scholarly journals DIPG-16. COMBINATION OF ARGININE DEPLETION AND POLYAMINE INHIBITION AS AN ANTICANCER STRATEGY FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii290-iii290
Author(s):  
Aaminah Khan ◽  
Laura Gamble ◽  
Ruby Pandher ◽  
Mark R Burns ◽  
Francis Mussai ◽  
...  
Keyword(s):  
Single Agent ◽  
Tumor Development ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Normal Brain ◽  
Gene Encoding ◽  
Triple Combination Therapy ◽  
Polyamine Transport ◽  
Arginase Ii ◽  
Inhibitory Agents ◽  
Improvement In Survival

Abstract DIPG is an aggressive pediatric brainstem tumor, with a median survival below 12 months. Tumor cells are dependent upon arginine, a semi-essential amino acid, metabolised by arginase enzymes into ornithine, a pivotal precursor to the polyamine pathway. Polyamines, frequently upregulated in cancer, are intracellular polycations controlling key biological processes – the inhibition of which we have previously shown to be highly efficacious in preclinical DIPG models. Pegylated arginase (BCT-100) has recently been shown to significantly delay tumor development, prolonging survival of neuroblastoma-prone Th-MYCN mice. This study investigated the effects of arginine depletion therapy as a single agent and in combination with polyamine pathway inhibitors in DIPG. We found that ARG2, the gene encoding for arginase II, is expressed significantly more highly in DIPG tumors compared to normal brain. Arginine depletion via BCT-100 reduced DIPG cell proliferation and colony formation in patient-derived cell lines. Using orthotopic patient-derived xenograft models of DIPG, we found that frequent dosing of BCT-100 (4x/week) significantly delayed tumor development and increased the survival of the mice (p<0.0001). DFMO is an FDA-approved inhibitor of the enzyme ornithine decarboxylase, a key driver of polyamine synthesis. The combination of BCT-100 with DFMO led to significant enhancement in DIPG survival (p<0.005 compared to single agent treatments). Triple combination therapy with addition of the polyamine transport inhibitor AMXT-1501 led to a potent and profound improvement in survival. These data show that arginine depletion therapy using BCT-100 combined with dual polyamine inhibitory agents represents a potentially exciting new approach for the treatment of DIPG.

scholarly journals Preclinical Evaluation of the HDAC Inhibitor Chidamide in Transformed Follicular Lymphoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Mengya Zhong ◽  
Jinshui Tan ◽  
Guangchao Pan ◽  
Yuelong Jiang ◽  
Hui Zhou ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Follicular Lymphoma ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
Treatment Strategies ◽  
Annexin V ◽  
Gene Encoding ◽  
New Treatment ◽  
Transformed Follicular Lymphoma

The key factors leading to transformed follicular lymphoma (t-FL) include the aberrations of epigenetic modifiers as early and driving events, especially mutations in the gene encoding for histone acetyltransferase. Therefore, reversal of this phenomenon by histone deacetylase (HDAC) inhibitors is essential for the development of new treatment strategies in t-FL. Several t-FL cell lines were treated with various doses of chidamide and subjected to cell proliferation, apoptosis and cell cycle analyses with CCK-8 assay, Annexin V/PI assay and flow cytometry, respectively. Chidamide dose-dependently inhibited cell proliferation, caused G0/G1 cycle arrest and triggered apoptosis in t-FL cells. In addition, the effects of chidamide on tumor growth were evaluated in vivo in xenograft models. RNA-seq analysis revealed gene expression alterations involving the PI3K-AKT signaling pathway might account for the mechanism underlying the antitumor activity of chidamide as a single agent in t-FL. These findings provide a basis for further clinical exploration of chidamide as a promising treatment for FL.

scholarly journals The Long Non-Coding RNA H19 Drives the Proliferation of Diffuse Intrinsic Pontine Glioma with H3K27 Mutation

2021 ◽  
Vol 22 (17) ◽  
pp. 9165
Author(s):  
David Roig-Carles ◽  
Holly Jackson ◽  
Katie F. Loveson ◽  
Alan Mackay ◽  
Rebecca L. Mather ◽  
...  
Keyword(s):  
Large Family ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Locked Nucleic Acid ◽  
Normal Brain ◽  
Pontine Glioma ◽  
Incurable Cancer ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
Long Non Coding Rna

