The Experts below are selected from a list of 1332 Experts worldwide ranked by ideXlab platform
Eric Raabe - One of the best experts on this subject based on the ideXlab platform.
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abstract 4943 the stem cell factor lin28b regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma
Cancer Research, 2020Co-Authors: Huizi Guo, Harpreet Kaur, Charles G Eberhart, Eric RaabeAbstract:Diffuse Intrinsic Pontine Glioma (DIPG) is a lethal pediatric brain tumor. With radiation therapy as the primary treatment, the median survival after diagnosis is 6 months. Identifying molecular markers that regulate tumor growth is urgently needed to develop targeted therapies. LIN28B is a stem cell factor expressed during normal neural development and re-expressed in cancer cells. In many cancers, LIN28B acts as an RNA-binding protein and downregulates the tumor-suppressing let-7 microRNAs. We had previously shown that LIN28A, a homolog of LIN28B, regulates invasion and tumorigenicity in adult high-grade Gliomas. LIN28B is known to be highly expressed in DIPG. Thus, we hypothesized that LIN28B would be important in DIPG by promoting tumor growth. We observed that LIN28B was expressed in patient-derived DIPG cell lines (JHHDIPG1, JHHDIPG16A, SUDIPGXIII, HSJD-007, SF7761). Knockdown of LIN28B using short hairpin RNAs decreased DIPG cell proliferation (BrdU incorporation) between 50% to 90% (p Citation Format: Huizi Guo, Harpreet Kaur, Charles G. Eberhart, Eric H. Raabe. The stem cell factor LIN28B regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4943.
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abstract 3868 the stem cell factor lin28b regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma
Cancer Research, 2017Co-Authors: Huizi Guo, Harpreet Kaur, Sepehr Akhtarkhavari, Charles G Eberhart, Eric RaabeAbstract:Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable, invasive and aggressive pediatric brain tumor. Identifying molecular markers that regulate tumor growth and invasion are needed for developing efficient treatment strategies. LIN28B is a stem cell factor expressed during normal fetal development and re-expressed in cancer cells. We had previously shown that LIN28A, another family member of LIN28 proteins, regulates invasion and tumorigenicity in adult high grade Gliomas. We observed increased LIN28B expression in patient-derived DIPG neurosphere cell lines using western blotting. We hypothesized that LIN28B promotes proliferation and prevents apoptosis in DIPG. Using two different lentiviral transduced short hairpin RNAs (shRNA), we suppressed LIN28B protein levels in DIPG neurospheres, as confirmed by western blotting. DIPG neurospheres that have been treated with LIN28B shRNA showed reduced proliferation as measured by BrdU incorporation (P Citation Format: Huizi Guo, Sepehr Akhtarkhavari, Charles G. Eberhart, Harpreet Kaur, Eric H. Raabe. The stem cell factor LIN28B regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3868. doi:10.1158/1538-7445.AM2017-3868
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abstract 4440 diffuse intrinsic Pontine Glioma epigenetic marks change depending on cell culture conditions implications for investigating epigenetically directed therapy
Cancer Research, 2016Co-Authors: Sama Ahsan, Charles G Eberhart, Michael C Haffner, Eric RaabeAbstract:Methylation of cytosine is viewed as repressive of transcription. 