ORCID Profile
0000-0003-4934-8887
Current Organisations
Wageningen University & Research
,
AstraZeneca
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Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476405
Abstract: Figure S2
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476390.V1
Abstract: Figure S7
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529392.V1
Abstract: AbstractPurpose: Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2–selective inhibitor, has had success in the clinic, another family member, Bcl-x sub L /sub , has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-x sub L /sub inhibitor that broadens the therapeutic activity while minimizing Bcl-x sub L /sub –mediated thrombocytopenia. Experimental Design: We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-x sub L /sub and assessed the activity against i in vitro /i cell lines, patient s les, and i in vivo /i models. We applied pharmacokinetic harmacodynamic (PK/PD) modeling to integrate our understanding of on-target activity of the dual inhibitor in tumors and platelets across dose levels and over time. Results: We discovered AZD4320, which has nanomolar affinity for Bcl-2 and Bcl-x sub L /sub , and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2– and Bcl-x sub L /sub –dependent hematologic cancer cell lines and enhanced activity in acute myeloid leukemia (AML) patient s les compared with the Bcl-2–selective agent venetoclax. A single intravenous bolus dose of AZD4320 induces tumor regression with transient thrombocytopenia, which recovers in less than a week, suggesting a clinical weekly schedule would enable targeting of Bcl-2/Bcl-x sub L /sub –dependent tumors without incurring dose-limiting thrombocytopenia. AZD4320 demonstrates monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models. Conclusions: AZD4320 is a potent molecule with manageable thrombocytopenia risk to explore the utility of a dual Bcl-2/Bcl-x sub L /sub inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins. /
Publisher: Springer Science and Business Media LLC
Date: 28-04-2015
DOI: 10.1038/NCOMMS7857
Abstract: While Amazonian forests are extraordinarily erse, the abundance of trees is skewed strongly towards relatively few ‘hyperdominant’ species. In addition to their ersity, Amazonian trees are a key component of the global carbon cycle, assimilating and storing more carbon than any other ecosystem on Earth. Here we ask, using a unique data set of 530 forest plots, if the functions of storing and producing woody carbon are concentrated in a small number of tree species, whether the most abundant species also dominate carbon cycling, and whether dominant species are characterized by specific functional traits. We find that dominance of forest function is even more concentrated in a few species than is dominance of tree abundance, with only ≈1% of Amazon tree species responsible for 50% of carbon storage and productivity. Although those species that contribute most to biomass and productivity are often abundant, species maximum size is also influential, while the identity and ranking of dominant species varies by function and by region.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476408
Abstract: Figure S11
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.IJPARA.2013.10.007
Abstract: Schistosomiasis japonica, caused by Schistosoma japonicum, is an important zoonotic disease in China, the Philippines and small pockets of Indonesia. In addition to infecting people, S. japonicum can infect over 40 species of wild and domestic animals which have varying impacts on human infection. It is now generally accepted that bovines, particularly water buffaloes, are the major reservoir for human infection in China as they are naturally infected with schistosomes and deposit more eggs into the environment than humans or any other animal host. This complicates control efforts and the economic burden associated with schistosomiasis morbidity and mortality has taken its toll on both human and livestock populations. Over the last 50years, the schistosomiasis control program in China has made great strides in reducing prevalence and morbidity, and the Chinese authorities now aim to eliminate the disease nationwide in the next decade. Current Chinese control strategies place particular importance on interventions targeting bovines including: praziquantel treatment, barrier farming to prevent grazing in transmission areas, their replacement with mechanized tractors and possible bovine vaccination. A number of studies have shown that in the period following S. japonicum infection, the worm burden drops sharply in water buffaloes and some other animal hosts such as pigs. This is due to a self-cure phenomenon whereby there is parasite clearance by both immune and non-immune factors. Here we review studies investigating the self-cure effect, paying particular attention to S. japonicum infection in water buffaloes, and discuss its potential impact on the future schistosomiasis control and elimination efforts in China. Further understanding of the mechanism of self-cure in water buffaloes could be important for future schistosome vaccine design and delivery.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476405.V1
Abstract: Figure S2
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476396.V1
Abstract: Figure S5
Publisher: Wiley
Date: 08-11-2018
DOI: 10.1111/GCB.14413
Publisher: Springer Science and Business Media LLC
Date: 03-2015
DOI: 10.1038/NATURE14283
Abstract: Atmospheric carbon dioxide records indicate that the land surface has acted as a strong global carbon sink over recent decades, with a substantial fraction of this sink probably located in the tropics, particularly in the Amazon. Nevertheless, it is unclear how the terrestrial carbon sink will evolve as climate and atmospheric composition continue to change. Here we analyse the historical evolution of the biomass dynamics of the Amazon rainforest over three decades using a distributed network of 321 plots. While this analysis confirms that Amazon forests have acted as a long-term net biomass sink, we find a long-term decreasing trend of carbon accumulation. Rates of net increase in above-ground biomass declined by one-third during the past decade compared to the 1990s. This is a consequence of growth rate increases levelling off recently, while biomass mortality persistently increased throughout, leading to a shortening of carbon residence times. Potential drivers for the mortality increase include greater climate variability, and feedbacks of faster growth on mortality, resulting in shortened tree longevity. The observed decline of the Amazon sink erges markedly from the recent increase in terrestrial carbon uptake at the global scale, and is contrary to expectations based on models.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476390
