ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma

Carvalho, Diana; Taylor, Kathryn R.; Olaciregui, Nagore G.; Molinari, Valeria; Clarke, Matthew; Mackay, Alan; Ruddle, Ruth; Henley, Alan T.; Valenti, Melanie; Hayes, Angela; Brandon, Alexis de Haven; Eccles, Suzanne A.; Raynaud, Florence I.; Boudhar, Aicha; Monje, Michelle; Popov, Sergey; Moore, Andrew S.; Mora, Jaume; Cruz, Ofelia; Vinci, Maria; Brennan, P.E.; Bullock, Alex N.; Carcaboso, Ángel M.; Jones, Chris

doi:10.1038/s42003-019-0420-8

Cited by 95 publications

(143 citation statements)

References 44 publications

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“…Recent genetic studies have shown that up to 90% of DMGs have H3K27M mutations in H3F3A encoding histone H3.3 or (Figure 5) (10,36,39). We established a DIPG cell line harboring the H3.1 H3K27M and ACVR1 G328E mutations.…”

Section: Discussionmentioning

confidence: 99%

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MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas

et al. 2020

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Diffuse midline gliomas (DMGs) show resistance to many chemotherapeutic agents including temozolomide (TMZ). Histone gene mutations in DMGs trigger epigenetic changes including DNA hypomethylation, one of which is a frequent lack of O6-methyl-guanine-DNA methyltransferase (MGMT) promoter methylation, resulting in increased MGMT expression. We established the NGT16 cell line with HIST1H3B K27M and ACVR1 G328E gene mutations from a DMG patient and used this cell line and other DMG cell lines with H3F3A gene mutation (SF7761, SF8628, JHH-DIPG1) to analyze MGMT promoter methylation, MGMT protein expression, and response to TMZ. Three out of 4 DMG cell lines (NGT16, SF8628, and JHH-DIPG1) had unmethylated MGMT promoter, increased MGMT expression, and showed resistance to TMZ treatment. SF7761 cells with H3F3A gene mutation showed MGMT promoter methylation, lacked MGMT expression, and sensitivity to TMZ treatment. NGT16 line showed response to ALK2 inhibitor K02288 treatment in vitro. We confirmed in vitro that MGMT expression contributes to TMZ resistance in DMG cell lines. There is an urgent need to develop new strategies to treat TMZ-resistant DMGs.

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Section: Discussionmentioning

confidence: 99%

“…Data from the present research suggests that BMP pathway can be activated in ACVR1-wildtype DMGs as well. Development of multiple DMG cell lines which harbor ACVR1 mutation is necessary for further research (39).…”

Section: Future Directionsmentioning

confidence: 99%

MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas

et al. 2020

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“…66) In an orthotopic xenograft mouse model bearing the H3K27M mutation, and in ACVR1 R206H mutant HSJDDIPG-007 cells, both compounds significantly extended survival compared with vehicle controls. 66) Despite these several potent ALK2 kinase inhibitors in development, none of these compounds is currently in clinical trials. However, BLU-782 was reported as a new scaffold ALK2 inhibitor, 67) which is currently in a phase II.…”

Section: Small-molecule Alk2 Inhibitorsmentioning

confidence: 94%

“…65) LDN-193189 and LDN-214117 exhibit oral bioavailability and were well-tolerated, with good brain penetration at potentially active concentrations. 66) In an orthotopic xenograft mouse model bearing the H3K27M mutation, and in ACVR1 R206H mutant HSJDDIPG-007 cells, both compounds significantly extended survival compared with vehicle controls. 66) Despite these several potent ALK2 kinase inhibitors in development, none of these compounds is currently in clinical trials.…”

Section: Small-molecule Alk2 Inhibitorsmentioning

confidence: 99%

ALK2: A Therapeutic Target for Fibrodysplasia Ossificans Progressiva and Diffuse Intrinsic Pontine Glioma

2020

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Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are diseases that typically manifest in childhood and are associated with severely reduced life expectancy. However, there are currently no effective therapies for these diseases, which remain incurable. Activin receptor-like kinase-2 (ALK2), encoded by the ACVR1 gene, is a bone morphogenetic protein (BMP) type-I receptor subtype that plays an important physiological role in the development of bones, muscles, brain, and other organs. Constitutively active mutants of ALK2 have been identified as causative of FOP and involved in the tumorigenesis of DIPG owing to abnormal activation of BMP signaling, and therefore have emerged as promising treatment targets. Here, we describe these two diseases, along with the link to ALK2 signal transduction, and highlight potential ALK2 inhibitors that are under development to offer new hope for patients with FOP and DIPG.

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“…The World Health Organization 2016 classi cation of central nervous system tumors describes 80% of DIPG tumors as having a histone mutation, H3 K27M mutant, which is associated with worse clinical outcome (4). ACVR1 mutations are the second most common mutation in DIPG, with approximately 25% of cases harboring this mutation (5). These mutations contribute to the aggressive biology and poor treatment response.…”

Section: Introductionmentioning

confidence: 99%

OKlahoma Nitrone-007: Novel Treatment for Diffuse Intrinsic Pontine Glioma

Thomas

Smith

Saunders

et al. 2020

Preprint

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Background: Diffuse intrinsic pontine glioma (DIPG) is the most common brainstem cancer in childhood. This rapidly progressing brainstem glioma holds a very dismal prognosis with median survival of less than 1 year. Despite extensive research, no significant therapeutic advancements have been made to improve overall survival in DIPG patients. Methods: Here, we used an orthotopic xenograft pediatric DIPG (HSJD-DIPG-007) mouse model to monitor the effects of anti-cancer agent, OKlahoma Nitrone-007 (OKN-007), as an inhibitor of tumor growth after 28 days of treatment. Using magnetic resonance imaging (MRI), we confirmed the previously described efficacy of LDN-193189, a known activin A receptor, type I (ACVR1) inhibitor, in decreasing tumor burden and found that OKN-007 was equally efficacious. Results: After 28 days of treatment, the tumor volumes were significantly decreased in OKN-007 treated mice (p<0.01). The apparent diffusion coefficient (ADC), as a measure of tissue structural alterations, was significantly decreased in OKN-007 treated tumor-bearing mice (p<0.0001). Histological analysis also showed a significant decrease in CD34 expression, essential for angiogenesis, of OKN-007 treated mice (p<0.05) compared to LDN-193189 treated mice. OKN-007-treated mice also significantly decreased protein expression of the human nuclear antigen (HNA) (p<0.001), ACVR1 (p<0.0001), and c-MET (p<0.05), as well as significantly increased expression of cleaved caspase 3 (p<0.001), compared to untreated mouse tumors.Conclusions: With the dismal prognosis and limited effective chemotherapy available for DIPG, there is significant room for continued research studies and OKN-007 merits further exploration as a therapeutic agent.

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ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma

Cited by 95 publications

References 44 publications

MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas

MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas

ALK2: A Therapeutic Target for Fibrodysplasia Ossificans Progressiva and Diffuse Intrinsic Pontine Glioma

OKlahoma Nitrone-007: Novel Treatment for Diffuse Intrinsic Pontine Glioma

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