Publications by authors named "Wanhua Zhang"

14 Publications

  • Page 1 of 1

Discovery of a Series of Hydroxamic Acid-Based Microtubule Destabilizing Agents with Potent Antitumor Activity.

J Med Chem 2021 10 14;64(20):15379-15401. Epub 2021 Oct 14.

State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China.

Hydroxamic acid group is one of the characteristic pharmacophores of histone deacetylase (HDAC) inhibitors. But here, we discovered a series of hydroxamic acid-based microtubule destabilizing agents (MDAs), which were derived from shortening the length of the linker in HDAC6 inhibitor SKLB-23bb. Interestingly, the low nanomolar antiproliferative activity of these MDAs depended on the presence of hydroxamic acid groups, but their inhibitory effects on HDAC were lost. Among them, showed favorable metabolism stability, high bioavailability, and potent antitumor activity in multidrug-resistant cell lines and A2780/T xenograft model. More importantly, in the patient-derived xenograft models of triple-negative breast cancer and osimertinib-resistant non-small-cell lung cancer, both 20 mg/kg oral and 10 mg/kg intravenous administration of could induce more than 70% tumor inhibition without obvious toxicity. Overall, we discovered that , as a novel MDA based on hydroxamic acid, could serve as a potential MDA for further investigation.
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http://dx.doi.org/10.1021/acs.jmedchem.1c01451DOI Listing
October 2021

Association of minimal residual disease with clinical outcomes in Philadelphia chromosome positive acute lymphoblastic leukemia in the tyrosine kinase inhibitor era: A systemic literature review and meta-analysis.

PLoS One 2021 26;16(8):e0256801. Epub 2021 Aug 26.

West China School of Medicine, Sichuan University, Chengdu, Sichuan Province, China.

Minimal residual disease (MRD) appeared to be a potent prognostic indicator in patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), with potential value in informing individualized treatment decisions. Hence, we performed herein a systemic literature review and meta-analysis to comprehensively address the prognostic value of MRD in Ph+ ALL. Systematic literature review was conducted in PubMed, Embase, and Cochrane databases with the data access date up to September 23, 2020. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Furthermore, subgroup analyses were performed to assess the robustness of the associations. 27 studies with a total number of 3289 patients were eligible for this meta-analysis. Combined HRs suggested that MRD positivity was associated with inferior event-free survival (EFS) (HR = 2.00, 95% CI 1.77-2.26) and overall survival (OS) (HR = 2.34, 95% CI 1.86-2.95). The associations remained statistically significant in subgroup analyses including age group, MRD timing, disease status at MRD, MRD cutoff level, et al. Our findings suggested MRD as a potent clinical tool for assessing the prognosis of Ph+ ALL. Further studies using MRD-based risk stratification might help optimize individualized treatment strategies for Ph+ ALL patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256801PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389458PMC
August 2021

Role of BCR-ABL1 isoforms on the prognosis of Philadelphia chromosome positive acute lymphoblastic leukemia in the tyrosine kinase inhibitor era: A meta-analysis.

PLoS One 2020 18;15(12):e0243657. Epub 2020 Dec 18.

Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.

BCR-ABL1 fusion gene is the driver mutation of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Although the prognostic value of BCR-ABL1 isoforms in Ph+ ALL patients has been investigated in numerous studies in the tyrosine kinase inhibitor (TKI) era, the results were still conflicting. Hence we performed herein the meta-analysis to comprehensively assess the impact of BCR-ABL1 isoforms on the clinical outcomes of Ph+ ALL patients. Systematic literature review was conducted in PubMed, Embase, and Cochrane databases with the data access date up to June 15, 2020. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Furthermore, subgroup analyses were performed to assess the robustness of the associations. Nine studies with a total number of 1582 patients were eligible for this meta-analysis. Combined HRs suggested that p210 was slightly associated with inferior event-free survival (EFS) (HR = 1.34, 95% CI 1.05-1.72). The overall survival (OS) was not significantly affected (HR = 1.15, 95% CI 0.92-1.45). In subgroup analyses, the HRs showed a trend toward adverse impact of p210 on clinical outcomes. However, the confidence intervals were not crossing the null value only in a minority of subgroups including Caucasian studies, first-generation TKI treated cohort and transplant cohort. Our findings suggested that p210 might pose a mild adverse impact on the EFS of Ph+ ALL patients. This effect might be compromised by the use of second- or third-generation TKIs. Further studies are needed to verify our conclusions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243657PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748129PMC
February 2021

