Translational Modeling of Drug-Induced Myelosuppression and Effect of Pretreatment Myelosuppression for AZD5153, a Selective BRD4 Inhibitor

Collins, Teresa; Hattersley, Maureen M.; Yates, James; Clark, Edwin; Mondal, Madhu; Mettetal, Jerome

doi:10.1002/psp4.12194

Cited by 21 publications

(48 citation statements)

References 32 publications

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“…2 describes the drug effect as independent of any feedback mechanism activated by perturbations, which improves the computational tractability of our model when compared with previous approaches. 17,31 Under these assumptions, our model explained the lack of synchronicity between free platinum plasma kinetics (Figures 3 and S1) and the depletion of bone marrow populations previously described.…”

Section: Qsp Model For Haematotoxicitymentioning

confidence: 60%

“…Moreover, Eq. describes the drug effect as independent of any feedback mechanism activated by perturbations, which improves the computational tractability of our model when compared with previous approaches …”

Section: Resultsmentioning

confidence: 89%

“…Although extrapolation beyond the observed data must always be undertaken with caution, our multidisciplinary approach can be easily adapted to model the impact of other drugs on patients’ bone marrow, where the sampling of such cells is rarely feasible. Likewise, bone marrow disease models, such as for acute myeloid leukemia, can be straightforwardly built on our theoretical framework to provide prospective clinical predictions for different patient populations.…”

Section: Discussionmentioning

confidence: 99%

“…sampling of such cells is rarely feasible. Likewise, bone marrow disease models, such as for acute myeloid leukemia, 31 can be straightforwardly built on our theoretical framework to provide prospective clinical predictions for different patient populations. Altogether, our quantitative systems toxicology approach enables the investigation of the effects of compounds and combinations, with substantial potential to explore new schedules and inform drug-induced effects in man, prior to the initiation of clinical trials.…”

Section: (B) (A) (C)mentioning

confidence: 99%

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Quantifying Drug‐Induced Bone Marrow Toxicity Using a Novel Haematopoiesis Systems Pharmacology Model

Fornari

O’Connor

et al. 2019

CPT Pharmacom & Syst Pharma

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Haematological toxicity associated with cancer therapeutics is monitored by changes in blood cell count, and their primary effect is on proliferative progenitors in the bone marrow. Using observations in rat bone marrow and blood, we characterize a mathematical model that comprises cell proliferation and differentiation of the full haematopoietic phylogeny, with interacting feedback loops between lineages in homeostasis as well as following carboplatin exposure. We accurately predicted the temporal dynamics of several mature cell types related to carboplatin‐induced bone marrow toxicity and identified novel insights into haematopoiesis. Our model confirms a significant degree of plasticity within bone marrow cells, with the number and type of both early progenitors and circulating cells affecting cell balance, via feedback mechanisms, through fate decisions of the multipotent progenitors. We also demonstrated cross‐species translation of our predictions to patients, applying the same core model structure and considering differences in drug‐dependent and physiology‐dependent parameters.

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Section: Qsp Model For Haematotoxicitymentioning

confidence: 60%

Section: Resultsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: (B) (A) (C)mentioning

confidence: 99%

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Quantifying Drug‐Induced Bone Marrow Toxicity Using a Novel Haematopoiesis Systems Pharmacology Model

Fornari

O’Connor

et al. 2019

CPT Pharmacom & Syst Pharma

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“…Recent studies have proposed BRD4 as an important oncotarget protein for prostate cancer [12][13][14]. Here, we show that AZD5153, a novel bivalent BRD4 inhibitor [21][22][23], inhibited survival and proliferation of established (PC-3 and LNCaP lines) and primary human prostate cancer cells. Further, AZD5153 induced apoptosis activation and cell cycle arrest in prostate cancer cells.…”

