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Genomic and epigenomic predictors of response to Guadecitabine in relapsed/refractory Acute Myelogenous Leukemia

ABSTRACT: Genomic and epigenomic predictors of response to Guadecitabine in relapsed/refractory Acute Myelogenous Leukemia

PROVIDER: PRJNA449238 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6963600_1.fastq.gz	Fastqsanger.gz
	SRR6963600_2.fastq.gz	Fastqsanger.gz
	SRR6963610_1.fastq.gz	Fastqsanger.gz
	SRR6963610_2.fastq.gz	Fastqsanger.gz
	SRR6963620_1.fastq.gz	Fastqsanger.gz

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Genomic and epigenomic predictors of response to Guadecitabine in relapsed/refractory Acute Myelogenous Leukemia

Project description:Guadecitabine is a second generation DNA methylation inhibitor with improved pharmacokinetics and clinical activity in relapsed/refractory AML (rrAML). Here we report genome-wide DNA methylation profiles in pre-treatment samples from 116 rrAML patients treated at therapeutic doses of guadecitabine in a phase I/II study. Response rate to guadecitabine was 22 % (16CR, 42 12CRi/CRp). There were no strong mutation or methylation predictors of response. Gene expression defined a subset of patients (~20%) that had (i) high DNMT3B and low CDKN2B, CTCF and CDA expression, (ii) enrichment for KRAS/NRAS mutations, (iii) frequent CpG island hypermethylation (iv) low LINE1 hypomethylation after treatment and (v) resistance to guadecitabine in both phase I (response rate 0 % vs 33 %, p=0.07) and phase II components of the study (response rate 5 % vs. 30 %, p=0.02). Multivariate analysis identified peripheral blood blasts and hemoglobin as predictors of response and cytogenetics, gene expression, RAS mutations and hemoglobin as predictors of survival. Thus, a subset of patients (∿ 20%) with rrAML are unlikely to benefit from single agent guadecitabine. In the remaining 80%, guadecitabine is a viable option with a median survival of ∿ 8 months and a three year survival rate of over 20%.

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Genomic and epigenomic predictors of response to guadecitabine in relapsed/refractory acute myelogenous leukemia.

Project description:BACKGROUND:Guadecitabine is a novel DNA methyltransferase (DNMT) inhibitor with improved pharmacokinetics and clinical activity in a subset of patients with relapsed/refractory acute myeloid leukemia (r/r AML), but identification of this subset remains difficult. METHODS:To search for biomarkers of response, we measured genome-wide DNA methylation, mutations of 54 genes, and expression of a panel of 7 genes in pre-treatment samples from 128 patients treated at therapeutic doses in a phase I/II study. RESULTS:Response rate to guadecitabine was 17% (2 complete remission (CR), 3 CR with incomplete blood count recovery (CRi), or CR with incomplete platelets recovery (CRp)) in the phase I component and 23% (14 CR, 9 CRi/CRp) in phase II. There were no strong mutation or methylation predictors of response. Gene expression clustering defined a subset of patients (~?20%) that had (i) high DNMT3B and low CDKN2B, CTCF, and CDA expression; (ii) enrichment for KRAS/NRAS mutations; (iii) frequent CpG island hypermethylation; (iv) low long interspersed nuclear element 1 (LINE-1) hypomethylation after treatment; and (v) resistance to guadecitabine in both phase I (response rate 0% vs. 33%, p?=?0.07) and phase II components of the study (response rate 5% vs. 30%, p?=?0.02). Multivariate analysis identified peripheral blood (PB) blasts and hemoglobin as predictors of response and cytogenetics, gene expression, RAS mutations, and hemoglobin as predictors of survival. CONCLUSIONS:A subset of patients (~?20%) with r/r AML is unlikely to benefit from guadecitabine as a single agent. In the remaining 80%, guadecitabine is a viable option with a median survival of 8?months and a 2-year survival rate of 21%. TRIAL REGISTRATION:NCT01261312 .

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Project description:Germ cell tumors (GCTs) can be cured with cisplatin-based therapy, although a clinically significant number of patents are refractory and die of progressive disease. Based on preclinical studies indicating that refractory testicular GCTs are hypersensitive to hypomethylating agents (HMA), we conducted a phase I trial [NCT02429466] of the next-generation HMA guadecitabine (SGI-110) in combination with cisplatin in patients with recurrent, cisplatin-resistant GCTs. The primary endpoint was safety and toxicity including DLT and MTD. A total of 14 patients were enrolled. The majority of patients were heavily pretreated. MTD was determined to be 30 mg/m2 guadecitabine followed by cisplatin 100 mg/m2. DLTs were neutropenia and thrombocytopenia. Three patients had partial responses by RECIST criteria, two of these patients qualified as complete responses by serum tumor marker criteria with survival of 16 and 26 months. Three patients also had stable disease for an overall response rate of 23% and clinical benefit rate of 46%. Genome-wide analysis pre- and post-guadecitabine indicated dramatic and widespread global DNA demethylation in cell-free plasma samples including in the promoters of genes of cancer related pathways. In summary, the combination of guadecitabine followed by cisplatin was tolerable and demonstrated biological activity in patients with platinum refractory GCTs.

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Chidamide triggers BTG1-mediated autophagy and reverses the chemotherapy resistance in the relapsed/refractory B cell lymphoma

Project description:Rituximab/chemotherapy relapsed and refractory B cell lymphoma patients have a poor overall prognosis, and it is urgent to develop novel drugs for improving the therapies of these patients. A new oral histone deacetylase inhibitor, chidamide shows anti-tumor activity by activating the pro-apoptosis pathway in some other hematological malignancies, suggesting its potential application to the relapsed and refractory B cell lymphoma. In this study, we examined the therapeutic effects of chidamide on the cell and mouse models of the rituximab/chemotherapy resistant B cell lymphoma, as well as the primary B cell lymphoma cells. In Raji-4RH and RL-4RH cells, the rituximab/chemotherapy resistant B cell lymphoma cell lines (RRCL), chidamide treatment induced growth inhibition and G0/G1 cell cycle arrest, which were associated with E2F1/2 inactivation and CDK2 degradation. The primary B cell lymphoma cells from Rituximab/chemotherapy relapsed and refractory patients were also very sensitive to chidamide treatment. Interestingly, chidamide triggered the cell death via the autophagy pathway instead of the activation of apoptosis in Raji-4RH and RL-4RH cells, likely due to the lack of the pro-apoptotic proteins in these resistant cells. In the RNA-seq and chromatin immunoprecipitation (ChIP) analysis, we identified BTG1 and FOXO1 as the direct target genes of chidamide, which control the autophagy and cell cycle respectively in RRCL treated with chidamide. Moreover, the combination of chidamide with the chemotherapy drug Cisplatin sensitized the RRCL to growth inhibition in a synergistic manner. Chidamide-Cisplatin combination significantly reduced the tumor burden of a mouse lymphoma model established with engraftment of RRCL. Taken together, our studies provides a theoretic and mechanistic basis for further evaluation of the chidamide-based clinical trial for rituximab/chemotherapy relapsed and refractory B cell lymphoma patients.

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