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Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
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Repurposing mefloquine for diffuse intrinsic pontine glioma therapy
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive brain tumors found in an area of the brainstem called the pons, which controls many of the body’s most vital functions such as breathing, blood pressure, and heart rate. DIPG is the leading cause of pediatric death by brain tumor. Median survival after diagnosis is only 9 months, and 5-year survival is less than 1%. Unfortunately, complete surgical removal is not an option in the treatment of these tumors due to their extensively infiltrative nature and related severe neurological damages to the most vital functions of the body caused by the surgery. The only effective traditional limited-field radiation produces responses in more than 90% of DIPG patients but only transiently. Despite intensive multimodality treatment, refractory disease and relapses are frequent events in these tumors. Numerous trials to increase the dose of radiation have been performed and have not improved patient survival. Experimental chemo- and biologic agents in addition to radiation are actively investigated. More than 250 clinical trials have been conducted in the past decades and several trials evaluating new agents are either underway or have been recently completed but none of these trials have shown any benefit in the likelihood or the median length of survival. Thus, new agents that can be used for adjuvant DIPG therapy are desperately needed.  Using DIPG cells established from newly diagnosed and recurrent patients, which retain stem-like cells features including the ability to self-renew and differentiate into multiple neural cell lineages, we performed a repurposing drug screen aiming at evaluating the potential of recycling of old known drugs for DIPG therapy. Repurposing drugs that are already approved to treat certain diseases or conditions to see if they are safe and effective for treating other diseases provides quicker translation from bench to bedside. We identified that a subset of quinoline class of anti-malaria agents to have significant DIPG killing properties. Among them, we selected the FDA-approved off-patent compound mefloquine due to its efficacy and potency in killing DIPG cells, with an IC50 less than 0.5 µM in all the tested cultures. Mefloquine remains a useful anti-malarial drug for many patients and is the drug of choice for U.S military deployed overseas and travelers. However, a growing body of evidence suggests that mefloquine causes adverse central nervous system effects, including posttraumatic stress disorder-like syndromes such as nightmares and paranoia, because after being absorbed into the bloodstream, it accumulates in the brain at relatively high concentrations, which compromises its use.    
 
Identifying new indications for existing drugs, even taking advantage of the adverse effects of these compounds, is not uncommon in drug development.   In this proposal, we will take advantage of this unique characteristic of mefloquine and use low dose (2.5 - 7.5mg/kg in mouse) of this compound to achieve enough amounts in the brain (300 nM - 1 µM) and target the infiltrative DIPG reservoir, while avoiding the neurological side effects.  Anti-malaria studies suggested that this group of drugs induce cell apoptosis in host and parasites through increased production of reactive oxygen species (ROS). We will evaluate ROS pathway as a potential mechanism in mefloquine-induced DIPG cell death.  Our preliminary research using mefloquine at low doses restricted DIPG xenograft growth and improved the survival of mice. We will take advantage of the adverse side effect of mefloquine, when used as an anti-malaria drug, and investigate the possibility of achieving desired concentration in DIPG using low dose of this compound. Further, the ROS stress induced by mefloquine will specifically target the invasive DIPG cells in the brain.  We hypothesize that low dose of mefloquine can cross the blood-brain barrier, achieve the desired local concentration, and induce DIPG cell death through increased ROS production, thus halt tumor growth and prolong animal survival.  Investigating the efficiency and safety of mefloquine in animal models is the first step to move this agent to the clinic to treat DIPG patients.  Upon completion of the proposed project, we expect that we will have the necessary evidence to move this drug into a clinical trial. 

Executive Summary

Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive brain tumors found in an area of the brainstem called the pons, which controls many of the body’s most vital functions such as breathing, blood pressure, and heart rate. DIPG is the leading cause of pediatric death by brain tumor. Median survival after diagnosis is only 9 months, and 5-year survival is less than 1%. Unfortunately, complete surgical removal is not an option in the treatment of these tumors due to their extensively infiltrative nature and related severe neurological damages to the most vital functions of the body caused by the surgery. The only effective traditional limited-field radiation produces responses in more than 90% of DIPG patients but only transiently. Despite intensive multimodality treatment, refractory disease and relapses are frequent events in these tumors. Numerous trials to increase the dose of radiation have been performed and have not improved patient survival. Experimental chemo- and biologic agents in addition to radiation are actively investigated. More than 250 clinical trials have been conducted in the past decades and several trials evaluating new agents are either underway or have been recently completed but none of these trials have shown any benefit in the likelihood or the median length of survival. Thus, new agents that can be used for adjuvant DIPG therapy are desperately needed.  Using DIPG cells established from newly diagnosed and recurrent patients, which retain stem-like cells features including the ability to self-renew and differentiate into multiple neural cell lineages, we performed a repurposing drug screen aiming at evaluating the potential of recycling of old known drugs for DIPG therapy. Repurposing drugs that are already approved to treat certain diseases or conditions to see if they are safe and effective for treating other diseases provides quicker translation from bench to bedside. We identified that a subset of quinoline class of anti-malaria agents to have significant DIPG killing properties. Among them, we selected the FDA-approved off-patent compound mefloquine due to its efficacy and potency in killing DIPG cells, with an IC50 less than 0.5 µM in all the tested cultures. Mefloquine remains a useful anti-malarial drug for many patients and is the drug of choice for U.S military deployed overseas and travelers. However, a growing body of evidence suggests that mefloquine causes adverse central nervous system effects, including posttraumatic stress disorder-like syndromes such as nightmares and paranoia, because after being absorbed into the bloodstream, it accumulates in the brain at relatively high concentrations, which compromises its use.    
 
Identifying new indications for existing drugs, even taking advantage of the adverse effects of these compounds, is not uncommon in drug development.   In this proposal, we will take advantage of this unique characteristic of mefloquine and use low dose (2.5 - 7.5mg/kg in mouse) of this compound to achieve enough amounts in the brain (300 nM - 1 µM) and target the infiltrative DIPG reservoir, while avoiding the neurological side effects.  Anti-malaria studies suggested that this group of drugs induce cell apoptosis in host and parasites through increased production of reactive oxygen species (ROS). We will evaluate ROS pathway as a potential mechanism in mefloquine-induced DIPG cell death.  Our preliminary research using mefloquine at low doses restricted DIPG xenograft growth and improved the survival of mice. We will take advantage of the adverse side effect of mefloquine, when used as an anti-malaria drug, and investigate the possibility of achieving desired concentration in DIPG using low dose of this compound. Further, the ROS stress induced by mefloquine will specifically target the invasive DIPG cells in the brain.  We hypothesize that low dose of mefloquine can cross the blood-brain barrier, achieve the desired local concentration, and induce DIPG cell death through increased ROS production, thus halt tumor growth and prolong animal survival.  Investigating the efficiency and safety of mefloquine in animal models is the first step to move this agent to the clinic to treat DIPG patients.  Upon completion of the proposed project, we expect that we will have the necessary evidence to move this drug into a clinical trial. 

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.