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Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
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Defining the molecular mechanisms of DIPG development and progression to uncover novel theraputic targets
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary


 
Diffuse Intrinsic Pontine Gliomas (DIPGs) are devastating pediatric brainstem tumors that lack effective treatment and are uniformly fatal. Patient studies have identified recurrent genetic lesions that drive the development of these tumors. Almost all DIPGs carry mutations in genes encoding either replication-dependent histone-H3 proteins (mostly HIST1H3B) or in a replication-independent histone (H3F3A). These mutations always substitute lysine with methionine at position 27 (K27M) of the H3 protein. The tumorigenicity of histone K27M mutations is thought to stem from epigenetic reprogramming of tumor-initiating glial cells in the brain. Moreover, recent genetic data strongly suggest that DIPGs can be clustered into distinct subtypes based on specific “partner” mutations that co-occur with the K27M H3 mutations. For example, most H3F3AK27M mutant tumors carry lesions in the well-characterized tumor suppressor gene TP53. This is not the case for HIST1H3BK27M mutant malignancies, which instead commonly harbor lesions that either cause a gain-offunction in ACVR1, a bone morphogenetic protein (BMP) type I receptor, or hyperactivate the PTEN/PI3K pathway. The oncogenic mechanisms of action of activating mutations in ACVR1 are poorly characterized. Understanding the mechanisms that drive DIPG subtype development, and how these tumors might differ in therapeutic vulnerability, is crucial for the development of effective DIPG treatments.  
 
In our proposal, we will test the hypothesis that oncogenic synergy between epigenomic reprogramming induced by HIST1H3BK27M mutations and cellular hyperproliferation driven by ACVR1 and PTEN/PI3K pathway mutations underlie unique therapeutic vulnerabilities in DIPG tumors. We will deploy a multidisciplinary approach that combines complementary areas of expertise and reagents, including the generation and analysis of the first pre-clinical mouse models harboring DIPG-causing mutations in the endogenous Acvr1 and Hist1h3b genes. Using these models, we will characterize the molecular effects of Acvr1 and Hist1h3b mutations and dissect their interaction and synergy. We will then harness an innovative direct in vivo CRISPR/Cas9 platform to combine multiple co-occurring mutations and describe their oncogenic mechanisms of action. We will pay particular attention to investigating how PTEN/PI3K pathway hyperactivation cooperates with Acvr1 and Hist1h3b mutations. Finally, we will meld these analyses with human DIPG transcriptome data and perform functional experiments in patient-derived cell lines to uncover candidate therapeutic targets. We have already established a broad toolbox of reagents useful for our planned studies and have accumulated substantial preliminary data in support of our objectives.  
 
We expect that our project will uncover the molecular mechanisms whereby ACVR1, HIST1H3B and PTEN/PI3K pathway mutations cooperate to drive DIPG development and progression. We further anticipate that our studies will reveal candidate therapeutic targets for tumors harboring this combination of lesions, and possibly for DIPGs in general.  
 

Executive Summary


 
Diffuse Intrinsic Pontine Gliomas (DIPGs) are devastating pediatric brainstem tumors that lack effective treatment and are uniformly fatal. Patient studies have identified recurrent genetic lesions that drive the development of these tumors. Almost all DIPGs carry mutations in genes encoding either replication-dependent histone-H3 proteins (mostly HIST1H3B) or in a replication-independent histone (H3F3A). These mutations always substitute lysine with methionine at position 27 (K27M) of the H3 protein. The tumorigenicity of histone K27M mutations is thought to stem from epigenetic reprogramming of tumor-initiating glial cells in the brain. Moreover, recent genetic data strongly suggest that DIPGs can be clustered into distinct subtypes based on specific “partner” mutations that co-occur with the K27M H3 mutations. For example, most H3F3AK27M mutant tumors carry lesions in the well-characterized tumor suppressor gene TP53. This is not the case for HIST1H3BK27M mutant malignancies, which instead commonly harbor lesions that either cause a gain-offunction in ACVR1, a bone morphogenetic protein (BMP) type I receptor, or hyperactivate the PTEN/PI3K pathway. The oncogenic mechanisms of action of activating mutations in ACVR1 are poorly characterized. Understanding the mechanisms that drive DIPG subtype development, and how these tumors might differ in therapeutic vulnerability, is crucial for the development of effective DIPG treatments.  
 
In our proposal, we will test the hypothesis that oncogenic synergy between epigenomic reprogramming induced by HIST1H3BK27M mutations and cellular hyperproliferation driven by ACVR1 and PTEN/PI3K pathway mutations underlie unique therapeutic vulnerabilities in DIPG tumors. We will deploy a multidisciplinary approach that combines complementary areas of expertise and reagents, including the generation and analysis of the first pre-clinical mouse models harboring DIPG-causing mutations in the endogenous Acvr1 and Hist1h3b genes. Using these models, we will characterize the molecular effects of Acvr1 and Hist1h3b mutations and dissect their interaction and synergy. We will then harness an innovative direct in vivo CRISPR/Cas9 platform to combine multiple co-occurring mutations and describe their oncogenic mechanisms of action. We will pay particular attention to investigating how PTEN/PI3K pathway hyperactivation cooperates with Acvr1 and Hist1h3b mutations. Finally, we will meld these analyses with human DIPG transcriptome data and perform functional experiments in patient-derived cell lines to uncover candidate therapeutic targets. We have already established a broad toolbox of reagents useful for our planned studies and have accumulated substantial preliminary data in support of our objectives.  
 
We expect that our project will uncover the molecular mechanisms whereby ACVR1, HIST1H3B and PTEN/PI3K pathway mutations cooperate to drive DIPG development and progression. We further anticipate that our studies will reveal candidate therapeutic targets for tumors harboring this combination of lesions, and possibly for DIPGs in general.  
 

