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Research
Rheal A. Towner
Oklahoma Medical Research Foundation
Corresponding Author
ORCiD: https://orcid.org/0000-0001-7368-8983
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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.
Keywords
Diffuse intrinsic pontine glioma (DIPG), ACVR1 mutation, patient-derived xenograft (PDX), OKN-007, magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), microvessel density (MVD), apoptosis
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CURRENT STATUS: Published
View the published article at Journal of Translational Medicine.
No community comments so far
Review #1 received
Received 19 Oct, 2020
Editorial decision: Accept
On 19 Oct, 2020
Reviewer #1 agreed
On 11 Oct, 2020
Editor assigned
On 10 Oct, 2020
Reviewers invited
Invitations sent on 10 Oct, 2020
Submission checks complete
On 09 Oct, 2020
Editor invited
On 09 Oct, 2020
Version 1
Posted 07 Aug, 2020
No comments provided
Editorial decision: Major revision
On 10 Sep, 2020
Review #1 received
Received 06 Sep, 2020
Review #2 received
Received 06 Sep, 2020
Reviewer #2 agreed
On 25 Aug, 2020
Reviewers invited
Invitations sent on 14 Aug, 2020
Reviewer #1 agreed
On 14 Aug, 2020
Editor assigned
On 13 Aug, 2020
Editor invited
On 12 Aug, 2020
Submission checks complete
On 05 Aug, 2020
First submitted
On 30 Jul, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Translational Medicine
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A new preprint design is coming!
We have improved readability, clarity, accessibility, and opportunities for engagement.
See the published version of this preprint at Journal of Translational Medicine.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Rheal A. Towner
Oklahoma Medical Research Foundation
Corresponding Author
ORCiD: https://orcid.org/0000-0001-7368-8983
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Journal of Translational Medicine.
No community comments so far
Review #1 received
Received 19 Oct, 2020
Editorial decision: Accept
On 19 Oct, 2020
Reviewer #1 agreed
On 11 Oct, 2020
Editor assigned
On 10 Oct, 2020
Reviewers invited
Invitations sent on 10 Oct, 2020
Submission checks complete
On 09 Oct, 2020
Editor invited
On 09 Oct, 2020
Version 1
Posted 07 Aug, 2020
No comments provided
Editorial decision: Major revision
On 10 Sep, 2020
Review #1 received
Received 06 Sep, 2020
Review #2 received
Received 06 Sep, 2020
Reviewer #2 agreed
On 25 Aug, 2020
Reviewers invited
Invitations sent on 14 Aug, 2020
Reviewer #1 agreed
On 14 Aug, 2020
Editor assigned
On 13 Aug, 2020
Editor invited
On 12 Aug, 2020
Submission checks complete
On 05 Aug, 2020
First submitted
On 30 Jul, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Translational Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Journal of Translational Medicine.
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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11
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