3 profiling can be performed on tumor cells and can identify mechanisms a cell uses to evade apoptosis and anti-apoptotic dependency to the anti-apoptotic BCL-2 family members...
November 3, 2016: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/27779684/microfluidic-profiling-of-apoptosis-related-genes-after-treatment-with-bh3-mimetic-agents-in-astrocyte-and-glioblastoma-cell-lines
#4
Eva Vidomanova, Peter Racay, Ivana Pilchova, Erika Halasova, Jozef Hatok
Glioblastoma (GB) is the most frequent and biologically the most aggressive primary brain tumor in adults. Standard treatment for newly diagnosed GB consists of surgical resection, radiotherapy and chemotherapy. Resistance to therapy is a major obstacle, even with optimal treatment with a survival median of only 12-15 months. The heterogeneity and treatment response of GB makes this tumor type a challenging area of research. The aim of our study was to study the response of normal human astrocyte (HA) and human GB (T98G) cell lines to apoptosis inhibitors in vitro...
October 21, 2016: Oncology Reports
https://www.readbyqxmd.com/read/27775704/pim1-kinase-regulates-cell-death-tumor-growth-and-chemotherapy-response-in-triple-negative-breast-cancer
#5
Fara Brasó-Maristany, Simone Filosto, Steven Catchpole, Rebecca Marlow, Jelmar Quist, Erika Francesch-Domenech, Darren A Plumb, Leila Zakka, Patrycja Gazinska, Gianmaria Liccardi, Pascal Meier, Albert Gris-Oliver, Maggie Chon U Cheang, Anna Perdrix-Rosell, Manar Shafat, Elodie Noël, Nirmesh Patel, Kristen McEachern, Maurizio Scaltriti, Pau Castel, Farzana Noor, Richard Buus, Sumi Mathew, Johnathan Watkins, Violeta Serra, Pierfrancesco Marra, Anita Grigoriadis, Andrew N Tutt
Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC cells, but not nonmalignant mammary epithelial cells, were dependent on PIM1 for proliferation and protection from apoptosis. PIM1 knockdown reduced expression of the anti-apoptotic factor BCL2, and dynamic BH3 profiling of apoptotic priming revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines...
November 2016: Nature Medicine
https://www.readbyqxmd.com/read/27737950/micrornas-mir-23a-3p-mir-23b-3p-and-mir-149-5p-regulate-the-expression-of-pro-apoptotic-bh3-only-proteins-dp5-and-puma-in-human-pancreatic-beta-cells
#6
Fabio Arturo Grieco, Guido Sebastiani, Jonas Juan-Mateu, Olatz Villate, Laura Marroqui, Laurence Ladrière, Ksenya Tugay, Romano Regazzi, Marco Bugliani, Piero Marchetti, Francesco Dotta, Décio L Eizirik
Type 1 Diabetes is an autoimmune disease leading to beta cell destruction. MicroRNAs (miRNAs) are small non-coding RNAs that control gene expression and organ formation. They participate in the pathogenesis of several autoimmune diseases, but the nature of miRNAs contributing to beta cell death in T1D and their target genes remain to be clarified.We performed a miRNA expression profile on human islet preparations exposed to the cytokines IL-1β+IFN-γ. Confirmation of miRNAs and target genes modification in human beta cells was performed by real-time qPCR...
October 13, 2016: Diabetes
https://www.readbyqxmd.com/read/27689871/functional-disparities-among-bcl-2-members-in-tonsillar-and-leukemic-b-cell-subsets-assessed-by-bh3-mimetic-profiling
#7
Victor Peperzak, Erik Slinger, Johanna Ter Burg, Eric Eldering
For successful treatment of malignant B-cells it is crucial to understand intrinsic survival requirements in relation to their normal progenitors. Long-lived humoral immunity as well as most B-cell malignancies, originate in the germinal center (GC). Murine GC B-cells depend on pro-survival protein MCL-1, but not BCL-XL. In contrast, naive and memory B-cells depend on BCL-2, but not BCL-XL or MCL-1. For human B-cell subsets, the functional relationships among BCL-2 members are unclear, and also if and how they shift after malignant transformation...
September 30, 2016: Cell Death and Differentiation
https://www.readbyqxmd.com/read/27599292/functionally-identifiable-apoptosis-insensitive-subpopulations-determine-chemoresistance-in-acute-myeloid-leukemia
#8
Patrick D Bhola, Brenton G Mar, R Coleman Lindsley, Jeremy A Ryan, Leah J Hogdal, Thanh Trang Vo, Daniel J DeAngelo, Ilene Galinsky, Benjamin L Ebert, Anthony Letai
Upfront resistance to chemotherapy and relapse following remission are critical problems in leukemia that are generally attributed to subpopulations of chemoresistant tumor cells. There are, however, limited means for prospectively identifying these subpopulations, which hinders an understanding of therapeutic resistance. BH3 profiling is a functional single-cell analysis using synthetic BCL-2 BH3 domain-like peptides that measures mitochondrial apoptotic sensitivity or "priming." Here, we observed that the extent of apoptotic priming is heterogeneous within multiple cancer cell lines and is not the result of experimental noise...