Section: Discussionmentioning

confidence: 99%

AZD5153 Inhibits Prostate Cancer Cell Growth in Vitro and in Vivo

Shen¹,

Chen²,

Zhou³

et al. 2018

Cell Physiol Biochem

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Backgrounds/Aims: Bromodomain-containing protein 4 (BRD4) overexpression participates in prostate cancer progression by enhancing the transcriptional activity and expression of several key oncogenes. AZD5153 is a novel BRD4 inhibitor. Methods: Prostate cancer cells were treated with AZD5153. Cell survival was tested by MTT assay and clonogenicity assay. Cell proliferation was tested by [H³] DNA incorporation assay. Cell apoptosis was tested by caspase-3/-9 activity assay, Histone DNA ELISA assay, Annexin V FACS assay and TUNEL staining assay. Cell cycle progression was tested by propidium iodide (PI) FACS assay. Signaling was tested by Western blotting assay. The nude mice PC-3 xenograft model was applied to test AZD5153’s activity in vivo. Results: AZD5153 inhibited proliferation and survival of established and primary prostate cancer cells. AZD5153 induced apoptosis activation and cell cycle arrest in prostate cancer cells. AZD5153 was non-cytotoxic to the prostate epithelial cells. AZD5153 downregulated BRD4 targets (cyclin D1, Myc, Bcl-2, FOSL1 and CDK4) in PC-3 and primary prostate cancer cells. Further studies show that AKT could be the primary resistance factor of AZD5153. Pharmacological inhibition or genetic depletion of AKT induced BRD4 downregulation, sensitizing AZD5153-induced cytotoxicity in PC-3 cells. In vivo, AZD5153 oral administration inhibited PC-3 xenograft tumor growth in nude mice. Its anti-tumor activity was further enhanced with co-treatment of the AKT specific inhibitor MK-2206. Conclusion: Together, our results indicate a promising therapeutic value of the novel BRD4 inhibitor AZD5153 against prostate cancer cells.

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Genetic variations in relation to bleeding and pharmacodynamics of dabigatran in Chinese patients with nonvalvular atrial fibrillation: A nationwide multicentre prospective cohort study

Xiang

Xie

Liu

et al. 2022

Clinical & Translational Med

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Introduction To identify the potential factors responsible for the individual variability of dabigatran, we investigated the genetic variations associated with clinical outcomes and pharmacodynamics (PD) in Chinese patients with nonvalvular atrial fibrillation (NVAF). Materials and methods Chinese patients with NVAF taking dabigatran etexilate with therapeutic doses were enrolled. The primary (bleeding events) and secondary (thromboembolic and major adverse cardiac events) outcomes for a 2‐year follow‐up were evaluated. Peak and trough PD parameters (anti‐FIIa activity, activated partial thromboplastin time and prothrombin time) were detected. Whole‐exome sequencing, genome‐wide sequencing and candidate gene association analyses were performed. Results There were 170 patients with NVAF treated with dabigatran (110 mg twice daily) who were finally included. Two single‐nucleotide polymorphisms (SNPs) were significantly related with bleeding, which include UBASH3B rs2276408 (odds ratio [OR] = 8.79, 95% confidence interval [CI]: 2.99–25.83, p = 7.77 × 10−5 at sixth month visit) and FBN2 rs3805625 (OR = 8.29, 95% CI: 2.87–23.89, p = 9.08 × 10−5 at 12th month visit), as well as with increased trends at other visits (p < .05). Furthermore, minor allele carriers of 16 new SNPs increased PD levels, and those of one new SNP decreased PD values (p < 1.0 × 10−5). Lastly, 33 new SNPs were found to be associated with bleeding and PD among 14 candidate genes. Unfortunately, the low number of secondary outcomes precluded further association analyses. Conclusions Genetic variations indeed affected bleeding and PD in Chinese patients with NVAF treated with dabigatran. The functions of these suggestive genes and SNPs might further be explored and verified in more in vivo and in vitro investigations.

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Translational Modeling of Drug-Induced Myelosuppression and Effect of Pretreatment Myelosuppression for AZD5153, a Selective BRD4 Inhibitor

Cited by 21 publications

References 32 publications

Quantifying Drug‐Induced Bone Marrow Toxicity Using a Novel Haematopoiesis Systems Pharmacology Model

Quantifying Drug‐Induced Bone Marrow Toxicity Using a Novel Haematopoiesis Systems Pharmacology Model

AZD5153 Inhibits Prostate Cancer Cell Growth in Vitro and in Vivo

Genetic variations in relation to bleeding and pharmacodynamics of dabigatran in Chinese patients with nonvalvular atrial fibrillation: A nationwide multicentre prospective cohort study

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