5-methylcytosine (5mC) can be removed from DNA by activity of ten-eleven translocation (TET) methylcytosine dioxygenase. The first step in erasing the repressive 5mC mark is conversion to 5-hydroxymethylcytosine (5hmC) by TET. Subsequent steps lead to replacement of 5hmC by cytosine, providing a mechanism by which 5mC-mediated repression can be erased. We have previously identified 5hmC and 5mC as being imbalanced in primary tumor tissue samples from the universally fatal pediatric malignancy diffuse intrinsic Pontine Glioma (DIPG) compared normal brain and glioblastoma (GBM). The aberration in DNA methylation along with known aberrant histone methylation in DIPGs, likely creates an active transcriptional/translational state and potentiates tumor growth. We hypothesized that the elevation of 5hmC in DIPG is secondary to increased TET activity. We found two different epigenetic signatures for DIPG cells depending on their culture conditions. When cultured in serum-free media as neurospheres, to our surprise, we found cells had low 5hmC, in contrast to what we observed in primary tumor and in orthotopic xenograft tumors. We hypothesized that 5hmC status may vary depending on differentiation state, and found that when DIPG cells were differentiated on matrigel for 14 days in the presence of serum, 5hmC levels increased and were similar to that observed in primary tissue and xenograft tumors. Differentiation was confirmed by upregulation of GFAP (glial marker) and MAP2 (neuronal marker) expression and the elaboration of long processes. We also found that DIPG cells in the serum/matrigel/differentiated state had increased TET1 and TET2 mRNA expression relative to undifferentiated neurospheres (2.6 and 2.1 fold increase respectively for TET1 and TET2 mRNA expression). As a control for adherent versus nonadherent growth, we also plated DIPG cells on laminin in EGF/FGF media, and we found that the serum-differentiated cells upregulated TET1 and TET2 mRNA 6.7 and 3.3 fold respectively, compared to laminin-plated cells, providing further support that differentiation affects epigenetic marks in DIPG. In contrast to DIPG, GBM cells did not exhibit similar changes in TET mRNA expression when differentiated, emphasizing the uniqueness of the DIPG epigenetic signature. Our data shows that neurosphere cell culture models of DIPG may not be true epigenetic representations of DIPG tumor in vivo and the predicted response to potential therapeutic options may differ based on the epigenetic state used for preclinical testing. Citation Format: Sama Ahsan, Michael Haffner, Charles Eberhart, Eric Raabe. Diffuse intrinsic Pontine Glioma epigenetic marks change depending on cell culture conditions: Implications for investigating epigenetically directed therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4440.
Charles G Eberhart - One of the best experts on this subject based on the ideXlab platform.
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abstract 4943 the stem cell factor lin28b regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma
Cancer Research, 2020Co-Authors: Huizi Guo, Harpreet Kaur, Charles G Eberhart, Eric RaabeAbstract:Diffuse Intrinsic Pontine Glioma (DIPG) is a lethal pediatric brain tumor. With radiation therapy as the primary treatment, the median survival after diagnosis is 6 months. Identifying molecular markers that regulate tumor growth is urgently needed to develop targeted therapies. LIN28B is a stem cell factor expressed during normal neural development and re-expressed in cancer cells. In many cancers, LIN28B acts as an RNA-binding protein and downregulates the tumor-suppressing let-7 microRNAs. We had previously shown that LIN28A, a homolog of LIN28B, regulates invasion and tumorigenicity in adult high-grade Gliomas. LIN28B is known to be highly expressed in DIPG. Thus, we hypothesized that LIN28B would be important in DIPG by promoting tumor growth. We observed that LIN28B was expressed in patient-derived DIPG cell lines (JHHDIPG1, JHHDIPG16A, SUDIPGXIII, HSJD-007, SF7761). Knockdown of LIN28B using short hairpin RNAs decreased DIPG cell proliferation (BrdU incorporation) between 50% to 90% (p Citation Format: Huizi Guo, Harpreet Kaur, Charles G. Eberhart, Eric H. Raabe. The stem cell factor LIN28B regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4943.
