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https://www.readbyqxmd.com/read/28844952/targeting-cholangiocarcinoma
#1
REVIEW
Joachim C Mertens, Sumera Rizvi, Gregory J Gores
Cholangiocarcinoma (CCA) represents a diverse group of epithelial cancers associated with the biliary tract, and can best be stratified anatomically into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) subsets. Molecular profiling has identified genetic aberrations associated with these anatomic subsets. For example, IDH catalytic site mutations and constitutively active FGFR2 fusion genes are predominantly identified in iCCA, whereas KRAS mutations and PRKACB fusions genes are identified in pCCA and dCCA...
August 24, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28804127/discovery-of-novel-drug-sensitivities-in-t-pll-by-high-throughput-ex-vivo-drug-testing-and-mutation-profiling
#2
E I Andersson, S Pützer, B Yadav, O Dufva, S Khan, L He, L Sellner, A Schrader, G Crispatzu, M Oleś, H Zhang, S Adnan-Awad, S Lagström, D Bellanger, J P Mpindi, S Eldfors, T Pemovska, P Pietarinen, A Lauhio, K Tomska, C Cuesta-Mateos, E Faber, S Koschmieder, T H Brümmendorf, S Kytölä, E-R Savolainen, T Siitonen, P Ellonen, O Kallioniemi, K Wennerberg, W Ding, M-H Stern, W Huber, S Anders, J Tang, T Aittokallio, T Zenz, M Herling, S Mustjoki
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles...
August 14, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28802908/apoptosis-signaling-and-bcl-2-pathways-provide-opportunities-for-novel-targeted-therapeutic-strategies-in-hematologic-malignances
#3
REVIEW
Huanling Wu, L Jeffrey Medeiros, Ken H Young
Apoptosis is an essential biological process involved in tissue homeostasis and immunity. Aberrations of the two main apoptotic pathways, extrinsic and intrinsic, have been identified in hematological malignancies; many of these aberrations are associated with pathogenesis, prognosis and resistance to standard chemotherapeutic agents. Targeting components of the apoptotic pathways, especially the chief regulatory BCL-2 family in the intrinsic pathway, has proved to be a promising therapeutic approach for patients with hematological malignances, with the expectation of enhanced efficacy and reduced adverse events...
August 8, 2017: Blood Reviews
https://www.readbyqxmd.com/read/28799432/targeted-therapies-in-acute-myeloid-leukemia-a-focus-on-flt-3-inhibitors-and-abt199
#4
Kiran Naqvi, Marina Konopleva, Farhad Ravandi
Acute myeloid leukemia (AML) remains a therapeutic challenge. Despite ongoing research, the standard therapy for AML has not changed significantly in the past four decades. With the identification of cytogenetic and molecular abnormalities, several promising therapeutic agents are currently being investigated. FLT3 mutation is a well-recognized target seen in 30% of the cytogenetically normal AML. More recently, the BCL2 family of anti-apoptotic proteins have also generated great interest as a therapeutic target...
August 21, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28737741/rapidly-inducible-cas9-and-dsb-ddpcr-to-probe-editing-kinetics
#5
John C Rose, Jason J Stephany, William J Valente, Bridget M Trevillian, Ha V Dang, Jason H Bielas, Dustin J Maly, Douglas M Fowler
We developed a chemically inducible Cas9 (ciCas9) and a droplet digital PCR assay for double-strand breaks (DSB-ddPCR) to investigate the kinetics of Cas9-mediated generation and repair of DSBs in cells. ciCas9 is a rapidly activated, single-component Cas9 variant engineered by replacing the protein's REC2 domain with the BCL-xL protein and fusing an interacting BH3 peptide to the C terminus. ciCas9 can be tunably activated by a compound that disrupts the BCL-xL-BH3 interaction within minutes. DSB-ddPCR demonstrates time-resolved, highly quantitative, and targeted measurement of DSBs...
September 2017: Nature Methods
https://www.readbyqxmd.com/read/28724540/targeting-bcl-2-in-b-cell-lymphomas
#6
REVIEW
Matthew S Davids
The B-cell leukemia/lymphoma-2 (BCL-2) family of proteins governs the intrinsic pathway of mitochondrial apoptosis. Dysregulation of BCL-2 has long been known to be a crucial part of the pathophysiology of B-cell lymphomas; however, several early attempts to target this pathway therapeutically were unsuccessful because of toxicity, lack of efficacy, or both. Recently, a highly potent and selective oral BCL-2 antagonist, venetoclax, was approved in chronic lymphocytic leukemia, where it has proven to be highly active, even in patients with high-risk del(17p) disease...
August 31, 2017: Blood
https://www.readbyqxmd.com/read/28594323/epistatic-mutations-in-puma-bh3-drive-an-alternate-binding-mode-to-potently-and-selectively-inhibit-anti-apoptotic-bfl-1
#7
Justin M Jenson, Jeremy A Ryan, Robert A Grant, Anthony Letai, Amy E Keating
Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs...