October 3, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27520294/efficacy-and-biological-correlates-of-response-in-a-phase-ii-study-of-venetoclax-monotherapy-in-patients-with-acute-myelogenous-leukemia
#9
Marina Konopleva, Daniel A Pollyea, Jalaja Potluri, Brenda Chyla, Leah Hogdal, Todd Busman, Evelyn McKeegan, Ahmed Hamed Salem, Ming Zhu, Justin L Ricker, William Blum, Courtney D DiNardo, Tapan Kadia, Martin Dunbar, Rachel Kirby, Nancy Falotico, Joel Leverson, Rod Humerickhouse, Mack Mabry, Richard Stone, Hagop Kantarjian, Anthony Letai
: We present a phase II, single-arm study evaluating 800 mg daily venetoclax, a highly selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) or unfit for intensive chemotherapy. Responses were evaluated following revised International Working Group (IWG) criteria. The overall response rate was 19%; an additional 19% of patients demonstrated antileukemic activity not meeting IWG criteria (partial bone marrow response and incomplete hematologic recovery)...
October 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27419047/a-comparative-proteomics-study-of-a-synovial-cell-line-stimulated-with-tnf-%C3%AE
#10
Seiji Shibasaki, Miki Karasaki, Shunsuke Aburaya, Hironobu Morisaka, Yumiko Takeda, Wataru Aoki, Sachie Kitano, Masayasu Kitano, Mitsuyoshi Ueda, Hajime Sano, Tsuyoshi Iwasaki
To elucidate the pathogenesis of rheumatoid arthritis (RA), we used proteomic analysis to determine the protein profile in a synovial cell line, MH7A, established from patients with RA. Proteins were extracted from MH7A cells that were or were not stimulated with tumor necrosis factor-α (TNF-α), and then analyzed on a liquid chromatography/mass spectrometry system equipped with a unique long monolithic silica capillary. On the basis of the results of this proteomic analysis, we identified 2650 proteins from untreated MH7A cells and 2688 proteins from MH7A cells stimulated with TNF-α...
May 2016: FEBS Open Bio
https://www.readbyqxmd.com/read/27340250/to-bh3-profile-or-not-to-bh3-profile
#11
Matthew D Blunt, Andrew J Steele
No abstract text is available yet for this article.
June 23, 2016: Blood
https://www.readbyqxmd.com/read/27314085/dynamic-bh3-profiling-poking-cancer-cells-with-a-stick
#12
Joan Montero, Anthony Letai
The vast majority of efforts in precision medicine for cancer try to link static genetic information to tumor biology and from there predict clinical response. Dynamic BH3 profiling offers an alternative functional approach by measuring death signaling induced by specific drugs in tumors from patients ex vivo to predict clinical response.
May 2016: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/27092880/complementary-dynamic-bh3-profiles-predict-co-operativity-between-the-multi-kinase-inhibitor-tg02-and-the-bh3-mimetic-abt-199-in-acute-myeloid-leukaemia-cells
#13
Monica Pallis, Francis Burrows, Jeremy Ryan, Martin Grundy, Claire Seedhouse, Amina Abdul-Aziz, Joan Montero, Anthony Letai, Nigel Russell
Direct co-operation between sensitiser molecules BAD and NOXA in mediating apoptosis suggests that therapeutic agents which sensitise to BAD may complement agents which sensitise to NOXA. Dynamic BH3 profiling is a novel methodology that we have applied to the measurement of complementarity between sensitiser BH3 peptide mimetics and therapeutic agents. Using dynamic BH3 profiling, we show that the agent TG02, which downregulates MCL-1, sensitises to the BCL-2-inhibitory BAD-BH3 peptide, whereas the BCL-2 antagonist ABT-199 sensitises to MCL-1 inhibitory NOXA-BH3 peptide in acute myeloid leukaemia (AML) cells...
April 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27069256/the-bcl2-selective-inhibitor-venetoclax-induces-rapid-onset-apoptosis-of-cll-cells-in-patients-via-a-tp53-independent-mechanism
#14
Mary Ann Anderson, Jing Deng, John F Seymour, Constantine Tam, Su Young Kim, Joshua Fein, Lijian Yu, Jennifer R Brown, David Westerman, Eric G Si, Ian J Majewski, David Segal, Sari L Heitner 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...
June 23, 2016: Blood
https://www.readbyqxmd.com/read/26954718/bh3-profiling-and-a-toolkit-of-bh3-mimetic-drugs-predict-anti-apoptotic-dependence-of-cancer-cells
#15
Michael Butterworth, Andrew Pettitt, Shankar Varadarajan, Gerald M Cohen
BACKGROUND: Anti-apoptotic BCL-2 family members antagonise apoptosis by sequestering their pro-apoptotic counterparts. The balance between the different BCL-2 family members forms the basis of BH3 profiling, a peptide-based technique used to predict chemosensitivity of cancer cells. Recent identification of cell-permeable, selective inhibitors of BCL-2, BCL-XL and MCL-1, further facilitates the determination of the BCL-2 family dependency of cancer cells. METHODS: We use BH3 profiling in combination with cell death analyses using a chemical inhibitor toolkit to assess chemosensitivity of cancer cells...