Diffuse intrinsic pontine glioma (DIPG) is an incurable paediatric malignancy. Identifying the molecular drivers of DIPG progression is of the utmost importance. Long non-coding RNAs (lncRNAs) represent a large family of disease- and tissue-specific transcripts, whose functions have not yet been elucidated in DIPG. Herein, we studied the oncogenic role of the development-associated H19 lncRNA in DIPG. Bioinformatic analyses of clinical datasets were used to measure the expression of H19 lncRNA in paediatric high-grade gliomas (pedHGGs). The expression and sub-cellular location of H19 lncRNA were validated in DIPG cell lines. Locked nucleic acid antisense oligonucleotides were designed to test the function of H19 in DIPG cells. We found that H19 expression was higher in DIPG vs. normal brain tissue and other pedHGGs. H19 knockdown resulted in decreased cell proliferation and survival in DIPG cells. Mechanistically, H19 buffers let-7 microRNAs, resulting in the up-regulation of oncogenic let-7 target (e.g., SULF2 and OSMR). H19 is the first functionally characterized lncRNA in DIPG and a promising therapeutic candidate for treating this incurable cancer.

scholarly journals CBMT-08. IN VIVO EVALUATION OF PENTOSE PHOSPHATE PATHWAY ACTIVITY IN ORTHOTOPIC GLIOMA USING HYPERPOLARIZED δ-[1-13C]GLUCONOLACTONE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi34-vi34
Author(s):  
Georgios Batsios ◽  
Pavithra Viswanath ◽  
Peng Cao ◽  
Celine Taglang ◽  
Elavarasan Subramani ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Tumor Development ◽  
Pentose Phosphate ◽  
Response To Therapy ◽  
Metabolic Imaging ◽  
Normal Brain ◽  
In Vivo Evaluation ◽  
First Time ◽  
Orthotopic Glioma

Abstract The pentose phosphate pathway (PPP) generates NADPH and ribose 5-phosphate, which are involved in the scavenging of reactive oxygen species and the synthesis of nucleotides. As such, the PPP is typically upregulated in cancer cells to address the metabolic needs of rapid cell proliferation. Imaging PPP upregulation could therefore be useful in tumor assessment. One intermediate of the pathway is 6-phospho-δ-gluconolactone (6P-δ-GL), which is produced by phosphorylation of δ-gluconolactone. 6P-δ-GL is further metabolized to 6-phospho-gluconate (6PG). The goal of our study was to evaluate, for the first time, whether hyperpolarized (HP) δ-[1-13C]gluconolactone can be used to assess PPP flux and detect the presence of tumor in an orthotopic glioma rat model. Athymic nude rats bearing orthotropic U87 tumors or age-matched tumor-free controls were investigated. HP studies were performed following intravenous injection of HP δ-[1-13C]gluconolactone and metabolic images using a flyback spectral-spatial echo-planar spectroscopic imaging pulse were acquired. The data were processed using in-house Matlab code. 6P-δ-GL and 6-phospho-γ-[1-13C]gluconolactone were observed in all rats ~10 seconds after HP δ-[1-13C]gluconolactone injection, followed ~5 seconds later by production of 6PG observed at 179.3ppm. These data indicate that HP δ-[1-13C]gluconolactone likely crosses the blood-brain barrier, consistent with its transport via glucose transporters, and is rapidly metabolized. Importantly, 6PG was significantly higher in tumor voxels. The ratio of 6PG-to-6P-δ-GL was comparable in normal brain and in normal-appearing contralateral brain of tumor-bearing rats at 0.43±0.09 and 0.45±0.06 respectively (p=0.85), but significant higher in the tumor regions at 0.70±0.11 (p=0.04 and p=0.02 respectively), consistent with the elevated PPP flux that typically occurs in tumor cells. Our results indicate, to our knowledge for the first time, that metabolism of HP δ-[1-13C]gluconolactone can be assessed in the brain and that elevated 6PG production in glioma provides a potential metabolic imaging approach to probe tumor development, recurrence and response to therapy.