Validations of Top and Novel Susceptibility Variants in All-Age Chinese Patients With Acute Lymphoblastic Leukemia.

Front Genet 2020 25;11:1004. Epub 2020 Aug 25.

Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pediatric Hematology/Oncology, West China Second Hospital, Sichuan University, Ministry of Education, Chengdu, China.

Through genome-wide association studies (GWAS), multiple inherited predispositions to acute lymphoblastic leukemia (ALL) have been identified in children. Most recently, a novel susceptibility locus at was localized, exhibiting Hispanic-specific manner. In this study, we conducted a replication study to in all-age Chinese patients ( = 451), not only validating the novel locus, but also systematically determining the impact of age on association status of the top GWAS signals. We found that single nucleotide polymorphisms at , , , were only significantly associated with ALL susceptibility in childhood patients with no fusion, while signal exhibited its significance in adults no matter carrying fusion or not. Moreover, the novel SNP can be validated in pediatric patients without both and fusion. Our finding suggests the modifying effects of age on genetic predisposition to ALL, and highlights the impact of SNP in Chinese patients.
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http://dx.doi.org/10.3389/fgene.2020.01004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477633PMC
August 2020

Discovery of 1,2,4-oxadiazole-Containing hydroxamic acid derivatives as histone deacetylase inhibitors potential application in cancer therapy.

Eur J Med Chem 2019 Sep 3;178:116-130. Epub 2019 Jun 3.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. Electronic address:

In this study, a series of novel HDAC inhibitors, using 1,2,4-oxadiazole-containing as the cap group, were synthesized and evaluated in vitro. Compound 14b, N-hydroxy-2-(methyl((3-(1-(4-methylbenzyl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methyl)amino)pyrimidine-5-carboxamide, displayed the most potent histone deacetylase (HDAC) inhibition, especially against HDAC1, 2, and 3 with IC values of 1.8, 3.6 and 3.0 nM, respectively. In vitro antiproliferative studies confirmed that 14b was more potent than SAHA, with IC values against 12 types of cancer cell lines ranging from 9.8 to 44.9 nM. The results of Western blot assays showed that compound 14b can significantly up-regulate the acetylation of the biomarker his-H and molecular docking analyses revealed the mode of action of compound 14b against HDAC1. The results of flow-cytometry analysis suggested that compound 14b induces cell cycle arrest at the G1 phase and has apoptotic effects. Further investigation of the activity of 14b on the primary cells of three patients, showed IC values of 21.3, 61.1, and 77.4 nM. More importantly, an oral bioavailability of up to 53.52% was observed for 14b. An in vivo pharmacodynamic evaluation demonstrated that compound 14b can significantly inhibit tumor growth in a Daudi Burkitt's lymphoma xenograft model, with tumor inhibition rates of 53.8 and 46.1% observed at 20 and 10 mg/kg when administered p.o. and i.v., respectively. These results indicate that compound 14b may be a suitable lead for further evaluation and development as an HDAC inhibitor and a potent anticancer agent.
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http://dx.doi.org/10.1016/j.ejmech.2019.05.089DOI Listing
September 2019

Identification of Pyrrolo[2,3- d]pyrimidine-Based Derivatives as Potent and Orally Effective Fms-like Tyrosine Receptor Kinase 3 (FLT3) Inhibitors for Treating Acute Myelogenous Leukemia.

