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Increased expression of p53 with APR-246 (eprenetapopt) reprograms tumor-associated macrophages to promote the efficacy of immune checkpoint blockade

ABSTRACT: Increased expression of p53 with APR-246 (eprenetapopt) reprograms tumor-associated macrophages to promote the efficacy of immune checkpoint blockade

PROVIDER: PRJNA701459 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13691958_1.fastq.gz	Fastqsanger.gz
	SRR13691958_2.fastq.gz	Fastqsanger.gz
	SRR13691959_1.fastq.gz	Fastqsanger.gz
	SRR13691959_2.fastq.gz	Fastqsanger.gz
	SRR13691960_1.fastq.gz	Fastqsanger.gz

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Increased expression of p53 with APR-246 (eprenetapopt) reprograms tumor-associated macrophages to promote the efficacy of immune checkpoint blockade

Project description:Expression of genes in sorted CD4, CD8 and non-T CD45 cells isolated from TME of B16 tumors in wildtype B6, APR-246 treated wildtype B6 and Super p53 mice.

2022-02-11 | GSE166637 | GEO

APR-246 enhances colorectal cancer sensitivity to radiotherapy

Project description:p53 mutation is common and highly related to radiotherapy resistance in rectal cancer. APR-246, as a small molecule, can restore the tumor-suppressor function to mutant p53. There is no study on combining APR-246 with radiation in rectal cancer; therefore, we examined whether APR-246 sensitized colorectal cancer cells with different p53 status to radiation. The combination treatment had synergistic effects on HCT116p53-R248W/-(p53Mut) cells, followed by HCT116p53+/+(p53WT) cells, and exhibited an additive effect on HCT116p53-/-(p53Null) cells through inhibiting proliferation, enhancing reactive oxygen species, and apoptosis. The results were confirmed in zebrafish xenografts. Comparison of the transcriptome in colorectal cancer cells with different p53 status 72hrs post-treatment with APR-246, irradiation, or the combination of APR-246 with irradiation was carried out. p53Mut and p53WT cells shared more activated pathways and differentially expressed genes following the combination treatment, compared to p53Null cells, although the combination treatment regulated individual pathways in the different cell lines. APR-246 mediated radio-sensitization effects through p53-dependent and -independent ways.

2023-05-12 | GSE232305 | GEO

Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype

Project description:Identification of ovarian cancer (OvCa) patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22 % of the high grade OvCa tumors at diagnosis express CIP2A oncoprotein at low levels. Further, regardless of their significantly lower likelihood of disease relapse after standard chemotherapy, a portion of relapsed tumors retain their CIP2A-deficient phenotype. Through a screen for therapeutics that would preferentially kill CIP2A-deficient OvCa cells, we identified reactive oxygen species inducer APR-246, tested previously in OvCa clinical trials. Consistent with CIP2A-deficient OvCa subtype in humans, CIP2A is dispensable for development of MISIIR-Tag-driven mouse OvCa tumors. Nevertheless, CIP2A null OvCa tumor cells from MISIIR-Tag mice displayed APR-246 hypersensitivity both in vitro and in vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the OvCa cells to APR-246 by inhibition of NF-kB activity. Accordingly, combination of APR-246 and NF-kB inhibitor compounds strongly synergized in killing of CIP2A positive OvCa cells. Collectively, the results warrant consideration of clinical testing of APR-246 for CIP2A-deficient OvCa tumor subtype patients. Results also reveal CIP2A as a candidate APR-246 combination therapy target for ovarian cancer.

2022-02-02 | GSE195984 | GEO

Variability in functional p53 reactivation by Prima-1Met/APR-246 in Ewing sarcoma

Project description:Though p53 mutations are rare in Ewing sarcoma, there is a strong indication that p53-mutant tumors form a particularly bad prognosis group. As such, novel treatment strategies are warranted that would specifically target and eradicate tumor cells containing mutant-p53 in this subset of ES patients. PRIMA-1Met/APR-246 is a small organic molecule which has been shown to restore tumor suppressor function primarily to mutant p53 and to also induce cell death in various cancer cell types. We analyzed the apoptosis inducibility on Ewing sarcoma cells harbouring different p53 mutations upon exposure to APR-246. Gene expression profiles of three STA-ET-7 cell lines established from the same patient at different stages of the disease was assessed by microarray analysis as these cell lines responded variably to APR-246.

2013-11-12 | E-GEOD-49967 | biostudies-arrayexpress

Increased p53 expression induced by APR-246 reprograms tumor-associated macrophages to augment immune checkpoint blockade.

Project description:In addition to playing a major role in tumor cell biology, p53 generates a microenvironment that promotes antitumor immune surveillance via tumor-associated macrophages. We examined whether increasing p53 signaling in the tumor microenvironment influences antitumor T cell immunity. Our findings indicate that increased p53 signaling induced either pharmacologically with APR-246 (eprenetapopt) or in p53-overexpressing transgenic mice can disinhibit antitumor T cell immunity and augment the efficacy of immune checkpoint blockade. We demonstrated that increased p53 expression in tumor-associated macrophages induces canonical p53-associated functions such as senescence and activation of a p53-dependent senescence-associated secretory phenotype. This was linked with decreased expression of proteins associated with M2 polarization by tumor-associated macrophages. Our preclinical data led to the development of a clinical trial in patients with solid tumors combining APR-246 with pembrolizumab. Biospecimens from select patients participating in this ongoing trial showed that there was a suppression of M2-polarized myeloid cells and increase in T cell proliferation with therapy in those who responded to the therapy. Our findings, based on both genetic and a small molecule-based pharmacological approach, suggest that increasing p53 expression in tumor-associated macrophages reprograms the tumor microenvironment to augment the response to immune checkpoint blockade.

| S-EPMC9479603 | biostudies-literature

Genome-wide gene expression analysis in treatment for 24 h with 40 μM APR-246 in ARID1A-WT and ARID1A-KO HCT116 cells.

Project description:To explore the sensitivity of ARID1A-KO cells to APR-246

2019-01-28 | GSE122925 | GEO

Variability in functional p53 reactivation by Prima-1Met/APR-246 in Ewing sarcoma

2013-11-12 | GSE49967 | GEO

APR-246 enhances colorectal cancer sensitivity to radiotherapy

Project description:APR-246 enhances colorectal cancer sensitivity to radiotherapy

| PRJNA971584 | ENA

Transcriptomic analysis of SKM1 cells treated with APR-246 (APR), 5-Azacytidine (AZA) or both (APR-AZA)

Project description:Transcriptomic analysis of SKM1 cells treated with APR-246 (APR), 5-Azacytidine (AZA) or both (APR-AZA)

| PRJNA433156 | ENA

Transcriptomic analysis of SKM1 cells treated with APR-246 (APR), 5-Azacytidine (AZA) or both (APR-AZA)

Project description:In order to explain the synergistic effects observed by the combination APR+AZA in MDS cells by synergistic activated pathways, we performed a transcriptomic analysis of MDS cells treated with each drug alone and compared it to the combination.

2018-08-04 | GSE110198 | GEO

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