ONC201 in previously-irradiated pediatric H3 K27M-mutant glioma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 10046-10046 ◽  
Author(s):  
Sharon L. Gardner ◽  
Jeffrey C. Allen ◽  
Wafik Tharwat Zaky ◽  
Yazmin Odia ◽  
Doured Daghistani ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Body Weight ◽  
Dose Escalation ◽  
Single Agent ◽  
High Grade Glioma ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Open Label ◽  
Body Weights ◽  
Label Dose

10046 Background: ONC201 is the first DRD2 antagonist for clinical oncology. The recommended phase 2 dose (RP2D) of 625mg ONC201 orally once a week has been established in adult patients. ONC201 efficacy has been shown in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. We report results from the first Phase I pediatric clinical trial of ONC201. Methods: This multicenter, open-label, dose-escalation and dose-expansion clinical trial (NCT03416530) determined the RP2D of ONC201 in pediatric H3 K27M-mutant glioma patients as a single agent. ONC201 was orally administered once a week and scaled by body weight. Dose escalation was performed by a 3 + 3 design beginning with one 125mg capsule less than the adult RP2D equivalent. Three patients were treated at the starting dose and 19 were treated at the adult RP2D equivalent. Results: The primary endpoint was achieved by establishing the safety of the adult RP2D scaled by body weight to pediatric patients. Twenty-two patients with a median age of 9 (range 3-18) years old who received at least prior radiation have been treated with ONC201: 15 with diffuse intrinsic pontine glioma (DIPG) (4 recurrent; 11 not recurrent) and 7 with non-DIPG H3 K27M-mutant glioma (all not recurrent). As of February 5, 2019, patients have received a median of 18 ONC201 doses (range 3-41) without instance of dose-limiting toxicity. Pharmacokinetic profiles were comparable to those observed in adults (Cmax ~2.1ug/mL; AUC ~2.3hr*ug/mL) and exposure was similar across body weights. Nine of 22 patients remain on therapy, 13 have discontinued due to progression, and 4 off-study patients are alive with a median follow up of 5.8 months. Five of the 11 (45%) DIPG patients who initiated ONC201 following radiation, but prior to recurrence, remain on therapy (median 7.4 months; range 4.4-9.6): median PFS is 4.4 months from initiation of ONC201 and 9.7 months from diagnosis; 7 of 11 (64%) patients are alive with median follow up of 11.8 months from diagnosis. Conclusions: ONC201 was well tolerated and achieved therapeutic exposure in pediatric H3 K27M-mutant glioma patients at the adult RP2D scaled by body weight. Further investigation of first-line ONC201 to treat H3 K27M-mutant glioma and/or DIPG is ongoing. Clinical trial information: NCT03416530.

scholarly journals Ahi-1, a Novel Gene Encoding a Modular Protein with WD40-Repeat and SH3 Domains, Is Targeted by the Ahi-1 and Mis-2 Provirus Integrations

2002 ◽  
Vol 76 (18) ◽  
pp. 9046-9059 ◽  
Author(s):  
Xiaoyan Jiang ◽  
Zaher Hanna ◽  
Mohammadi Kaouass ◽  
Luc Girard ◽  
Paul Jolicoeur
Keyword(s):  
Integration Site ◽  
Leukemia Virus ◽  
Insertion Site ◽  
Tumor Development ◽  
Suppressor Gene ◽  
Tumor Formation ◽  
Gene Encoding ◽  
Novel Gene ◽  
Splicing Variants ◽  
Provirus Integration Site