Abstract: Figure S7
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476393
Abstract: Figure S6
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476411.V1
Abstract: Figure S10
Publisher: Springer Science and Business Media LLC
Date: 09-11-2020
DOI: 10.1038/S41467-020-18996-3
Abstract: The carbon sink capacity of tropical forests is substantially affected by tree mortality. However, the main drivers of tropical tree death remain largely unknown. Here we present a pan-Amazonian assessment of how and why trees die, analysing over 120,000 trees representing 3800 species from 189 long-term RAINFOR forest plots. While tree mortality rates vary greatly Amazon-wide, on average trees are as likely to die standing as they are broken or uprooted—modes of death with different ecological consequences. Species-level growth rate is the single most important predictor of tree death in Amazonia, with faster-growing species being at higher risk. Within species, however, the slowest-growing trees are at greatest risk while the effect of tree size varies across the basin. In the driest Amazonian region species-level bioclimatic distributional patterns also predict the risk of death, suggesting that these forests are experiencing climatic conditions beyond their adaptative limits. These results provide not only a holistic pan-Amazonian picture of tree death but large-scale evidence for the overarching importance of the growth–survival trade-off in driving tropical tree mortality.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476384.V1
Abstract: Figure S9
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529392
Abstract: AbstractPurpose: Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2–selective inhibitor, has had success in the clinic, another family member, Bcl-x sub L /sub , has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-x sub L /sub inhibitor that broadens the therapeutic activity while minimizing Bcl-x sub L /sub –mediated thrombocytopenia. Experimental Design: We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-x sub L /sub and assessed the activity against i in vitro /i cell lines, patient s les, and i in vivo /i models. We applied pharmacokinetic harmacodynamic (PK/PD) modeling to integrate our understanding of on-target activity of the dual inhibitor in tumors and platelets across dose levels and over time. Results: We discovered AZD4320, which has nanomolar affinity for Bcl-2 and Bcl-x sub L /sub , and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2– and Bcl-x sub L /sub –dependent hematologic cancer cell lines and enhanced activity in acute myeloid leukemia (AML) patient s les compared with the Bcl-2–selective agent venetoclax. A single intravenous bolus dose of AZD4320 induces tumor regression with transient thrombocytopenia, which recovers in less than a week, suggesting a clinical weekly schedule would enable targeting of Bcl-2/Bcl-x sub L /sub –dependent tumors without incurring dose-limiting thrombocytopenia. AZD4320 demonstrates monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models. Conclusions: AZD4320 is a potent molecule with manageable thrombocytopenia risk to explore the utility of a dual Bcl-2/Bcl-x sub L /sub inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476396
Abstract: Figure S5
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476399
Abstract: Figure S4
Publisher: Springer Science and Business Media LLC
Date: 04-01-2021
DOI: 10.1038/S41467-020-20537-X
Abstract: A Correction to this paper has been published: 0.1038/s41467-020-20537-x
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476411
Abstract: Figure S10
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476414
Abstract: Figure S1
Publisher: American Association for Cancer Research (AACR)
Date: 15-12-2020
DOI: 10.1158/1078-0432.CCR-20-0863
Abstract: Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2–selective inhibitor, has had success in the clinic, another family member, Bcl-xL, has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-xL inhibitor that broadens the therapeutic activity while minimizing Bcl-xL–mediated thrombocytopenia. We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-xL and assessed the activity against in vitro cell lines, patient s les, and in vivo models. We applied pharmacokinetic harmacodynamic (PK/PD) modeling to integrate our understanding of on-target activity of the dual inhibitor in tumors and platelets across dose levels and over time. We discovered AZD4320, which has nanomolar affinity for Bcl-2 and Bcl-xL, and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2– and Bcl-xL–dependent hematologic cancer cell lines and enhanced activity in acute myeloid leukemia (AML) patient s les compared with the Bcl-2–selective agent venetoclax. A single intravenous bolus dose of AZD4320 induces tumor regression with transient thrombocytopenia, which recovers in less than a week, suggesting a clinical weekly schedule would enable targeting of Bcl-2/Bcl-xL–dependent tumors without incurring dose-limiting thrombocytopenia. AZD4320 demonstrates monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models. AZD4320 is a potent molecule with manageable thrombocytopenia risk to explore the utility of a dual Bcl-2/Bcl-xL inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476387.V1
Abstract: Figure S8
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476402.V1
Abstract: Figure S3
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476393.V1
Abstract: Figure S6
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476399.V1
Abstract: Figure S4
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476381
Abstract: contains methods.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476408.V1
Abstract: Figure S11
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476384
Abstract: Figure S9
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476414.V1
Abstract: Figure S1
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476387
Abstract: Figure S8
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476381.V1
Abstract: contains methods.
Publisher: Springer Science and Business Media LLC
Date: 17-06-2019
DOI: 10.1038/S41467-019-09799-2
Abstract: The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for % of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476402
Abstract: Figure S3
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Elizabeth A. Coker.