J Med Chem 2019 04 15;62(8):4158-4173. Epub 2019 Apr 15.

A series of pyrrolo[2,3- d]pyrimidine derivatives were prepared and optimized for cytotoxic activities against FLT3-ITD mutant cancer cells. Among them, compound 9u possessed nanomolar FLT3 inhibitory activities and subnanomolar inhibitory activities against MV4-11 and Molm-13 cells. It also showed excellent inhibitory activities in FLT3-ITD-D835V and FLT3-ITD-F691L cells which were resistant to quizartinib. Furthermore, 9u exhibited over 40-fold selectivity toward FLT3 relative to c-Kit kinase, which might reduce myelosuppression toxicity. Cellular assays demonstrated that 9u inhibited phosphorylated FLT3 and downstream signaling factors and also induced cell cycle arrest in the G/G stage and apoptosis in MV4-11 and Molm-13 cells. Oral administration of 9u at 10 mg/kg could achieve rapid tumor extinction in the MV4-11 xenograft model and significantly inhibit the tumor growth in the MOLM-13 xenograft model with a tumor growth inhibitory rate of 96% without obvious toxicity. Additionally, 9u demonstrated high bioavailability ( F = 59.5%) and suitable eliminated half-life time ( T = 2.06 h), suggesting that 9u may be a potent candidate for treating acute myelogenous leukemia.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00223DOI Listing
April 2019

Regulatory Network and Prognostic Effect Investigation of PIP4K2A in Leukemia and Solid Cancers.

Front Genet 2018 15;9:721. Epub 2019 Jan 15.

Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

Germline variants of impact susceptibility of acute lymphoblastic leukemia (ALL) through inducing its overexpression. Although limited reports suggested the oncogenic role of in cancers, regulatory network and prognostic effect of this gene remains poorly understood in tumorigenesis and leukemogenesis. In this study, we conducted genome-wide gene expression association analyses in pediatric B-ALL cohorts to discover expression associated genes and pathways, which is followed by the bioinformatics analyses to investigate the prognostic role of and its related genes in multiple cancer types. 214 candidates were identified to be significantly associated with expression in ALL patients, with known cancer-related genes rankings the top (e.g., , , and ). These candidates do not only tend to be clustered in the same types of leukemia, but can also separate the patients into novel molecular subtypes. is noticed to be frequently overexpressed in multiple other types of leukemia and solid cancers from cancer cohorts including TCGA, and associated with its candidates in subtype-specific and cancer-specific manners. Interestingly, the association status varied in tumors compared to their matched normal tissues. Moreover, and its related candidates exhibit stage-independent prognostic effects in multiple cancers, mostly with its lower expression significantly associated with longer overall survival ( < 0.05). Our findings reveal the transcriptional regulatory network of in leukemia, and suggest its potentially important role on molecular subtypes of multiple cancers and subsequent treatment outcomes.
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http://dx.doi.org/10.3389/fgene.2018.00721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341070PMC
January 2019

Discovery of Novel Dual Histone Deacetylase and Mammalian Target of Rapamycin Target Inhibitors as a Promising Strategy for Cancer Therapy.

J Med Chem 2019 02 24;62(3):1577-1592. Epub 2019 Jan 24.

In the present study, a series of novel dual-target histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) inhibitors were designed and synthesized using pyrimidine-pyrazolyl pharmacophore to append HDAC recognition cap and hydroxamic acid as a zinc-binding motif. Among them, 12l was the optimal lead compound with potent inhibition activities against mTOR and HDAC1 with half-maximal inhibitory concentration of 1.2 and 0.19 nM, respectively. Western blot confirmed that 12l could upregulate acetylation of H3 and α-tubulin and downregulate mTOR-related downstream mediators. 12l could also stimulate cell cycle arrest in G/G phase and induce tumor cell apoptosis. 12l showed comparable antitumor activity with the combination medication in MM1S xenograft model with a tumor growth inhibitory rate of 72.5%, without causing significant loss of body weight and toxicity. All of the results indicated that 12l could be a promising dual target inhibitor for treating hematologic malignancies.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01825DOI Listing
February 2019

Prognostic significance of CDKN2A/B deletions in acute lymphoblastic leukaemia: a meta-analysis.