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abstract 4850 the minor groove binding agent quinacrine inhibits growth and increases apoptotic death in diffuse intrinsic Pontine Glioma tumor cells
Cancer Research, 2018Co-Authors: Huizi Guo, Harpreet Kaur, Sepehr Akhtarkhavari, Charles G Eberhart, Eric H RaabeAbstract:Diffuse intrinsic Pontine Glioma (DIPG) is an invasive, incurable and aggressive pediatric brain tumor found in the brainstem. Improved understanding of the biology of DIPG tumors is urgently needed to develop novel treatments. Our previous studies have shown that DIPG tumors and cell lines express high levels of the DNA-binding stem cell factor high mobility group AT-hook 2 (HMGA2).. Targeting HMGA2 using lentiviral shRNA decreased DIPG cell invasion, proliferation and increased apoptosis in our studies. We hypothesized that inhibiting HMGA2 using DNA minor groove binding drugs like quinacrine would decrease DIPG proliferation and increase apoptotic cell death. We used three DIPG cell lines (JHHDIPG1, JHHDIPG16A, and SUDIPG13) to test the effect of quinacrine. Quinacrine has traditionally been used as an anti-malarial drug and is known to strongly bind to DNA. We used BrdU incorporation as a measure of proliferation and expression of cleaved caspase-3 (CC-3) as a measure of apoptosis. Treatment of DIPG cells with quinacrine showed a dose dependent increase in cell death (CC-3 expression) from 3uM to 20uM, with the most effective doses being from 3uM to 5uM. In all three DIPG cell lines, treatment with 1uM to 5uM quinacrine showed a significant reduction in cell proliferation (BrdU) from 3uM to 5uM compared to vehicle-treated cells (P Citation Format: Huizi Guo, Harpreet Kaur, Sepehr Akhtarkhavari, Charles G. Eberhart, Eric H. Raabe. The minor groove binding agent quinacrine inhibits growth and increases apoptotic death in diffuse intrinsic Pontine Glioma tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4850.
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abstract 3868 the stem cell factor lin28b regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma
Cancer Research, 2017Co-Authors: Huizi Guo, Harpreet Kaur, Sepehr Akhtarkhavari, Charles G Eberhart, Eric RaabeAbstract:Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable, invasive and aggressive pediatric brain tumor. Identifying molecular markers that regulate tumor growth and invasion are needed for developing efficient treatment strategies. LIN28B is a stem cell factor expressed during normal fetal development and re-expressed in cancer cells. We had previously shown that LIN28A, another family member of LIN28 proteins, regulates invasion and tumorigenicity in adult high grade Gliomas. We observed increased LIN28B expression in patient-derived DIPG neurosphere cell lines using western blotting. We hypothesized that LIN28B promotes proliferation and prevents apoptosis in DIPG. Using two different lentiviral transduced short hairpin RNAs (shRNA), we suppressed LIN28B protein levels in DIPG neurospheres, as confirmed by western blotting. DIPG neurospheres that have been treated with LIN28B shRNA showed reduced proliferation as measured by BrdU incorporation (P Citation Format: Huizi Guo, Sepehr Akhtarkhavari, Charles G. Eberhart, Harpreet Kaur, Eric H. Raabe. The stem cell factor LIN28B regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3868. doi:10.1158/1538-7445.AM2017-3868
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abstract 4440 diffuse intrinsic Pontine Glioma epigenetic marks change depending on cell culture conditions implications for investigating epigenetically directed therapy
