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Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
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MRI Guided Focused Ultrasound: Targeted Drug Delivery in Diffuse Intrinsic Pontine Glioma
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

Hypothesis & Anticipated Results

Diffuse Intrinsic Pontine Glioma, (DIPG) is a fatal cancer and the leading cause of death from  brain tumours in young children. Despite numerous existing chemotherapeutic agents and  promising new molecular therapies, one overriding challenge remains: to overcome the blood  brain barrier (BBB) and achieve effective delivery of these agents to the tumour site. We  propose to use MRI guided focused ultrasound (MRIgFUS) to achieve non-invasive, focal and  reversible disruption of the BBB thereby creating a window of opportunity for drug delivery.  We believe that not only will MRIgFUS of the brainstem be safe but it will significantly enhance  drug concentrations within the tumour and in turn confer improved survival.     ii) Specific Aims Aim 1: To determine the safety of transient disruption of the BBB of the murine brainstem by  MRIgFUS  Aim 2: To develop and optimize preclinical models of DIPG for delivery of known and novel  chemotherapeutics using MRIgFUS.    iii)! Background!and!Rationale:!   a)! Diffuse Intrinsic Pontine Glioma (DIPG): A devastating cancer  Primary brain tumours occur across all age groups and confer a poor prognosis in the majority.  Gliomas are the predominant tumour type, constituting 65% of all primary brain tumours.  Diffuse Intrinsic Pontine Glioma is a high grade glioma that arises in the pons and occurs  almost exclusively in young children. Its eloquent location and aggressive nature results in a  near 100% fatality rate within 2 years of diagnosis and as such, is a truly devastating diagnosis  for families of afflicted patients1. The diffuse growth pattern of these tumours precludes  surgical resection and current treatment is confined to radiotherapy which provides only  transient remission.  Numerous clinical trials assessing a multitude of chemotherapeutic  agents have failed to demonstrate an improvement in survival2. As such, DIPG is now the  leading cause of brain tumour deaths in children3.    b) Molecular Developments & Preclinical Models  Through  a  combination  of  autopsy  samples  and  the  advent  of  safe  brainstem  biopsy  techniques, significant strides have been made in elucidating the underlying molecular drivers  of DIPG. The most commonly found mutation is now known to be that of a Lys27met (K27M)  substitution in histone H3 (70-84%) with resultant local hypomethylation4-7. Mutations and  copy number alterations have also been identified in TP53 (42 – 71%) and ACVR1 (20-32%)  which encodes the activin A receptor type 12,8. Identification of these genes has not only led  to the determination of pathways leading to tumorigenesis and subsequent new targets for  therapy but has also helped advance the sophistication of pre-clinical models. 

Executive Summary

Hypothesis & Anticipated Results

Diffuse Intrinsic Pontine Glioma, (DIPG) is a fatal cancer and the leading cause of death from  brain tumours in young children. Despite numerous existing chemotherapeutic agents and  promising new molecular therapies, one overriding challenge remains: to overcome the blood  brain barrier (BBB) and achieve effective delivery of these agents to the tumour site. We  propose to use MRI guided focused ultrasound (MRIgFUS) to achieve nonLinvasive, focal and  reversible disruption of the BBB thereby creating a window of opportunity for drug delivery.  We believe that not only will MRIgFUS of the brainstem be safe but it will significantly enhance  drug concentrations within the tumour and in turn confer improved survival.     ii)! Specific!Aims! Aim 1: To determine the safety of transient disruption of the BBB of the murine brainstem by  MRIgFUS  Aim 2: To develop and optimize preclinical models of DIPG for delivery of known and novel  chemotherapeutics using MRIgFUS.    iii) Background!and!Rationale:   a) Diffuse Intrinsic Pontine Glioma (DIPG): A devastating cancer  Primary brain tumours occur across all age groups and confer a poor prognosis in the majority.  Gliomas are the predominant tumour type, constituting 65% of all primary brain tumours.  Diffuse Intrinsic Pontine Glioma is a high grade glioma that arises in the pons and occurs  almost exclusively in young children. Its eloquent location and aggressive nature results in a  near 100% fatality rate within 2 years of diagnosis and as such, is a truly devastating diagnosis  for families of afflicted patients1. The diffuse growth pattern of these tumours precludes  surgical resection and current treatment is confined to radiotherapy which provides only  transient remission.  Numerous clinical trials assessing a multitude of chemotherapeutic  agents have failed to demonstrate an improvement in survival2. As such, DIPG is now the  leading cause of brain tumour deaths in children3.    ! b) Molecular Developments & Preclinical Models  Through  a  combination  of  autopsy  samples  and  the  advent  of  safe  brainstem  biopsy  techniques, significant strides have been made in elucidating the underlying molecular drivers  of DIPG. The most commonly found mutation is now known to be that of a Lys27met (K27M)  substitution in histone H3 (70-84%) with resultant local hypomethylation4-7. Mutations and  copy number alterations have also been identified in TP53 (42 – 71%) and ACVR1 (20-32%)  which encodes the activin A receptor type 12,8. Identification of these genes has not only led  to the determination of pathways leading to tumorigenesis and subsequent new targets for  therapy but has also helped advance the sophistication of preLclinical models. 

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.

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.