Brain tumors are the leading cause of mortality and morbidity from cancer in children and young adults. Malignant gliomas, including supra9tentorial high grade gliomas (HGG) and Diffuse Intrinsic Pontine Gliomas (DIPG), remain a major therapeutic challenge in pediatric oncology because they are still incurable. The failure of current treatments is explained by the difficulties to do a complete surgical resection, and by the low penetration of drugs commonly used neuro9oncology. This low penetration is related to the existence of the blood9brain barrier (BBB), that consists partly of endothelial cells intimately linked together by tight junctions and prevents about 98% of small molecules and 100% of large molecules to reach the brain parenchyma.
It is now proven that the application on brain parenchyma of low power pulsed ultrasound (US) in combination with an US microbubble contrast agent (UCA) can safely and transiently open the BBB (Hynynen et al, Radiology 2001). A significant increase in penetration of several antineoplastic drugs, high molecular weight antibodies, DNA plasmid and neural stem cells has been observed after US9induced opening of the BBB. Studies on murine models of gliomas even showed an improved tumor control and increasing animal survival. These studies, initially conducted on small animals, have recently been applied by us in primates with confirmation of previous results (Horodyckid et al, J Neurosurg in press).
The skull represents the main obstacle to the use of US in neuro9oncology, since the bone induces distortions and attenuation of ultrasonic energy. Considering the fact that a surgical procedure is systematically carried out during the treatment of primary brain tumors (resection or biopsy), the research team CarThéra™, directed by Pr Alexandre Carpentier, has recently developed an implantable ultrasonic transducer. The concept was described in a recent publication with opening of the BBB in rabbits (Beccaria et al, J Neurosurg 2013). The team was able to demonstrate a significant increase in intracerebral concentration of Temozolomide and Irinotecan in rabbits following US9induced opening of the BBB (Beccaria et al, J Neurosurg 2015). The first clinical trial is under way in La Pitié Salpétrière Hopistal (Paris, France) under the coordination of Pr A. Carpentier (NCT02253212 ; see also Carpentier et al, Sci Transl Med in press).
A few of molecules have shown a very good anti9tumor efficacy on DIPG primary cell lines but many of them have poor diffusion across the BBB (Grasso et al, Nat Med 2015). One of the most effective drugs, the panHDAC inhibitor Panobinostat has recently shown a strong anti9 tumor activity in vitro and in vivo, but this molecule presents a low penetrance through the blood9brain barrier (~10% in mouse), and its therapeutic index is limited by hematotoxicity.
There is therefore a strong rationale to explore panobinostat with unfocused US in a preclinical xenograft model of DIPG deriving from treatment9naive biopsies. After adaptation and validation of US parameters in mice, we will explore the pharmacokinetics of panobinostat in blood and brain (pons, cortex, thalamus) in healthy mice and then in DIPG mouse models after opening of the BBB with US. Depending on the results, we will evaluate the anti9tumor activity of panobinostat combined or not with unfocused US in comparison to panobinostat alone in the preclinical xenograft DIPG models. This project has been validated by the ethical committee CEEA 26 and Research Ministry (approval number 2015071316539600 v3, APAFIS#1141). In case preclinical data and safety data in the brainstem are encouraging in mice, we will test the safety of US9mediated BBB disruption in the brainstem of primates. The goal is to obtain the necessary preclinical data to justify the development of a phase I clinical trial to evaluate the feasibility and safety of the technique in children treated for a HGG and DIPG.
Brain tumors are the leading cause of mortality and morbidity from cancer in children and young adults. Malignant gliomas, including supra9tentorial high grade gliomas (HGG) and Diffuse Intrinsic Pontine Gliomas (DIPG), remain a major therapeutic challenge in pediatric oncology because they are still incurable. The failure of current treatments is explained by the difficulties to do a complete surgical resection, and by the low penetration of drugs commonly used neuro9oncology. This low penetration is related to the existence of the blood9brain barrier (BBB), that consists partly of endothelial cells intimately linked together by tight junctions and prevents about 98% of small molecules and 100% of large molecules to reach the brain parenchyma.
It is now proven that the application on brain parenchyma of low power pulsed ultrasound (US) in combination with an US microbubble contrast agent (UCA) can safely and transiently open the BBB (Hynynen et al, Radiology 2001). A significant increase in penetration of several antineoplastic drugs, high molecular weight antibodies, DNA plasmid and neural stem cells has been observed after US9induced opening of the BBB. Studies on murine models of gliomas even showed an improved tumor control and increasing animal survival. These studies, initially conducted on small animals, have recently been applied by us in primates with confirmation of previous results (Horodyckid et al, J Neurosurg in press).
The skull represents the main obstacle to the use of US in neuro9oncology, since the bone induces distortions and attenuation of ultrasonic energy. Considering the fact that a surgical procedure is systematically carried out during the treatment of primary brain tumors (resection or biopsy), the research team CarThéra™, directed by Pr Alexandre Carpentier, has recently developed an implantable ultrasonic transducer. The concept was described in a recent publication with opening of the BBB in rabbits (Beccaria et al, J Neurosurg 2013). The team was able to demonstrate a significant increase in intracerebral concentration of Temozolomide and Irinotecan in rabbits following US9induced opening of the BBB (Beccaria et al, J Neurosurg 2015). The first clinical trial is under way in La Pitié Salpétrière Hopistal (Paris, France) under the coordination of Pr A. Carpentier (NCT02253212 ; see also Carpentier et al, Sci Transl Med in press).
A few of molecules have shown a very good anti9tumor efficacy on DIPG primary cell lines but many of them have poor diffusion across the BBB (Grasso et al, Nat Med 2015). One of the most effective drugs, the panHDAC inhibitor Panobinostat has recently shown a strong anti9 tumor activity in vitro and in vivo, but this molecule presents a low penetrance through the blood9brain barrier (~10% in mouse), and its therapeutic index is limited by hematotoxicity.
There is therefore a strong rationale to explore panobinostat with unfocused US in a preclinical xenograft model of DIPG deriving from treatment9naive biopsies. After adaptation and validation of US parameters in mice, we will explore the pharmacokinetics of panobinostat in blood and brain (pons, cortex, thalamus) in healthy mice and then in DIPG mouse models after opening of the BBB with US. Depending on the results, we will evaluate the anti9tumor activity of panobinostat combined or not with unfocused US in comparison to panobinostat alone in the preclinical xenograft DIPG models. This project has been validated by the ethical committee CEEA 26 and Research Ministry (approval number 2015071316539600 v3, APAFIS#1141). In case preclinical data and safety data in the brainstem are encouraging in mice, we will test the safety of US9mediated BBB disruption in the brainstem of primates. The goal is to obtain the necessary preclinical data to justify the development of a phase I clinical trial to evaluate the feasibility and safety of the technique in children treated for a HGG and DIPG.
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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.
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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.
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.
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.