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Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
Funding Progress: $§ / $§§§§§

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EPIGENETIC ALTERATIONS AS THERAPEUTIC TARGETS IN PEDIATRIC BRAIN TUMORS
Clinical
DIPG, Childhood (Brain Cancer)
Lay Summary

We and others co-discovered the presence of activating mutations in ACVR1 in 25% of human DIPGs in 2014. Subsequently, my laboratory has developed a murine DIPG model incorporating R206H ACVR1 and observed that R206H ACVR1 significantly accelerates brainstem gliomagenesis. In addition, short-term treatment with a bone morphogenetic protein pathway inhibitor (LDN-212854), significantly reduced proliferation in this model. Furthermore, we have preliminary data that the MAPK pathway is upregulated in human DIPGs with ACVR1 mutations and that the MAPK pathway remains activated in our murine DIPG model despite BMP pathway inhibition.

Therefore, we hypothesize that inhibiting both the BMP pathway and the MAPK pathway will significantly prolong survival of ACVR1 mutant DIPG-bearing mice. Here are proposing to test two treatment strategies: 1) LDN-212854 (a BMP pathway inhibitor) in combination with a MEK inhibitor (PD-0325901), and 2) E6201, a small molecule inhibitor that inhibits both the BMP pathway and the MAPK pathway. Of note, both PD-0325901 and E6201 are already in clinical trials in adult cancers.

The biology in pediatric HGG is poorly understood and understudied. There is a crucial need to identify targets to design new therapeutic agents. This pilot study will significantly contribute to the understanding of the biology of this devastating disease and may lead to the recognition of a targetable pathway and ultimately to a cure.  This is the first study targeting EZH2 in pediatric brain tumors.

We request $100,000 to cover the cost of the above studies.

Executive Summary

Brain tumors remain the leading cause of cancer-related deaths in children. Even among survivors, long-term neurocognitive and neuroendocrine sequelae of current therapies are often devastating. Hence, there is an urgent need to develop novel therapies that not only improve outcome, but mitigate long-term complications in children with brain tumors. Pediatric non-brainstem high-grade glioma (pNBS-HGG) and diffuse intrinsic pontine glioma (DIPG) are among the deadliest pediatric brain tumors. Epigenetic modulation of histones plays an important role in regulation of gene expression and oncogenic transformation in many cancer types. Among the most impactful findings to date has been the discovery in pNBS-HGG and DIPG of high prevalence mutations in chromatin remodeling genes H3F3A and HIST1H3B encoding histones H3.3 and H3.1, respectively. The consequence of these mutant histones relates to epigenetic modulation, mediated in large part by EZH2, a key component of the multi-protein histone methyltrasferase polycomb repressive complex 2 (PRC2). EZH2 catalyzes the trimethylation of histone H3 lysine 27 (H3K27me3), a repressive chromatin mark. H3.3K27M has been identified as a major driver mutation in pNBS-HGG and DIPG, and has been shown to be particularly prevalent in children. The presence of this mutation defines a clinically and biologically distinct subgroup of tumors and is associated with strikingly short survival. H3.3K27M is believed to target EZH2 activity to genes associated with tumorigenesis such as p16Ink4A and produces a repressive epigenetic alteration, thereby causing a decrease in the expression of these genes leading to tumor development. We hypothesize that EZH2 activity is critical for the establishment and the development of pNBS-HGG and DIPG and its specific inhibition will lead to the expression of tumor suppressor genes; thus, to the inhibition of tumor growth. We propose to evaluate the activity of a potent EZH2 inhibitor in DIPG and pNBS-HGG patient-derived cells and in mouse models of pNBS-HGG and DIPG.

 

The biology in pediatric HGG is poorly understood and understudied. There is a crucial need to identify targets to design new therapeutic agents. This pilot study will significantly contribute to the understanding of the biology of this devastating disease and may lead to the recognition of a targetable pathway and ultimately to a cure.  This is the first study targeting EZH2 in pediatric brain tumors.

We request $100,000 to cover the cost of the above studies.

Description of Research Proposal

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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.

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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.