Description of Research Proposal

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Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.

Morbi orci urna, ornare non pretium eget, pulvinar eget magna. Ut consectetur efficitur varius. Fusce ac aliquet mauris, at mattis ligula. Quisque est libero, interdum id orci et, ornare luctus diam. Proin commodo lectus id accumsan blandit. Nulla eu turpis interdum, luctus ante ac, imperdiet tellus. In semper enim eu tristique aliquam.

Integer fermentum vestibulum lacinia. Duis id aliquam nibh, ut mattis leo. Nulla ac dui at sapien posuere facilisis ut quis ex. Aliquam vestibulum blandit tristique. Integer pretium dui ac nulla accumsan, et finibus velit euismod. Proin placerat, nunc eu sodales facilisis, tellus justo efficitur risus, non blandit diam nulla ac ligula. Aliquam ullamcorper quam leo, porttitor dictum ex tempor ac. Ut efficitur, justo et auctor volutpat, ex ex pulvinar est, sed consequat turpis leo nec ipsum. Nunc tempor, turpis ut ullamcorper tempor, dolor dui varius dui, et congue quam nisi vel nunc.

Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Donec faucibus, turpis sit amet maximus dapibus, sapien nisl bibendum turpis, pharetra commodo tellus libero vel nulla. Sed nec velit viverra, congue sapien et, gravida libero. Proin eget ante eget turpis egestas accumsan. Aliquam arcu nibh, aliquam rhoncus vulputate in, pellentesque at sem. Maecenas cursus tempus nibh id tempus. Mauris dolor sapien, lacinia sit amet condimentum at, dapibus eget lectus. Phasellus vel pellentesque ex. Nunc aliquam in ligula at tristique. In mollis suscipit felis eu finibus. Nullam non dignissim nibh, nec suscipit ex. Suspendisse tincidunt et mauris id finibus. Aliquam vehicula a sem quis venenatis.

Suspendisse leo odio, rutrum et viverra ut, consequat finibus enim. Vivamus dolor nisl, viverra eu egestas vel, blandit in nulla. Curabitur auctor purus non est volutpat bibendum. Proin fringilla magna sed metus maximus, in dictum neque suscipit. Sed ornare ut mi ut sodales. Nulla efficitur urna nunc, non molestie nunc egestas ut. Nunc arcu lorem, semper ut tincidunt ac, eleifend quis elit.

Sed at tortor et tortor tincidunt feugiat id in dui. Vivamus eget justo nisl. Aenean congue laoreet nisl a elementum. Nunc consectetur velit non ligula sollicitudin, quis eleifend urna sollicitudin. Sed tincidunt, nisl quis varius venenatis, dui massa condimentum tellus, sed sollicitudin diam magna mollis augue. Sed venenatis commodo purus id malesuada. Aenean volutpat elit vel gravida consectetur. Vestibulum diam quam, lacinia ac tortor eget, tincidunt dapibus dui. Pellentesque habitant morbi tristique senectus et netus et malesuada fames ac turpis egestas. Proin nisl leo, pretium sed arcu imperdiet, hendrerit sollicitudin sem. Duis non magna at nunc sagittis ullamcorper a id est. Maecenas cursus nisl in faucibus hendrerit.

Sed hendrerit vitae purus et tempor. Aenean vitae varius velit. Nullam aliquet ipsum elit. Mauris vestibulum purus et metus imperdiet, quis gravida eros pretium. Curabitur rutrum nunc vitae tincidunt condimentum. Aenean sit amet augue velit. Nunc tristique quis lorem id pharetra. Pellentesque sollicitudin, eros sed egestas rutrum, nulla nisl sodales elit, ut imperdiet nunc lectus sit amet nulla. Ut malesuada finibus libero. Curabitur mi dolor, sollicitudin quis bibendum quis, dictum sed enim.

Pellentesque nibh erat, egestas sit amet sagittis malesuada, rhoncus at neque. Mauris maximus commodo tortor, non egestas magna finibus vitae. Sed hendrerit nulla vel venenatis tempor. Suspendisse tristique tincidunt libero et placerat. Nam tincidunt condimentum lorem, vel pharetra est iaculis sed. Nullam ac tincidunt orci. Quisque pharetra ut sem sit amet aliquam. Phasellus risus libero, varius in condimentum vel, commodo id ipsum. Aliquam in metus cursus, mattis diam ut, aliquam magna. Suspendisse facilisis dui et orci varius, suscipit facilisis augue dapibus. In eget nibh ipsum. Suspendisse eget pharetra est, quis condimentum felis. Fusce scelerisque congue libero, sed aliquam mi elementum a. Etiam scelerisque ante non auctor porta. Nam eu nunc id ex finibus dictum. Praesent dui ex, dictum ac massa eget, rutrum gravida nisi.

Sed egestas arcu in dui euismod, eget faucibus massa iaculis. Etiam efficitur lectus et purus lobortis, ac blandit eros rutrum. Proin bibendum consectetur leo vel gravida. Etiam et ultricies sapien. Nam lacinia tellus erat, id facilisis est consequat et. Morbi quis risus in neque iaculis pharetra ut consectetur libero. Aenean feugiat tempor mi eu posuere.

Budget

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.

Morbi orci urna, ornare non pretium eget, pulvinar eget magna. Ut consectetur efficitur varius. Fusce ac aliquet mauris, at mattis ligula. Quisque est libero, interdum id orci et, ornare luctus diam. Proin commodo lectus id accumsan blandit. Nulla eu turpis interdum, luctus ante ac, imperdiet tellus. In semper enim eu tristique aliquam.

Collaborations and Conflicts of Interest

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.