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Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
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Establishment of a pre-clinical model for pediatric glioblastoma
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

Glioblastoma is a highly aggressive astrocytoma affecting thousands of adults and children each year in the United States. Current treatments are ineffective and as a consequence, overall survival is dismal. Moreover, there have been few clinical gains achieved in the last three decades. Accumulating evidence obtained through the study of primary high-grade astrocytomas (HGAs) suggests that pediatric and adult tumors have different molecular pathologies that may underlie differences in the clinical behavior of these patients. Interestingly, there is recent evidence that diffuse intrinsic pontine gliomas (DIPGs) may share some molecular pathological features with pediatric HGAs but not adult tumors. This suggests that effective molecularly targeted therapies for adults may be ineffective or minimally effective in pediatric patients. However, major gaps in our understanding of pediatric HGA biology remain and one hurdle is the lack of animal models that faithfully recapitulate these tumors. We have generated a mouse model for HGA by using inducible Cre-loxP mice to target brainspecific inactivation of the tumor suppressors Pten, p53 and the Rb pocket family members Rb1 and Rbl1 (which encodes p107). These genes regulate core pathways that are frequently dysregulated in pediatric HGA. Preliminary data indicates that this model gives rise to highly penetrant, spontaneously occurring brain tumors that bear a striking histopathological resemblance to pediatric HGA. We hypothesize that a comparative analysis of secondary mutations occurring in mouse tumors and those occurring in pediatric HGA will lead to the identification of critical genes and pathways governing tumor growth and survival. Moreover, we propose that the use of this model in pre-clinical multi-agent trials will accelerate the investigation of combined targeted agents in clinical trials. The specific aims of the proposal are three-fold. 1) We will perform a comprehensive and comparative molecular pathological characterization of mouse and pediatric HGAs in order to identify mutations and pathways contributing to tumor growth and survival. This will involve the interrogation of tumors with microarray technology (array comparative genomic hybridization, gene expression microarray and microRNA expression array) coupled with an integrative analysis of the data and independent validation of potential targets. 2) We will demonstrate proof-of-concept for the use of this mouse model in preclinical studies by comparing the effect on in vivo HGA growth in mice treated with “standard of care” (cranial irradiation) to targeted therapy against a core pathway in glioblastoma, the PI3K/Akt/mTor pathway (rapamycin or BEZ-235). Treatment with these targeted agents is expected to result in delayed growth but not eradication of HGA. 3) To identify the most promising targets for combination therapy, we will perform gene expression profiling on HGA treated in vivo with rapamycin or BEZ-235. The comparison of gene expression profiles between untreated and treated tumors will highlight growth and survival pathways that allow tumors to escape single agent therapies, which have been uniformly disappointing in clinical trials to date. Targeted agents against these pathways will be used in combination with rapamycin or BEZ-235 for in vivo treatment of mice to test for synergy against HGA growth. This scheme will be applied iteratively to build a multi-agent treatment protocol. Our goal is to harness the power of genetically engineered mouse models for cancer, which have been found to replicate human tumors more faithfully than cell lines or xenografts, and the growing library of molecularly-targeted small molecule inhibitors in order to rapidly develop rational protocols of treatment for this devastating disease that can be tested in clinical trials. In addition to the principal investigator’s expertise in clinical neuro-oncology and in the design, handling and analyses of mouse models for brain tumors, this project will also draw on the expertise of a clinical neuropathologist familiar with the histology of mouse tumors (Dr. Lili Miles) and a bioinformatician who has developed novel pathway analysis tools using gene expression data (Dr. Zhandong Liu). This project will also provide the preliminary data required to secure external funding for further preclinical studies. 
SECTION 3 1. Hypothesis and Anticipated Results  We hypothesize that appropriately designed genetically 

Executive Summary

Glioblastoma is a highly aggressive astrocytoma affecting thousands of adults and children each year in the United States. Current treatments are ineffective and as a consequence, overall survival is dismal. Moreover, there have been few clinical gains achieved in the last three decades. Accumulating evidence obtained through the study of primary high-grade astrocytomas (HGAs) suggests that pediatric and adult tumors have different molecular pathologies that may underlie differences in the clinical behavior of these patients. Interestingly, there is recent evidence that diffuse intrinsic pontine gliomas (DIPGs) may share some molecular pathological features with pediatric HGAs but not adult tumors. This suggests that effective molecularly targeted therapies for adults may be ineffective or minimally effective in pediatric patients. However, major gaps in our understanding of pediatric HGA biology remain and one hurdle is the lack of animal models that faithfully recapitulate these tumors. We have generated a mouse model for HGA by using inducible Cre-loxP mice to target brainspecific inactivation of the tumor suppressors Pten, p53 and the Rb pocket family members Rb1 and Rbl1 (which encodes p107). These genes regulate core pathways that are frequently dysregulated in pediatric HGA. Preliminary data indicates that this model gives rise to highly penetrant, spontaneously occurring brain tumors that bear a striking histopathological resemblance to pediatric HGA. We hypothesize that a comparative analysis of secondary mutations occurring in mouse tumors and those occurring in pediatric HGA will lead to the identification of critical genes and pathways governing tumor growth and survival. Moreover, we propose that the use of this model in pre-clinical multi-agent trials will accelerate the investigation of combined targeted agents in clinical trials. The specific aims of the proposal are three-fold. 1) We will perform a comprehensive and comparative molecular pathological characterization of mouse and pediatric HGAs in order to identify mutations and pathways contributing to tumor growth and survival. This will involve the interrogation of tumors with microarray technology (array comparative genomic hybridization, gene expression microarray and microRNA expression array) coupled with an integrative analysis of the data and independent validation of potential targets. 2) We will demonstrate proof-of-concept for the use of this mouse model in preclinical studies by comparing the effect on in vivo HGA growth in mice treated with “standard of care” (cranial irradiation) to targeted therapy against a core pathway in glioblastoma, the PI3K/Akt/mTor pathway (rapamycin or BEZ-235). Treatment with these targeted agents is expected to result in delayed growth but not eradication of HGA. 3) To identify the most promising targets for combination therapy, we will perform gene expression profiling on HGA treated in vivo with rapamycin or BEZ-235. The comparison of gene expression profiles between untreated and treated tumors will highlight growth and survival pathways that allow tumors to escape single agent therapies, which have been uniformly disappointing in clinical trials to date. Targeted agents against these pathways will be used in combination with rapamycin or BEZ-235 for in vivo treatment of mice to test for synergy against HGA growth. This scheme will be applied iteratively to build a multi-agent treatment protocol. Our goal is to harness the power of genetically engineered mouse models for cancer, which have been found to replicate human tumors more faithfully than cell lines or xenografts, and the growing library of molecularly-targeted small molecule inhibitors in order to rapidly develop rational protocols of treatment for this devastating disease that can be tested in clinical trials. In addition to the principal investigator’s expertise in clinical neuro-oncology and in the design, handling and analyses of mouse models for brain tumors, this project will also draw on the expertise of a clinical neuropathologist familiar with the histology of mouse tumors (Dr. Lili Miles) and a bioinformatician who has developed novel pathway analysis tools using gene expression data (Dr. Zhandong Liu). This project will also provide the preliminary data required to secure external funding for further preclinical studies. 
SECTION 3 1. Hypothesis and Anticipated Results  We hypothesize that appropriately designed genetically 

Description of Research Proposal

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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.

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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.