June 8, 2017: ELife
https://www.readbyqxmd.com/read/28525842/indole-coumarin-thiadiazole-hybrids-an-appraisal-of-their-mcf-7%C3%A2-cell-growth-inhibition-apoptotic-antimetastatic-and-computational-bcl-2-binding-potential
#8
Pooja R Kamath, Dhanya Sunil, Manu M Joseph, Abdul Ajees Abdul Salam, Sreelekha T T
Cancer therapeutic potential of thiadiazole hybrids incorporating pharmacologically active indole and coumarin moieties have not been explored much. In the current investigation, three new thiadiazole hybrids with spacers of varying lengths linking indole and thiadiazole units were synthesized and their structures were well-established using various spectroscopic techniques. 3-(1-(5-(3-(1H-indol-3-yl)propyl)-1,3,4-thiadiazol-2-ylimino)ethyl)-6-bromo-2H-chromen-2-one (IPTBC) exhibited dose-dependent cytotoxicity in breast adenocarcinoma (MCF-7) cells...
May 11, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28511583/deciphering-the-crucial-residues-involved-in-heterodimerization-of-bak-peptide-and-anti-apoptotic-proteins-for-apoptosis
#9
Parthiban Marimuthu, Kalaimathy Singaravelu
B-cell lymphoma 2 (Bcl-2) family proteins are the central regulators of apoptosis, functioning via mitochondrial outer membrane permeabilization. The family members are involved in several stages of apoptosis regulation. The overexpression of the anti-apoptotic proteins leads to several cancer pathological conditions. This overexpression is modulated or inhibited by heterodimerization of pro-apoptotic BH3 domain or BH3-only peptides to the hydrophobic groove present at the surface of anti-apoptotic proteins...
June 2, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28469964/comprehensive-pharmacological-profiling-of-neurofibromatosis-cell-lines
#10
Jianman Guo, Michael R Grovola, Hong Xie, Grace E Coggins, Patrick Duggan, Rukhsana Hasan, Jiale Huang, Danny W Lin, Claire Song, Gabriela M Witek, Simon Berritt, David C Schultz, Jeffrey Field
Patients with Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2) are predisposed to tumors of the nervous system. NF1 patients predominantly develop neurofibromas, and Malignant Peripheral Nerve Sheath Tumors (MPNST) while NF2 patients develop schwannomas and meningiomas. Here we quantified the drug sensitivities of NF1 and NF2 tumor cell lines in a high throughput platform. The platform contained a comprehensive collection of inhibitors of MEK, RAF, RAS, farnesyl transferase, PAK and ERK, representative drugs against many other cancer pathways including Wnt, Hedgehog, p53, EGF, HDAC, as well as classical cytotoxic agents recommended for treating MPNST, such as doxorubicin and etoposide...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28439883/an-update-for-richter-syndrome-new-directions-and-developments
#11
REVIEW
Toby A Eyre, Anna Schuh
High-grade transformation of chronic lymphocytic leukaemia [Richter syndrome (RS)] is rare and represents a unique and uncommon clinical challenge. Clonally related diffuse large B cell type RS is a chemotherapy-resistant and devastating disease. Patients are typically elderly, immunosuppressed and present with a rapidly deteriorating performance status. Historical outcomes suggest a median overall survival of approximately 8 months. RS remains is an area of high unmet clinical need. The molecular profile and treatment needs of patients are likely to change over time with the advent of novel B cell receptor inhibitors, monoclonal antibodies and BH3 mimetics...
August 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28425914/epstein-barr-virus-ensures-b-cell-survival-by-uniquely-modulating-apoptosis-at-early-and-late-times-after-infection
#12
Alexander M Price, Joanne Dai, Quentin Bazot, Luv Patel, Pavel A Nikitin, Reza Djavadian, Peter S Winter, Cristina A Salinas, Ashley Perkins Barry, Kris C Wood, Eric C Johannsen, Anthony Letai, Martin J Allday, Micah A Luftig
Latent Epstein-Barr virus (EBV) infection is causally linked to several human cancers. EBV expresses viral oncogenes that promote cell growth and inhibit the apoptotic response to uncontrolled proliferation. The EBV oncoprotein LMP1 constitutively activates NFκB and is critical for survival of EBV-immortalized B cells. However, during early infection EBV induces rapid B cell proliferation with low levels of LMP1 and little apoptosis. Therefore, we sought to define the mechanism of survival in the absence of LMP1/NFκB early after infection...
April 20, 2017: ELife
https://www.readbyqxmd.com/read/28401226/the-charge-transfer-limit-of-a-chemical-adduct-the-role-of-perturbation-on-external-potential
#13
Aabid Hamid, Atul Anand, Ram Kinkar Roy
Full profiles of the components (positive and negative) of density functional reactivity theory (DFRT) based stabilization energy with respect to the amount of charge transfer (ΔN) are investigated on three different Diels-Alder pairs and twelve different charge transfer complexes formed by BH3-NH3 and their derivatives. One interesting observation is that the stabilization energy is zero when the charge transfer (ΔN) is either zero (lower limit, L.L.) or two times (higher limit, H.L.) the charge transfer at equilibrium (i...