Ann Med 2019 02 14;51(1):28-40. Epub 2019 Feb 14.

a Department of Haematology , West China Hospital, Sichuan University , Chengdu , P.R. China.

Background: Cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) genes are frequently altered in acute lymphoblastic leukaemia (ALL) patients. The aim of this meta-analysis was to comprehensively assess the prognostic value of CDKN2A/B deletions in ALL patients.

Methods: Systematic literature review was conducted in PubMed, Embase and Cochrane databases up to July 2018. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models.

Results: A total of thirteen studies including 2857 patients were eligible for this meta-analysis. Combined HRs suggested that CDKN2A/B deletions were poor prognostic factors for both overall survival (OS) (HR = 2.15, 95% CI 1.82-2.54) and event-free survival (EFS)/disease-free survival (DFS)/relapse-free survival (RFS) (HR = 2.16, 95% CI 1.73-2.69). The adverse impact remained significant in both adult and paediatric ALL patients, and also in subgroups by ethnicity, ALL type, detection method of CDKN2A/B deletions, statistical method and endpoint.

Conclusions: Our findings suggested that CDKN2A/B deletions were associated with poor prognosis independently in both adult and childhood ALL patients. Inclusion of CDKN2A/B status may further improve the risk stratification of ALL patients. Key Messages Although numerous studies have explored the prognostic significance of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions in acute lymphoblastic leukaemia (ALL) patients, the results remain conflicting. In this meta-analysis, we found that CDKN2A/B deletions were independent poor prognostic markers for both adult and paediatric ALL patients. Our findings justify the inclusion of CDKN2A/B status in the risk stratification of ALL patients.
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http://dx.doi.org/10.1080/07853890.2018.1564359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857473PMC
February 2019

Combination of IKZF1 deletion and early molecular response show significant roles on prognostic stratification in Philadelphia chromosome-positive acute lymphoblastic leukemia patients.

Leuk Lymphoma 2018 08 7;59(8):1890-1898. Epub 2017 Dec 7.

a Department of Hematology, Hematologic Research Laboratory , West China Hospital of Sichuan University , Chengdu , China.

We retrospectively analyzed the samples collected from 66 patients with PhALL enrolled on ChiCTR-TNRC-09000309 clinical trial. CR rate was 95.5%, and estimated 2-year OS and DFS were 51.7 ± 11.7% and 26.9 ± 11.6%, 3-year OS and DFS were 31.6 ± 12.0% and 23.4 ± 11.6%. By combining IKZF1 deletion and early molecular responses, we redefined the patients as low, intermediate, and high risk 3 groups separately. Patients with double negative in IKZF1 and early molecular response experienced significant superior survival, while patients with double positive would have the worst outcome, and patients who were one or the other with IKZF1 deletion or MRD status had intermediate outcome. Significant differences were found among 3 groups in regard to both OS (p < .001) and DFS (p < .001). Our findings suggest that PhALL is a heterogeneous group of diseases with significantly different prognosis. Combination of IKZF1 deletion and MRD status enable better risk stratification of patients for assignment to optimal therapeutic strategies.
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http://dx.doi.org/10.1080/10428194.2017.1406933DOI Listing
August 2018

Prognostic significance of IKZF1 deletion in adult B cell acute lymphoblastic leukemia: a meta-analysis.

Ann Hematol 2017 Feb 4;96(2):215-225. Epub 2016 Nov 4.

Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Guoxuexiang 37, Chengdu, 610041, People's Republic of China.