Cancer Research, 2016Co-Authors: Sama Ahsan, Charles G Eberhart, Michael C Haffner, Eric RaabeAbstract:Methylation of cytosine is viewed as repressive of transcription. 5-methylcytosine (5mC) can be removed from DNA by activity of ten-eleven translocation (TET) methylcytosine dioxygenase. The first step in erasing the repressive 5mC mark is conversion to 5-hydroxymethylcytosine (5hmC) by TET. Subsequent steps lead to replacement of 5hmC by cytosine, providing a mechanism by which 5mC-mediated repression can be erased. We have previously identified 5hmC and 5mC as being imbalanced in primary tumor tissue samples from the universally fatal pediatric malignancy diffuse intrinsic Pontine Glioma (DIPG) compared normal brain and glioblastoma (GBM). The aberration in DNA methylation along with known aberrant histone methylation in DIPGs, likely creates an active transcriptional/translational state and potentiates tumor growth. We hypothesized that the elevation of 5hmC in DIPG is secondary to increased TET activity. We found two different epigenetic signatures for DIPG cells depending on their culture conditions. When cultured in serum-free media as neurospheres, to our surprise, we found cells had low 5hmC, in contrast to what we observed in primary tumor and in orthotopic xenograft tumors. We hypothesized that 5hmC status may vary depending on differentiation state, and found that when DIPG cells were differentiated on matrigel for 14 days in the presence of serum, 5hmC levels increased and were similar to that observed in primary tissue and xenograft tumors. Differentiation was confirmed by upregulation of GFAP (glial marker) and MAP2 (neuronal marker) expression and the elaboration of long processes. We also found that DIPG cells in the serum/matrigel/differentiated state had increased TET1 and TET2 mRNA expression relative to undifferentiated neurospheres (2.6 and 2.1 fold increase respectively for TET1 and TET2 mRNA expression). As a control for adherent versus nonadherent growth, we also plated DIPG cells on laminin in EGF/FGF media, and we found that the serum-differentiated cells upregulated TET1 and TET2 mRNA 6.7 and 3.3 fold respectively, compared to laminin-plated cells, providing further support that differentiation affects epigenetic marks in DIPG. In contrast to DIPG, GBM cells did not exhibit similar changes in TET mRNA expression when differentiated, emphasizing the uniqueness of the DIPG epigenetic signature. Our data shows that neurosphere cell culture models of DIPG may not be true epigenetic representations of DIPG tumor in vivo and the predicted response to potential therapeutic options may differ based on the epigenetic state used for preclinical testing. Citation Format: Sama Ahsan, Michael Haffner, Charles Eberhart, Eric Raabe. Diffuse intrinsic Pontine Glioma epigenetic marks change depending on cell culture conditions: Implications for investigating epigenetically directed therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4440.
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disrupting notch slows diffuse intrinsic Pontine Glioma growth enhances radiation sensitivity and shows combinatorial efficacy with bromodomain inhibition
Journal of Neuropathology and Experimental Neurology, 2015Co-Authors: Isabella Taylor, Katherine E. Warren, Charles G Eberhart, Javad Nazarian, Madhuri Kambhampati, Marianne Huttcabezas, William D Brandt, Howard T Chang, Eric H RaabeAbstract:NOTCH regulates stem cells during normal development and stemlike cells in cancer, but the roles of NOTCH in the lethal pediatric brain tumor diffuse intrinsic Pontine Glioma (DIPG) remain unknown. Because DIPGs express stem cell factors such as SOX2 and MYCN, we hypothesized that NOTCH activity would be critical for DIPG growth. We determined that primary DIPGs expressed high levels of NOTCH receptors, ligands, and downstream effectors. Treatment of the DIPG cell lines JHH-DIPG1 and SF7761 with the γ-secretase inhibitor MRK003 suppressed the level of the NOTCH effectors HES1, HES4, and HES5; inhibited DIPG growth by 75%; and caused a 3-fold induction of apoptosis. Short hairpin RNAs targeting the canonical NOTCH pathway caused similar effects. Pretreatment of DIPG cells with MRK003 suppressed clonogenic growth by more than 90% and enhanced the efficacy of radiation therapy. The high level of MYCN in DIPG led us to test sequential therapy with the bromodomain inhibitor JQ1 and MRK003, and we found that JQ1 and MRK003 inhibited DIPG growth and induced apoptosis. Together, these results suggest that dual targeting of NOTCH and MYCN in DIPG may be an effective therapeutic strategy in DIPG and that adding a γ-secretase inhibitor during radiation therapy may be efficacious initially or during reirradiation.
Huizi Guo - One of the best experts on this subject based on the ideXlab platform.