March 15, 2016: British Journal of Cancer
https://www.readbyqxmd.com/read/26910743/ibh3-simple-fixable-bh3-profiling-to-determine-apoptotic-priming-in-primary-tissue-by-flow-cytometry
#16
Jeremy Ryan, Joan Montero, James Rocco, Anthony Letai
Dysregulation of the mitochondrial pathway of apoptosis, controlled by the BCL-2 family of proteins, leads to disease states including cancer. Rapid analysis of a cell's dependency on the BCL-2 family of proteins is hindered by the complex interactions of more than a dozen proteins. Transcript or even protein levels are therefore generally insufficient to predict a cell's response to perturbations like chemotherapy. Previously, we developed the JC-1 BH3 method to provide a same day functional assay to assess a cell's propensity to undergo apoptosis and demonstrated its utility in predicting response to chemotherapy...
July 1, 2016: Biological Chemistry
https://www.readbyqxmd.com/read/26641257/differential-expression-of-bcl-2-family-proteins-determines-the-sensitivity-of-human-follicular-lymphoma-cells-to-dexamethasone-mediated-and-anti-bcr-mediated-apoptosis
#17
Jemal Adem, Antti Ropponen, Jonna Eeva, Mine Eray, Ulla Nuutinen, Jukka Pelkonen
Bcl-2 family comprises proapoptotic and antiapoptotic proteins. The balance between these proteins is critical for the survival of the cells. Overexpression of the antiapoptotic protein, Bcl-2, is the hallmark of follicular lymphoma (FL). High expression of Bcl-2 provides survival advantage and may facilitate chemotherapeutic resistance in FL. In the present study, we examined expression profile of Bcl-2 family proteins such as Bcl-2, Bcl-xL, and Bim in human FL cell lines, HF1A3 and HF28. We assessed the correlation between the expression levels of these proteins and cells' sensitivity to dexamethasone (Dex)-mediated and B-cell receptor (BCR)-mediated apoptosis...
January 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/26567361/bcl-2-antagonism-to-target-the-intrinsic-mitochondrial-pathway-of-apoptosis
#18
REVIEW
Christopher J Gibson, Matthew S Davids
Despite significant improvements in treatment, cure rates for many cancers remain suboptimal. The rise of cytotoxic chemotherapy has led to curative therapy for a subset of cancers, though intrinsic treatment resistance is difficult to predict for individual patients. The recent wave of molecularly targeted therapies has focused on druggable-activating mutations, and is thus limited to specific subsets of patients. The lessons learned from these two disparate approaches suggest the need for therapies that borrow aspects of both, targeting biologic properties of cancer that are at once distinct from normal cells and yet common enough to make the drugs widely applicable across a range of cancer subtypes...
November 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26493374/bcl-2-phosphorylation-confers-resistance-on-chronic-lymphocytic-leukaemia-cells-to-the-bh3-mimetics-abt-737-abt-263-and-abt-199-by-impeding-direct-binding
#19
Ting Song, Gaobo Chai, Yubo Liu, Xiaoyan Yu, Ziqian Wang, Zhichao Zhang
BACKGROUND AND PURPOSE: Although the ongoing clinical trials of ABT-263 and ABT-199 in chronic lymphocytic leukaemia (CLL) have indicated that BH3 mimetics hold considerable promise, understanding the mechanism of CLL resistance to BH3 mimetics remains a challenge. EXPERIMENTAL APPROACH: The LD50 values of ABT-737, ABT-263 and ABT-199 in a number of primary CLL cells from 40 patients, were determined. The levels of Bcl-2 family proteins, including phosphorylated Bcl-2 (pBcl-2) and their interactions were measured by immunoblotting and co-immunoprecipitation...
February 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/26486506/bak-is-a-predictive-and-prognostic-biomarker-for-the-therapeutic-effect-of-docetaxel-treatment-in-patients-with-advanced-gastric-cancer
#20
Tomohiro Kubo, Yutaka Kawano, Nobuaki Himuro, Shintaro Sugita, Yasushi Sato, Kazuma Ishikawa, Kohichi Takada, Kazuyuki Murase, Koji Miyanishi, Tsutomu Sato, Rishu Takimoto, Masayoshi Kobune, Takayuki Nobuoka, Koichi Hirata, Tetsuji Takayama, Mitsuru Mori, Tadashi Hasegawa, Junji Kato
BACKGROUND: Preoperative chemotherapy is a promising strategy for downstaging advanced gastric cancer before radical resection, although severe adverse events can occur and clinical outcomes are often unsatisfactory. To identify predictive biomarkers of drug sensitivity, we used a well-designed functional apoptosis assay and assessed the correlations between chemosensitivity and clinical outcomes. METHODS: Drug sensitivity to docetaxel, cisplatin, and 5-fluorouracil was examined in 11 gastric cancer cell lines...
July 2016: Gastric Cancer
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