The IKAROS family zinc finger 1 (IKZF1) gene is frequently altered in adults with B cell acute lymphoblastic leukemia (ALL). Although many studies have indicated that IKZF1 alterations might be associated with poor outcomes in adults with ALL, the results remain controversial. A previous meta-analysis demonstrated the negative prognostic significance of IKZF1 deletion in ALL. However, most of the included studies (14 out of 15) were conducted in pediatric patients with ALL, and age was identified as a significant source of heterogeneity. Thus, performing the present meta-analysis provides valuable information to further elucidate the prognostic value of IKZF1 deletion in adults with ALL. Eight studies were identified that had been published prior to August 1, 2016. The studies included a total of 1008 patients. Hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival (OS) and disease-free survival (DFS)/relapse-free survival (RFS)/progression-free survival (PFS)/event-free survival (EFS) were pooled to estimate the prognostic power of IKZF1 deletion. Pooled HRs suggested that IKZF1 deletion had a negative impact on both OS (HR = 1.40, 95% CI 1.13-1.73) and DFS/RFS/PFS/EFS (HR = 1.67, 95% CI 1.28-2.17) in the overall population. Subgroup analyses indicated that IKZF1 deletion could independently predict unfavorable OS (HR = 1.60, 95% CI 1.25-2.06) and DFS/RFS/PFS/EFS (HR = 1.67, 95% CI 1.28-2.17) in BCR-ABL1-negative but not in BCR-ABL1-positive B cell ALL patients. Our meta-analysis suggests that IKZF1 deletion is a poor prognostic factor for adults with B cell ALL and may be more valuable in BCR-ABL1-negative B cell ALL patients.
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http://dx.doi.org/10.1007/s00277-016-2869-6DOI Listing
February 2017

The first case of acute T-cell lymphoblastic leukemia containing the e19a2 BCR-ABL1 transcript: a durable molecular response using imatinib-based chemotherapy.

Leuk Lymphoma 2017 05 5;58(5):1262-1264. Epub 2016 Oct 5.

a Department of Hematology and Hematology Research Laboratory , West China Hospital, Sichuan University , Chengdu , P.R. China.

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http://dx.doi.org/10.1080/10428194.2016.1235275DOI Listing
May 2017

Screening ABL1 kinase domain mutations in patients with de novo Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

Leuk Lymphoma 2017 04 23;58(4):1005-1007. Epub 2016 Sep 23.

c West China School of Medicine , Sichuan University , Chengdu , P.R. China.

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http://dx.doi.org/10.1080/10428194.2016.1225205DOI Listing
April 2017

Inhibitory effects of recombinant porcine interferon-α on high- and low-virulence porcine reproductive and respiratory syndrome viruses.

Res Vet Sci 2012 Oct 4;93(2):1060-5. Epub 2012 Jan 4.

Institute of Animal Science and Veterinary Medicine, Shanghai Academy of Agricultural Sciences, Shanghai 201106, China.

The inhibitory effects of recombinant porcine interferon alpha (rPoIFN-α) on the propagation of low-virulence PRRSV (lvPRRSV) in MARC-145 cells, and on the progress and severity of high virulence PRRSV (hvPRRSV)-induced infections in pigs, were determined. Pre-treatment of MARC-145 cells with increasing concentrations of rPoIFN-α prior to infection with lvPRRSV decreased the observed cytopathic effects (CPEs) in a concentration-dependent manner. Viral propagation and antibody response were temporarily delayed in swine treated with rPoIFN-α either at the same time as the hvPRRSV challenge was administered or post-challenge. Exposure of challenged animals to rPoIFN-α after the onset of disease symptoms alleviated associated hyperthermia. Variations in lymphocyte subsets indicated that rPoIFN-α treatment might alleviate damage to the immune system or enhance propagation of host cytotoxic T-lymphocytes when the treatment was applied simultaneously with the virus or 1dpc, respectively.
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http://dx.doi.org/10.1016/j.rvsc.2011.12.006DOI Listing
October 2012
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