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abstract 4943 the stem cell factor lin28b regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma
Cancer Research, 2020Co-Authors: Huizi Guo, Harpreet Kaur, Charles G Eberhart, Eric RaabeAbstract:Diffuse Intrinsic Pontine Glioma (DIPG) is a lethal pediatric brain tumor. With radiation therapy as the primary treatment, the median survival after diagnosis is 6 months. Identifying molecular markers that regulate tumor growth is urgently needed to develop targeted therapies. LIN28B is a stem cell factor expressed during normal neural development and re-expressed in cancer cells. In many cancers, LIN28B acts as an RNA-binding protein and downregulates the tumor-suppressing let-7 microRNAs. We had previously shown that LIN28A, a homolog of LIN28B, regulates invasion and tumorigenicity in adult high-grade Gliomas. LIN28B is known to be highly expressed in DIPG. Thus, we hypothesized that LIN28B would be important in DIPG by promoting tumor growth. We observed that LIN28B was expressed in patient-derived DIPG cell lines (JHHDIPG1, JHHDIPG16A, SUDIPGXIII, HSJD-007, SF7761). Knockdown of LIN28B using short hairpin RNAs decreased DIPG cell proliferation (BrdU incorporation) between 50% to 90% (p Citation Format: Huizi Guo, Harpreet Kaur, Charles G. Eberhart, Eric H. Raabe. The stem cell factor LIN28B regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4943.
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abstract 4850 the minor groove binding agent quinacrine inhibits growth and increases apoptotic death in diffuse intrinsic Pontine Glioma tumor cells
Cancer Research, 2018Co-Authors: Huizi Guo, Harpreet Kaur, Sepehr Akhtarkhavari, Charles G Eberhart, Eric H RaabeAbstract:Diffuse intrinsic Pontine Glioma (DIPG) is an invasive, incurable and aggressive pediatric brain tumor found in the brainstem. Improved understanding of the biology of DIPG tumors is urgently needed to develop novel treatments. Our previous studies have shown that DIPG tumors and cell lines express high levels of the DNA-binding stem cell factor high mobility group AT-hook 2 (HMGA2).. Targeting HMGA2 using lentiviral shRNA decreased DIPG cell invasion, proliferation and increased apoptosis in our studies. We hypothesized that inhibiting HMGA2 using DNA minor groove binding drugs like quinacrine would decrease DIPG proliferation and increase apoptotic cell death. We used three DIPG cell lines (JHHDIPG1, JHHDIPG16A, and SUDIPG13) to test the effect of quinacrine. Quinacrine has traditionally been used as an anti-malarial drug and is known to strongly bind to DNA. We used BrdU incorporation as a measure of proliferation and expression of cleaved caspase-3 (CC-3) as a measure of apoptosis. Treatment of DIPG cells with quinacrine showed a dose dependent increase in cell death (CC-3 expression) from 3uM to 20uM, with the most effective doses being from 3uM to 5uM. In all three DIPG cell lines, treatment with 1uM to 5uM quinacrine showed a significant reduction in cell proliferation (BrdU) from 3uM to 5uM compared to vehicle-treated cells (P Citation Format: Huizi Guo, Harpreet Kaur, Sepehr Akhtarkhavari, Charles G. Eberhart, Eric H. Raabe. The minor groove binding agent quinacrine inhibits growth and increases apoptotic death in diffuse intrinsic Pontine Glioma tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4850.
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abstract 3868 the stem cell factor lin28b regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma
Cancer Research, 2017Co-Authors: Huizi Guo, Harpreet Kaur, Sepehr Akhtarkhavari, Charles G Eberhart, Eric RaabeAbstract:Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable, invasive and aggressive pediatric brain tumor. Identifying molecular markers that regulate tumor growth and invasion are needed for developing efficient treatment strategies. LIN28B is a stem cell factor expressed during normal fetal development and re-expressed in cancer cells. We had previously shown that LIN28A, another family member of LIN28 proteins, regulates invasion and tumorigenicity in adult high grade Gliomas. We observed increased LIN28B expression in patient-derived DIPG neurosphere cell lines using western blotting. We hypothesized that LIN28B promotes proliferation and prevents apoptosis in DIPG. Using two different lentiviral transduced short hairpin RNAs (shRNA), we suppressed LIN28B protein levels in DIPG neurospheres, as confirmed by western blotting. DIPG neurospheres that have been treated with LIN28B shRNA showed reduced proliferation as measured by BrdU incorporation (P Citation Format: Huizi Guo, Sepehr Akhtarkhavari, Charles G. Eberhart, Harpreet Kaur, Eric H. Raabe. The stem cell factor LIN28B regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3868. doi:10.1158/1538-7445.AM2017-3868
Javad Nazarian - One of the best experts on this subject based on the ideXlab platform.