ABSTRACT The Ahi-1 locus was initially identified as a common helper provirus integration site in Abelson pre-B-cell lymphomas and shown to be closely linked to the c-myb proto-oncogene. Since no significant alteration of c-myb expression was found in Abelson murine leukemia virus-induced pre-B-lymphomas harboring a provirus inserted within the Ahi-1 locus, this suggested that it harbors another gene whose dysregulation is involved in tumor formation. Here we report the identification of a novel gene (Ahi-1) targeted by these provirus insertional mutations and the cloning of its cDNA. The Ahi-1 proviral insertions were found at the 3′ end of the gene, in an inverse transcriptional orientation, with most of them located around and downstream of the last exon, whereas another insertion was within intron 22. In addition, another previously identified provirus insertion site, Mis-2, was found to map within the 16th intron of the Ahi-1 gene. The Ahi-1 cDNA encodes a 1,047-amino-acid protein. The predicted Ahi-1 protein is a modular protein that contains one SH3 motif and seven WD40 repeats. The Ahi-1 gene is conserved in mammals and encodes two major RNA species of 5 and 4.2 kb and several other shorter splicing variants. The Ahi-1 gene is expressed in mouse embryos and in several organs of the mouse and rat, notably at high levels in the brain and testes. In tumor cells harboring insertional mutations in Ahi-1, truncated Ahi-1/viral fused transcripts were identified, including some splicing variants with deletion of the SH3 domain. Therefore, Ahi-1 is a novel gene targeted by provirus insertion and encoding a protein that exhibits several features of a signaling molecule. Thus, Ahi-1 may play an important role in signal transduction in normal cells and may be involved in tumor development, possibly in cooperation with other oncogenes (such as v-abl and c-myc) or with a tumor suppressor gene (Nf1), since Ahi-1 insertion sites were identified in tumors harboring v-abl defective retroviruses or a c-myc transgene or in tumors exhibiting deletion of Nf1.

scholarly journals Found in Transcription: Gene fusions arise through defects in RNA processing in the absence of chromosomal rearrangements

2019 ◽  
Author(s):  
Yue Jiang ◽  
Michael J. Apostolides ◽  
Mia Husić ◽  
Robert Siddaway ◽  
Man Yu ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
Chromosomal Rearrangements ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Normal Brain ◽  
Sequencing Analysis ◽  
Tissue Samples ◽  
Complete Representation ◽  
Normal Tissues ◽  
Gene Dysregulation ◽  
Definition Of

AbstractRecent advancements in high throughput sequencing analysis have enabled the characterization of cancer-driving fusions, improving our understanding of cancer development. Most fusion calling methods, however, examine either RNA or DNA information alone and are limited to a rigid definition of what constitutes a fusion. For this study we developed a pipeline that incorporates several fusion calling methods and considers both RNA and DNA to capture a more complete representation of the tumour fusion landscape. Interestingly, most of the fusions we identified were specific to RNA, with no evidence of corresponding genomic restructuring. Further, while the average total number of fusions in tumour and normal brain tissue samples is comparable, their overall fusion profiles vary significantly. Tumours have an over-representation of fusions occurring between coding genes, whereas fusions involving intergenic or non-coding regions comprised the vast majority of those in normals. Tumours were also more abundant in unique, sample-specific fusions compared to normals, though several fusions exhibited strong recurrence in the tumour type examined (diffuse intrinsic pontine glioma; DIPG) and were absent from both normal tissues and other cancers. Intriguingly, tumours also show broad up- or down-regulation of spliceosomal gene expression, which significantly correlates with fusion number (p=0.007). Our results show that RNA-specific fusions are abundant in both tumour and normal tissue and are associated with spliceosomal gene dysregulation. RNA-specific fusions should be considered as a potential mechanism that may contribute to cancer formation initiation and maintenance alongside more traditional structural events.

Improved Remission Induction Rate of Childhood AML: Preliminary Results of the AML02 Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 275-275 ◽  
Author(s):  
Jeffrey Rubnitz ◽  
Bassem Razzouk ◽  
Paul Bowman ◽  
Gary Dahl ◽  
Norman Lacayo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Low Dose ◽  
Single Agent ◽  
Remission Induction ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Triple Combination Therapy ◽  
Cns Relapse ◽  
Low Dose Cytarabine ◽  
Bone Marrow Blasts

