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Study of CPI-0209 in patients with advanced tumors.

ABSTRACT: Study of CPI-0209 in patients with advanced tumors.

PROVIDER: PRJNA736432 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14768300_1.fastq.gz	Fastqsanger.gz
	SRR14768300_2.fastq.gz	Fastqsanger.gz
	SRR14768301_1.fastq.gz	Fastqsanger.gz
	SRR14768301_2.fastq.gz	Fastqsanger.gz
	SRR14768302_1.fastq.gz	Fastqsanger.gz

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Study of CPI-0209 in patients with advanced tumors.

Project description:Advanced bladder cancer remains a difficult cancer to treat, and for the majority of patients, current standard treatments ultimately prove ineffective. These tumors frequently harbor mutations in the BAF complex subunit ARID1A, which has been reported to confer sensitivity to EZH2 inhibition in several tumor types. Here we describe the generation of CPI-0209, a best-in-class, orally available EZH2 inhibitor. We show that mutant bladder cancer lines harboring ARID1A loss of function (LOF) mutations are preferentially sensitive to inhibition of EZH2. Treatment with CPI-0209 not only elicits a significant monotherapeutic response in ARID1A mutant models, it also outperforms cisplatin and improves response in chemo-resistant models. These findings shine light on new therapeutic opportunities for patients with advanced urothelial carcinoma.

2024-06-26 | GSE176490 | GEO

Epigenomic profile of bladder cancer cell line HT1376 treated with CPI-0209

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Transcriptomic change of bladder cancer cell lines treated with CPI-0209 [2]

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Epigenomic change of ARDI1A mutant bladder cancer cell line treated with CPI-0209 or induced ARID1A expression

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Transcriptomic change of ARDI1A mutant bladder cancer cell line treated with CPI-0209 or induced ARID1A expression

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Transcriptomic change of whole blood cells from mice treated with CPI-0209

Project description:Recurrent mutations in ARID1A occur frequently in advanced urothelial carcinoma, endometrial cancers and ovarian clear cell carcinoma, and may create an alternative chromatin state that can be exploited therapeutically. Previously, the histone methyltransferase EZH2 was identified as a targetable vulnerability in the context of ARID1A mutations. Here we describe the discovery of tulmimetostat (CPI-0209), a novel, orally available, clinical stage EZH2 inhibitor with remarkably long residence time and elucidate aspects of its application potential in ARID1A mutant tumors. Tulmimetostat administration as a single agent achieves in vivo efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improves cisplatin response in chemotherapy-resistant models. Consistent with its potency and the comprehensive and durable level of target coverage, tulmimetostat demonstrates greater efficacy than other PRC2-targeted inhibitors at comparable or lower exposures in a bladder cancer xenograft mouse model due to greater changes in gene expression and a profound reduction of H3K27me3 levels in the tumors. Importantly, we report the identification of a tulmimetostat controlled gene expression signature in whole blood from a cohort of 32 cancer patients, whereby the number of genes altered in expression as well as the magnitude of expression changes exquisitely correlate with tulmimetostat exposure, thus representing a novel pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, our data suggest tulmimetostat may unlock the full potential of EZH2 inhibition as a cancer therapeutic mechanism with potential applications in hematologic malignancies and in solid tumors, including in an ARID1A mutant setting.

2024-05-31 | GSE264383 | GEO

Epigenomic profile of bladder cancer cell line HT1376 treated with CPI-0209

Project description:Epigenomic profile of bladder cancer cell line HT1376 treated with CPI-0209

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Transcriptomic change of whole blood cells from mice treated with CPI-0209

Project description:Transcriptomic change of whole blood cells from mice treated with CPI-0209

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Transcriptomic change of bladder cancer cell lines treated with CPI-0209 [2]

Project description:Transcriptomic change of bladder cancer cell lines treated with CPI-0209 [2]

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Xenograft of bladder cancer cell line HT1376 were treated with or without EZH2 inhibitors before subject to RNA-seq

2024-06-26 | GSE176485 | GEO