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histone tail analysis reveals h3k36me2 and h4k16ac as epigenetic signatures of diffuse intrinsic Pontine Glioma
Journal of Experimental & Clinical Cancer Research, 2020Co-Authors: Jeannie M Camarillo, Javad Nazarian, Tina Yiting Huang, Juliette A Morris, Madeline A Zoltek, Mandana Behbahani, Madhuri Kambhampati, Neil L KelleherAbstract:Diffuse intrinsic Pontine Glioma (DIPG) is an aggressive pediatric brainstem tumor. Most DIPGs harbor a histone H3 mutation, which alters histone post-translational modification (PTM) states and transcription. Here, we employed quantitative proteomic analysis to elucidate the impact of the H3.3K27M mutation, as well as radiation and bromodomain inhibition (BRDi) with JQ1, on DIPG PTM profiles. We performed targeted mass spectrometry on H3.3K27M mutant and wild-type tissues (n = 12) and cell lines (n = 7). We found 29.2 and 26.4% of total H3.3K27 peptides were H3.3K27M in mutant DIPG tumor cell lines and tissue specimens, respectively. Significant differences in modification states were observed in H3.3K27M specimens, including at H3K27, H3K36, and H4K16. In addition, H3.3K27me1 and H4K16ac were the most significantly distinct modifications in H3.3K27M mutant tumors, relative to wild-type. Further, H3.3K36me2 was the most abundant co-occurring modification on the H3.3K27M mutant peptide in DIPG tissue, while H4K16ac was the most acetylated residue. Radiation treatment caused changes in PTM abundance in vitro, including increased H3K9me3. JQ1 treatment resulted in increased mono- and di-methylation of H3.1K27, H3.3K27, H3.3K36 and H4K20 in vitro. Taken together, our findings provide insight into the effects of the H3K27M mutation on histone modification states and response to treatment, and suggest that H3K36me2 and H4K16ac may represent unique tumor epigenetic signatures for targeted DIPG therapy.
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acvr1 r206h cooperates with h3 1k27m in promoting diffuse intrinsic Pontine Glioma pathogenesis
Nature Communications, 2019Co-Authors: Christine M. Hoeman, Javad Nazarian, Katie Misuraca, Megan M. Romero, Herminio J. Cardona, Rintaro Hashizume, Francisco Cordero, Roger E Mclendon, Daniele Procissi, Samantha GaddAbstract:Diffuse intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor, with approximately 25% of DIPGs harboring activating ACVR1 mutations that commonly co-associate with H3.1K27M mutations. Here we show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces Glioma-like lesions but is not sufficient for full Gliomagenesis. However, in combination with PDGFA signaling, ACVR1 R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment. Together, our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate Gliomagenesis, promote a mesenchymal profile partly due to Stat3 activation, and identify LDN212854 as a promising compound to treat DIPG.