Abstract The multicenter AML02 trial randomly assigns patients to receive high-dose or low-dose cytarabine (A), daunorubicin (D), and etoposide (E) as Induction I; all subsequent therapy is risk-adapted. Pharmacokinetic, pharmacodynamic, and gene expression studies are performed after exposure to high-dose or low-dose cytarabine. Patients with no response (NR, ≥ 25% bone marrow blasts) to Induction I receive low-dose ADE + gemtuzumab ozogamicin (GO) as Induction II, whereas all others receive ADE. Minimal residual disease (MRD) is monitored by flow cytometry and is defined as ≥ 0.1% cells with leukemia-associated immunophenotypes among bone marrow mononuclear cells. Patients who are MRD+ after induction therapy receive GO as a single agent before consolidation chemotherapy or stem cell transplantation. Among the 112 patients enrolled since October 2002, 37 had -7, FAB M6 or M7, FLT3 internal tandem duplication (ITD), or MDS or treatment-related AML and were classified as high-risk (HR); 32 had AML1-ETO, CBFβ-MYH11, or MLL-AF9 (low-risk; LR); the remaining 43 were considered as standard-risk (SR). The rate of complete response (CR, <5% bone marrow blasts) was 84% after Induction I and 97% after Induction II. Of the 3 patients who did not attain CR, 2 had partial responses and 1 died of streptococcal sepsis during Induction II. CR rates differed according to risk group after Induction I (LR, 100%; SR, 91%, HR 61%) but not after Induction II (LR, 100%; SR, 98%, HR 94%). The association between risk groups and MRD (determined successfully in 95% of cases) was more striking: the rate of MRD negativity after Induction I was 88% in LR, 59% in SR, and 26% in HR patients; after Induction II, rates were 97%, 82%, and 53%, respectively. Response to initial therapy was particularly poor among patients with a FLT3-ITD: only 1 of 11 patients was MRD-negative after Induction I and only 3 were MRD-negative after Induction II. 5 of the 6 patients who had NR to Induction I attained CR after subsequent treatment with ADE + GO and all 6 had dramatic reductions in MRD levels (from a median of 26% to a median of 0.24%). An additional 14 patients with MRD levels 0.1% to 5.6% received GO at the beginning of consolidation: 9 became MRD-negative. Overall, there were 4 deaths from infection (2 bacterial, 1 fungal, 1 viral), which occurred during induction (1), consolidation (1), and after completion of chemotherapy (2). Because CNS relapse occurred in 3 of the first 33 patients treated, intrathecal therapy was changed from cytarabine alone to triple combination therapy with methotrexate, hydrocortisone, and cytarabine; none of the 79 subsequent patients has had a CNS relapse. The 1-year event-free and overall survival estimates are 76.8% (SE, 5.1%) and 89.1% (SE, 3.8%). In conclusion, AML02 therapy has produced a high overall remission rate and low treatment-related mortality, which we attribute to excellent supportive care and to the use of risk- and MRD-adapted therapy.

K-RAS mutations in colorectal cancer in patients from Podlaskie region

2016 ◽  
Vol 6 (1) ◽  
pp. 70-77
Author(s):  
M. Chomczyk ◽  
P. Czajka
Keyword(s):  
Colorectal Cancer ◽  
Genetic Predisposition ◽  
Tumor Development ◽  
Tumor Differentiation ◽  
Gene Encoding ◽  
Ras Mutation ◽  
Ras Mutations ◽  
Ras Protein ◽  
Study Population ◽  
Medical University

Introduction: In Poland, colorectal cancer is the second leading cause of death. The incidence of colorectal cancer increases with age and early onset indicates and increased likelihood for genetic predisposition for this disease. The somatic genetics of tumor development in relation to patients age, gender, sex and morphological factors are unknown in Podlaskie region, Poland. Materials and methods: We investigated seventy five patients (43 men and 32 women) who underwent surgery for cancer of the colorectal in the II Department of General and Gastroenterological Surgery, Medical University of Białystok in 2002- 2007. The average age of patients was 64.8 years (the average age of women 66.7, men 63.1). All patients for the study of molecular research (absence or presence of K-RAS mutations) had histopathology confirmed adenocarcinoma. Results: There was no correlation presence or absence of mutations in K-RAS of the following clinical and morphological factors: gender, age, location, degree of tumor differentiation, tumor size and metastases to lymph nodes and other organs The gene encoding the K-Ras protein is mutated in 20- 50% of cases of colorectal cancer. Such a difference of results is influenced by several factors: differences of the techniques used for detecting mutations, differences in codon of the gene that is considered codon 12 and /or 13 and / or 61 and differences in the selection and study population. Conclusions: These data suggest the clinical and morphological factors in patients with colorectal cancer have no effect on the presence of K-RAS. mutation.

