Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
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Repurposing antimalarial drugs for DIPG therapy
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

Diffuse intrinsic pontine gliomas (DIPGs) are rare but highly aggressive brain tumors found in the pons, an area of the brainstem that controls many of the body’s most vital functions such as breathing, blood pressure, and heart rate. Despite DIPG being the leading cause of pediatric death by gliomas, this tumor type remains to be underserved when it comes to research activity and any advancement in the clinic. 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. Despite intensive multimodality treatment, refractory disease and relapses are frequent events in these tumors. Experimental chemo- and biologic agents in addition to radiation are actively investigated, and so-far only 62 clinical trials have been directed against DIPG, but none of these trials have shown any benefit in the likelihood or the median length of survival. Therefore, new agents that can be used for adjuvant DIPG therapy are desperately needed. 

            Using DIPG cells established from patient tissues, we performed a repurposing drug screen aiming at evaluating the potential of recycling of known drugs against DIPG. 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 anti-malaria agents to have significant DIPG killing properties. Among them, we selected the FDA-approved compound mefloquine due to its efficacy and potency in killing DIPG cells in culture and in animal models.

Mefloquine was developed by the Walter Reed Army Institute of Research (WRAIR) to prevent and treat malaria and it remains to be the drug of choice for U.S military deployed overseas and travelers such as the Peace Corps. However, a growing body of evidence suggests that this drug causes adverse central nervous system (CNS) 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. In their search for novel antimalarial drugs with lower toxicity, researchers at WRAIR have amassed a large collection of structurally diverse mefloquine and related quinoline analogues. To find anti-malaria analogues with improved efficacy against DIPG, we teamed with investigators at WRAIR and obtained a collection of their antimalaria drugs and tested them against DIPG cells, and found one compound(2-TQM) to have increased potency at very low concentration (nM range), which is 100-fold lower compared to mefloquine. 

Identifying new indications for existing drugs, even taking advantage of the adverse effects of these compounds, is not uncommon in drug development. One of the main challenges in treating brain tumors in general and DIPG in particular is the ability of therapeutics to get to the brain, thus the high concentration of these antimalaria drugs observed in the brain offers a tremendous advantage for DIPG therapy. In this proposal, we will take advantage of this unique characteristic and further screen the WRAIR library to find an analogue with increased potency that targets the infiltrative DIPG reservoir, while avoiding the neurological side effects. 

Executive Summary

Diffuse intrinsic pontine gliomas (DIPGs) are rare but highly aggressive brain tumors found in the pons, an area of the brainstem that controls many of the body’s most vital functions such as breathing, blood pressure, and heart rate. Despite DIPG being the leading cause of pediatric death by gliomas, this tumor type remains to be underserved when it comes to research activity and any advancement in the clinic. 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. Despite intensive multimodality treatment, refractory disease and relapses are frequent events in these tumors. Experimental chemo- and biologic agents in addition to radiation are actively investigated, and so-far only 62 clinical trials have been directed against DIPG, but none of these trials have shown any benefit in the likelihood or the median length of survival. Therefore, new agents that can be used for adjuvant DIPG therapy are desperately needed. 

            Using DIPG cells established from patient tissues, we performed a repurposing drug screen aiming at evaluating the potential of recycling of known drugs against DIPG. 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 anti-malaria agents to have significant DIPG killing properties. Among them, we selected the FDA-approved compound mefloquine due to its efficacy and potency in killing DIPG cells in culture and in animal models.

Mefloquine was developed by the Walter Reed Army Institute of Research (WRAIR) to prevent and treat malaria and it remains to be the drug of choice for U.S military deployed overseas and travelers such as the Peace Corps. However, a growing body of evidence suggests that this drug causes adverse central nervous system (CNS) 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. In their search for novel antimalarial drugs with lower toxicity, researchers at WRAIR have amassed a large collection of structurally diverse mefloquine and related quinoline analogues. To find anti-malaria analogues with improved efficacy against DIPG, we teamed with investigators at WRAIR and obtained a collection of their antimalaria drugs and tested them against DIPG cells, and found one compound(2-TQM) to have increased potency at very low concentration (nM range), which is 100-fold lower compared to mefloquine. 

Identifying new indications for existing drugs, even taking advantage of the adverse effects of these compounds, is not uncommon in drug development. One of the main challenges in treating brain tumors in general and DIPG in particular is the ability of therapeutics to get to the brain, thus the high concentration of these antimalaria drugs observed in the brain offers a tremendous advantage for DIPG therapy. In this proposal, we will take advantage of this unique characteristic and further screen the WRAIR library to find an analogue with increased potency that targets the infiltrative DIPG reservoir, while avoiding the neurological side effects. 

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.