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ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic Pontine Glioma pathogenesis
Nature Publishing Group, 2019Co-Authors: Christine M. Hoeman, Javad Nazarian, Francisco J. Cordero, Katie Misuraca, Megan M. Romero, Herminio J. Cardona, Rintaro Hashizume, Roger MclendonAbstract:ACVR1 and H3.1K27M mutations co-occur in diffuse intrinsic Pontine Glioma. Here, the authors generate a mouse model that recapitulates these genetic lesions and show, using genetic and pharmacological approaches, that the bone morphogenetic protein pathway may be a therapeutic target in these tumours
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disrupting notch slows diffuse intrinsic Pontine Glioma growth enhances radiation sensitivity and shows combinatorial efficacy with bromodomain inhibition
Journal of Neuropathology and Experimental Neurology, 2015Co-Authors: Isabella Taylor, Katherine E. Warren, Charles G Eberhart, Javad Nazarian, Madhuri Kambhampati, Marianne Huttcabezas, William D Brandt, Howard T Chang, Eric H RaabeAbstract:NOTCH regulates stem cells during normal development and stemlike cells in cancer, but the roles of NOTCH in the lethal pediatric brain tumor diffuse intrinsic Pontine Glioma (DIPG) remain unknown. Because DIPGs express stem cell factors such as SOX2 and MYCN, we hypothesized that NOTCH activity would be critical for DIPG growth. We determined that primary DIPGs expressed high levels of NOTCH receptors, ligands, and downstream effectors. Treatment of the DIPG cell lines JHH-DIPG1 and SF7761 with the γ-secretase inhibitor MRK003 suppressed the level of the NOTCH effectors HES1, HES4, and HES5; inhibited DIPG growth by 75%; and caused a 3-fold induction of apoptosis. Short hairpin RNAs targeting the canonical NOTCH pathway caused similar effects. Pretreatment of DIPG cells with MRK003 suppressed clonogenic growth by more than 90% and enhanced the efficacy of radiation therapy. The high level of MYCN in DIPG led us to test sequential therapy with the bromodomain inhibitor JQ1 and MRK003, and we found that JQ1 and MRK003 inhibited DIPG growth and induced apoptosis. Together, these results suggest that dual targeting of NOTCH and MYCN in DIPG may be an effective therapeutic strategy in DIPG and that adding a γ-secretase inhibitor during radiation therapy may be efficacious initially or during reirradiation.
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clinicopathology of diffuse intrinsic Pontine Glioma and its redefined genomic and epigenomic landscape
Cancer Genetics and Cytogenetics, 2015Co-Authors: Javad Nazarian, Roger J Packer, Eshini Panditharatna, Kurt A Yaeger, Lindsay KilburnAbstract:Diffuse intrinsic Pontine Glioma (DIPG) is one of the most lethal pediatric central nervous system (CNS) cancers. Recently, a surge in molecular studies of DIPG has occurred, in large part due to the increased availability of tumor tissue through donation of post-mortem specimens. These new discoveries have established DIPGs as biologically distinct from adult Gliomas, harboring unique genomic aberrations. Mutations in histone encoding genes are shown to be associated with >70% of DIPG cases. However, the exact molecular mechanisms of the tumorigenicity of these mutations remain elusive. Understanding the driving mutations and genomic landscape of DIPGs can now guide the development of targeted therapies for this incurable childhood cancer.
Harpreet Kaur - One of the best experts on this subject based on the ideXlab platform.
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abstract 4943 the stem cell factor lin28b regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma
Cancer Research, 2020Co-Authors: Huizi Guo, Harpreet Kaur, Charles G Eberhart, Eric RaabeAbstract:Diffuse Intrinsic Pontine Glioma (DIPG) is a lethal pediatric brain tumor. With radiation therapy as the primary treatment, the median survival after diagnosis is 6 months. Identifying molecular markers that regulate tumor growth is urgently needed to develop targeted therapies. LIN28B is a stem cell factor expressed during normal neural development and re-expressed in cancer cells. In many cancers, LIN28B acts as an RNA-binding protein and downregulates the tumor-suppressing let-7 microRNAs. We had previously shown that LIN28A, a homolog of LIN28B, regulates invasion and tumorigenicity in adult high-grade Gliomas. LIN28B is known to be highly expressed in DIPG. Thus, we hypothesized that LIN28B would be important in DIPG by promoting tumor growth. We observed that LIN28B was expressed in patient-derived DIPG cell lines (JHHDIPG1, JHHDIPG16A, SUDIPGXIII, HSJD-007, SF7761). Knockdown of LIN28B using short hairpin RNAs decreased DIPG cell proliferation (BrdU incorporation) between 50% to 90% (p Citation Format: Huizi Guo, Harpreet Kaur, Charles G. Eberhart, Eric H. Raabe. The stem cell factor LIN28B regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4943.