scholarly journals Design considerations of an IL13Rα2 antibody–drug conjugate for diffuse intrinsic pontine glioma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Xiaolei Lian ◽  
Dina Kats ◽  
Samuel Rasmussen ◽  
Leah R. Martin ◽  
Anju Karki ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
The United States ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Normal Brain ◽  
Cell Models ◽  
Pontine Glioma ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

AbstractDiffuse intrinsic pontine glioma (DIPG), a rare pediatric brain tumor, afflicts approximately 350 new patients each year in the United States. DIPG is noted for its lethality, as fewer than 1% of patients survive to five years. Multiple clinical trials involving chemotherapy, radiotherapy, and/or targeted therapy have all failed to improve clinical outcomes. Recently, high-throughput sequencing of a cohort of DIPG samples identified potential therapeutic targets, including interleukin 13 receptor subunit alpha 2 (IL13Rα2) which was expressed in multiple tumor samples and comparably absent in normal brain tissue, identifying IL13Rα2 as a potential therapeutic target in DIPG. In this work, we investigated the role of IL13Rα2 signaling in progression and invasion of DIPG and viability of IL13Rα2 as a therapeutic target through the use of immunoconjugate agents. We discovered that IL13Rα2 stimulation via canonical ligands demonstrates minimal impact on both the cellular proliferation and cellular invasion of DIPG cells, suggesting IL13Rα2 signaling is non-essential for DIPG progression in vitro. However, exposure to an anti-IL13Rα2 antibody–drug conjugate demonstrated potent pharmacological response in DIPG cell models both in vitro and ex ovo in a manner strongly associated with IL13Rα2 expression, supporting the potential use of targeting IL13Rα2 as a DIPG therapy. However, the tested ADC was effective in most but not all cell models, thus selection of the optimal payload will be essential for clinical translation of an anti-IL13Rα2 ADC for DIPG.

scholarly journals DIPG-51. ACVR1 MUTATIONS PROMOTE TUMOR GROWTH IN MODELS OF DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii296-iii297
Author(s):  
Jennifer Ocasio Adorno ◽  
Laura Hover ◽  
Chen He ◽  
Xiaoyan Zhu ◽  
David Goldhamer ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cell Fate ◽  
High Grade Glioma ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Genetically Engineered ◽  
Gene Encoding ◽  
Human Patient ◽  
Complete Penetrance ◽  
Genetically Engineered Mice ◽  
Glial Progenitors

Abstract Mutations in the gene encoding activin A receptor type 1 (ACVR1) are found in approximately 25% of diffuse intrinsic pontine gliomas (DIPGs), a pediatric glioma with 2-year survival rate of less than 10%. ACVR1mutations frequently coincide with activating PIK3CA or PIK3R1 mutations, indicating a potential cooperative effect of BMP and PI3K signaling in gliomagenesis. We used genetically engineered mice with inducible knock-in of Acvr1R206H or Pik3caE545K alleles, such that cre-mediated recombination resulted in expression of the gain of function mutated genes from their endogenous promoters at physiological levels. Cre-mediated deletion in GFAP-CreER;Pik3caE545K/+;p53cKO mice (Pik3ca;p53) mediated Trp53 deletion and expression of Pik3caE545K in glial progenitors, and spontaneously induced high-grade glioma (HGG) in mice with complete penetrance. Heterozygous knock-in of the Acvr1R206H allele accelerated tumorigenesis and impaired survival in Pik3ca;p53 mice (Acvr1;Pik3ca;p53). Transcriptomic analysis of Acvr1;Pik3ca;p53 tumors compared to Pik3ca;p53 littermate controls, as in patient-derived tumors, revealed broad molecular signatures associated with cell fate commitment and chromosome maintenance. Pharmacologic inhibition of ACVR1 was sufficient to impair growth in human patient-derived DIPG cell lines. Together, our studies show that ACVR1 activation promotes tumor growth in spontaneous mouse HGG and patient-derived DIPG cells, suggesting that ACVR1 inhibition may produce a clinically significant therapeutic effect in DIPG.

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