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TP53 wild type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist

ABSTRACT: this study demonstrates the pre-clinical efcacy potential of RG7388 in the TP53 wild type/PPM1D mutant DIPG subgroup in the TP53 wild-type/PPM1D mutant DIPG subgroup mutant DIPG subgroup

ORGANISM(S): Homo sapiens

PROVIDER: GSE189152 | GEO | 2021/11/20

REPOSITORIES: GEO

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TP53 wild type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist

Project description:TP53 wild type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist

| PRJNA781664 | ENA

TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist.

Project description:Diffuse intrinsic pontine gliomas (DIPGs) are high-grade tumors of the brainstem that often occur in children, with a median overall survival of less than one year. Given the fact that DIPGs are resistant to chemotherapy and are not amenable to surgical resection, it is imperative to develop new therapeutic strategies for this deadly disease. The p53 pathway is dysregulated by TP53 (~ 60%) or PPM1D gain-of-function mutations (~ 30%) in DIPG cases. PPM1D gain-of-function mutations suppress p53 activity and result in DIPG tumorigenesis. While MDM2 is a major negative regulator of p53, the efficacy of MDM2 inhibitor has not been tested in DIPG preclinical models. In this study, we performed a comprehensive validation of MDM2 inhibitor RG7388 in patient-derived DIPG cell lines established from both TP53 wild-type/PPM1D-mutant and TP53 mutant/PPM1D wild-type tumors, as well in TP53 knockout isogenic DIPG cell line models. RG7388 selectively inhibited the proliferation of the TP53 wild-type/PPM1D mutant DIPG cell lines in a dose- and time-dependent manner. The anti-proliferative effects were p53-dependent. RNA-Seq data showed that differential gene expression induced by RG7388 treatment was enriched in the p53 pathways. RG7388 reactivated the p53 pathway and induced apoptosis as well as G1 arrest. In vivo, RG7388 was able to reach the brainstem and exerted therapeutic efficacy in an orthotopic DIPG xenograft model. Hence, this study demonstrates the pre-clinical efficacy potential of RG7388 in the TP53 wild-type/PPM1D mutant DIPG subgroup and may provide critical insight on the design of future clinical trials applying this drug in DIPG patients.

| S-EPMC8565061 | biostudies-literature

PPM1D Mutations Silence NAPRT Gene Expression and Confer NAMPT Inhibitor Sensitivity in Glioma

Project description:Genome wide DNA methylation profiling of wild type and PPM1D mutant astrocytes and patient-derived DIPG cell lines. The Illumina Human EPIC Bead Array (850k) platform was used to obtain methylation beta values of over 850k CpG sites throughout the genome across a panel of DIPG cell lines.

2019-07-12 | GSE134165 | GEO

RNA sequencing of tumors from PPM1D transgenic mouse model

Project description:The majority of cancers harbor alterations of the tumor suppressor TP53. However, childhood cancers, including unfavorable neuroblastoma, often lack TP53 mutations despite frequent loss of p53 function, suggesting alternative p53 inactivating mechanisms. Our study show that frequent gain of the p53-regulating gene PPM1D at chromosome 17q22.3 is linked to aggressive tumors and poor prognosis in neuroblastoma. A PPM1D transgenic mouse model develops cancers phenotypically and genetically similar to tumors arising in mice with dysfunctional p53 when subjected to low-dose irradiation. Tumors include T-cell lymphomas harboring Notch1- and Pten-mutations, adenocarcinomas and PHOX2B-expressing neuroblastomas, therey establishing PPM1D as a bona fide oncogene in wtTP53 cancer and childhood neuroblastoma. Pharmacological inhibition of WIP1 suppressed the growth of neural tumors in nude mice, proposing WIP1 as a therapeutic target in neural childhood tumors.

2020-12-31 | GSE157769 | GEO

Characterizing TP53 and PPM1D mutations as resistance drivers to radiation therapy in Diffuse Intrinsic Pontine Gliomas

Project description:Characterizing TP53 and PPM1D mutations as resistance drivers to radiation therapy in Diffuse Intrinsic Pontine Gliomas

| PRJNA714986 | ENA

Characterizing TP53 and PPM1D mutations as resistance drivers to radiation therapy in Diffuse Intrinsic Pontine Gliomas

Project description:Characterizing TP53 and PPM1D mutations as resistance drivers to radiation therapy in Diffuse Intrinsic Pontine Gliomas

| PRJNA714988 | ENA

SOD1 is a synthetic lethal target in PPM1D-mutant leukemia cells

Project description:Using CRISPR/Cas9 dropout screening, we identified superoxide dismutase-1 (SOD1) as a genetic dependency specific to PPM1D-mutant leukemia cells. We found that the mutant cells exhibited a compromised response to oxidative stress that can be rescued with SOD1 inhibitors. PPM1D-mutant fcells also exhibit significant genomic instability, highlighting the essential role of SOD1 in safeguarding against oxidative stress and DNA damage.