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abstract 4850 the minor groove binding agent quinacrine inhibits growth and increases apoptotic death in diffuse intrinsic Pontine Glioma tumor cells
Cancer Research, 2018Co-Authors: Huizi Guo, Harpreet Kaur, Sepehr Akhtarkhavari, Charles G Eberhart, Eric H RaabeAbstract:Diffuse intrinsic Pontine Glioma (DIPG) is an invasive, incurable and aggressive pediatric brain tumor found in the brainstem. Improved understanding of the biology of DIPG tumors is urgently needed to develop novel treatments. Our previous studies have shown that DIPG tumors and cell lines express high levels of the DNA-binding stem cell factor high mobility group AT-hook 2 (HMGA2).. Targeting HMGA2 using lentiviral shRNA decreased DIPG cell invasion, proliferation and increased apoptosis in our studies. We hypothesized that inhibiting HMGA2 using DNA minor groove binding drugs like quinacrine would decrease DIPG proliferation and increase apoptotic cell death. We used three DIPG cell lines (JHHDIPG1, JHHDIPG16A, and SUDIPG13) to test the effect of quinacrine. Quinacrine has traditionally been used as an anti-malarial drug and is known to strongly bind to DNA. We used BrdU incorporation as a measure of proliferation and expression of cleaved caspase-3 (CC-3) as a measure of apoptosis. Treatment of DIPG cells with quinacrine showed a dose dependent increase in cell death (CC-3 expression) from 3uM to 20uM, with the most effective doses being from 3uM to 5uM. In all three DIPG cell lines, treatment with 1uM to 5uM quinacrine showed a significant reduction in cell proliferation (BrdU) from 3uM to 5uM compared to vehicle-treated cells (P Citation Format: Huizi Guo, Harpreet Kaur, Sepehr Akhtarkhavari, Charles G. Eberhart, Eric H. Raabe. The minor groove binding agent quinacrine inhibits growth and increases apoptotic death in diffuse intrinsic Pontine Glioma tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4850.
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abstract 3868 the stem cell factor lin28b regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma
Cancer Research, 2017Co-Authors: Huizi Guo, Harpreet Kaur, Sepehr Akhtarkhavari, Charles G Eberhart, Eric RaabeAbstract:Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable, invasive and aggressive pediatric brain tumor. Identifying molecular markers that regulate tumor growth and invasion are needed for developing efficient treatment strategies. LIN28B is a stem cell factor expressed during normal fetal development and re-expressed in cancer cells. We had previously shown that LIN28A, another family member of LIN28 proteins, regulates invasion and tumorigenicity in adult high grade Gliomas. We observed increased LIN28B expression in patient-derived DIPG neurosphere cell lines using western blotting. We hypothesized that LIN28B promotes proliferation and prevents apoptosis in DIPG. Using two different lentiviral transduced short hairpin RNAs (shRNA), we suppressed LIN28B protein levels in DIPG neurospheres, as confirmed by western blotting. DIPG neurospheres that have been treated with LIN28B shRNA showed reduced proliferation as measured by BrdU incorporation (P Citation Format: Huizi Guo, Sepehr Akhtarkhavari, Charles G. Eberhart, Harpreet Kaur, Eric H. Raabe. The stem cell factor LIN28B regulates proliferation and apoptosis in diffuse intrinsic Pontine Glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3868. doi:10.1158/1538-7445.AM2017-3868