May 3, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28370955/supported-rhodium-catalysts-for-ammonia-borane-hydrolysis-dependence-of-the-catalytic-activity-on-the-highest-occupied-state-of-the-single-rhodium-atoms
#14
Liangbing Wang, Hongliang Li, Wenbo Zhang, Xiao Zhao, Jianxiang Qiu, Aowen Li, Xusheng Zheng, Zhenpeng Hu, Rui Si, Jie Zeng
Supported metal nanocrystals have exhibited remarkable catalytic performance in hydrogen generation reactions, which is influenced and even determined by their supports. Accordingly, it is of fundamental importance to determine the direct relationship between catalytic performance and metal-support interactions. Herein, we provide a quantitative profile for exploring metal-support interactions by considering the highest occupied state in single-atom catalysts. The catalyst studied consisted of isolated Rh atoms dispersed on the surface of VO2 nanorods...
March 30, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28279820/binding-affinity-of-pro-apoptotic-bh3-peptides-for-the-anti-apoptotic-mcl-1-and-a1-proteins-molecular-dynamics-simulations-of-mcl-1-and-a1-in-complex-with-six-different-bh3-peptides
#15
Vivek Modi, Ramasubbu Sankararamakrishnan
The anti-apoptotic members of Bcl-2 family of proteins bind to their pro-apoptotic counterparts to induce or prevent cell death.Based on the distinct binding profiles for specific pro-apoptotic BH3 peptides, the anti-apoptotic Bcl-2 proteins can be divided into at least two subclasses. The subclass that includes Bcl-XL binds strongly to Bad BH3 peptide while it has weak binding affinity for the second subclass of Bcl-2 proteins such as Mcl-1 and A1. Anti-apoptotic Bcl-2 proteins are considered to be attractive drug targets for anti-cancer drugs...
May 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28259821/inhibition-of-mapkinase-pathway-sensitizes-thyroid-cancer-cells-to-abt-737-induced-apoptosis
#16
Viswanath Gunda, Kristopher A Sarosiek, Eran Brauner, Yon Seon Kim, Salma Amin, Zhiheng Zhou, Antony Letai, Sareh Parangi
Bcl2 family proteins play an important role in the resistance of thyroid cancer cells to apoptosis induced by chemotherapeutic drugs and targeted therapies. BH3-profiling of seven fresh primary papillary thyroid cancer (PTC) tumors showed dependence for survival on Bcl-xL (2/7), Bcl2 (2/7), and Mcl-1 (2/7), while the majority of thyroid cell lines were mainly dependent on Bcl-xL. Targeting Bcl2 family proteins with the BH3 mimetic, ABT-737, while simultaneously inhibiting ERK pathway proteins with PLX4720 and PD325901 was shown to induce significantly high apoptosis in the majority of cell lines (8505c, SW1736, HTh7, BCPAP) and moderate apoptosis in the TPC-1 cell line...
June 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28187446/targeting-of-apoptotic-pathways-by-smac-or-bh3-mimetics-distinctly-sensitizes-paclitaxel-resistant-triple-negative-breast-cancer-cells
#17
Effrosini G Panayotopoulou, Anna-Katharina Müller, Melanie Börries, Hauke Busch, Guohong Hu, Sima Lev
Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC), and despite the good initial response, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines...
July 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28161988/therapeutic-inhibition-of-bcl-2-and-related-family-members
#18
REVIEW
Michelle A Levy, David F Claxton
BCL-2 proteins are key players in the balance of cell life and death. Their roles in the development and biology of cancer have been well established and continue to be investigated. Understanding the mechanisms by which these proteins regulate apoptosis has led to the development of small molecule targeted therapies that act to overcome the cell's ability to evade programmed cell death. Areas covered: The biology of the intrinsic apoptotic pathway is reviewed with attention to the varied roles of the anti-apoptotic members of the BCL-2 family...
March 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28140720/pathways-and-mechanisms-of-venetoclax-resistance
#19
Prithviraj Bose, Varsha Gandhi, Marina Konopleva
The approval of venetoclax, a 'BH3-mimetic' antagonist of the BCL-2 anti-apoptotic protein, for chronic lymphocytic leukemia represents a major milestone in translational apoptosis research. Venetoclax has already received 'breakthrough' designation for acute myeloid leukemia, and is being studied in many other tumor types. However, resistance to BCL-2 inhibitor monotherapy may rapidly ensue. Several studies have shown that the other two major anti-apoptotic BCL-2 family proteins, BCL-XL and MCL-1, are the main determinants of resistance to venetoclax...
September 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28119805/how-to-unleash-mitochondrial-apoptotic-blockades-to-kill-cancers
#20
REVIEW
Jing Deng
Apoptosis, especially the intrinsic mitochondrial cell death pathway, is regulated by the BCL-2 family of proteins. Defects in apoptotic machinery are one of the main mechanisms that cells employ to evade cell death and become cancerous. Targeting the apoptotic defects, either by direct inhibition of BCL-2 family proteins or through modulation of regulatory pathways, can restore cell sensitivity to cell death. This review will focus on the aspects of BCL-2 family proteins, their interactions with kinase pathways, and how novel targeted agents can help overcome the apoptotic blockades...
January 2017: Acta Pharmaceutica Sinica. B
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