2024-04-15 | GSE240874 | GEO

CDK4/6 inhibition mitigates chemotherapy-induced expansion of TP53-mutant clonal hematopoiesis

Project description:Therapy-related myeloid neoplasms (tMN) represent a fatal consequence of exposure to cytotoxic therapy administered in the treatment of cancer. Individuals with pre-existing TP53 clonal hematopoiesis (CH) are at high risk for development of tMN but currently avoidance of therapy is the only strategy to reduce tMN risk. Here, we show in four randomized clinical trials of the CDK4/6 inhibitor trilaciclib given in conjunction with a variety of chemotherapeutic regimens and across diverse cancer patient populations that trilaciclib mitigates expansion of chemotherapy-related CH clones with mutations in DNA damage response genes (including TP53, PPM1D, and CHEK2 mutations). This finding was also observed in a syngeneic murine model of TP53 mutant CH demonstrating that trilaciclib blocks platinum-induced TP53 competitive repopulation through promoting hematopoietic stem and progenitor quiescence and decreasing TP53 mutant stemness advantage. This represents the first demonstration of a pharmacologic strategy to block chemotherapy-induced expansion of pre-leukemic TP53-mutant clones.

2025-01-09 | GSE285875 | GEO

Potent anti-tumor efficacy of palbociclib in H3K27M-mutant diffuse intrinsic pontine glioma

Project description:Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain cancer without cure. DIPG has high percentage histone mutation at K27M on histone H3 locus, which is believed to be one of the drivers of the tumorigenesis. Dysregulation of G1/S cell cycle checkpoint is more enriched in the H3.3K27M mutant subgroup. In this study, we reported that palbociclib (PD0332991), a specific and cytostatic inhibitor of CDK4/6, effectively suppresses the growth of DIPG cells in vitro and in vivo. We established patient derived cell lines from treatment-naïve specimens, which all have H3.3K27M mutation. And our DIPG cell lines with H3.3K27M mutation have high CDK4/6 expression. Then, we showed that depletion of CDK4 or CDK6 inhibits DIPG cells growth and blocks G1/S transition. Furthermore, palbociclib effectively repressed all 8 cell lines self-renewal, proliferation and cell cycle progression from G1 to S phase in vitro. Transcriptome analysis showed that palbociclib not only blocks G1/S transition, it also blocks other oncogenic targets such as Myc. Finally, palbociclib activity was assayed in vivo against DIPG orthotropic xenografts to demonstrate the high efficiency of blocking tumor growth. Our findings revealed that palbociclib could be the therapy strategy for DIPG.

2019-06-20 | GSE115976 | GEO

DNA sequencing of human nontransformed retinal pigment epithelia RPE-PPM1D-T2 cells carrying a truncating mutation in exon 6 of the PPM1D

Project description:Human nontransformed retinal pigment epithelia RPE-PPM1D-T2 cells carrying a truncating mutation in exon 6 of the PPM1D were exposed to ionising radiation (3 Gy) and subsequently were grown in semisolid media for 8 weeks. Six spheroid clones (RPE-PPM1D-T2-SA clones 1-6) were recovered and then were cultivated in adherent conditions. DNA was isolated from asynchronically growing parental RPE-PPM1D-T2 and transformed RPE-PPM1D-T2-SA-1 to 6 cells and was subjected to whole exome sequencing. DNA sequencing libraries were prepared using KAPA EvoPlus Kit (Roche) and were sequenced on the NovaSeq 6000 system using NovaSeq S1 Reagent Kit v1.5, 200 cycles (Illumina) with mean coverage >35 DNA samples, respectively. DNA fastq files were mapped to the hg19 reference using Novoalign (novoalign_2.08.03). PCR duplicates were removed from the BAM files using Picard Tools (picard-tools 1.129), and variant calling was performed using GATK HaplotypeCaller (3.8). Copy number variations (CNV) were analyzed using CNVkit version 0.7.4. Areas with median coverage >20 were included in the analysis. RNA fastq files were mapped to the hg19 reference using STAR (STAR-2.5.2b). The PCR duplicates were removed using Picard Tools (picard-tools 1.129).

2024-04-05 | E-MTAB-13923 | biostudies-arrayexpress

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