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Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
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Validation of TAK228 as an effective drug for treating children with DIPG
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

Validation of TAK228 as an Effective Drug for Treating Children Diagnosed with DIPG Diffuse intrinsic pontine glioma (DIPG) is an untreatable childhood cancer.  DIPGs develop in pons making them surgically unresectable.  We and others have identified mutations in histone and their obligate partner mutations that seem to drive tumorigenicity. While epigenetic drugs targeting histone mutation have shown positive outcome in preclinical setting, these drugs have yet to show effectiveness in the clinic.  Moreover, >70% of DIPGs are driven by AKT gain or PTEN loss.  Our collaborative team at Children’s National and Johns Hopkins School of Medicine have achieved robust preliminary success in targeting AKT and PTEN pathways using TAK228, also known as sapanisertib, MLN0128 and INK128. We also find that TAK228 in combination with radiation leads to increased DIPG apoptosis. We also find preliminary evidence of synergy between panobinostat and TAK228, consistent with findings in other tumor types that mTOR inhibition in combination with panobinostat leads to improved cell killing (20, 21). We hypothesize that combinatorial regimen of TAK228, radiation, and panobinostat can effectively target H3.3 and H3.1K27M mutant cells in vitro and in vivo and that any mechanism of drug resistance are identifiable using cutting edge protein and gene studies. In this study, two Specific Aims will be tested: Specific Aim 1. Assess TAK228 efficacy in H3.3 and H3.1 DIPG models, alone and in combination with radiation and panobinostat.   Specific Aim 2. Determine mechanisms of cellular resistance to TAK228.  Our collaborative team has all necessary resources to carry the outlines experiments. The experiments detailed here will provide the pre-clinical justification of a phase I/II clinical trial of TAK228 in patients with newly diagnosed DIPG. 
 
Innovation. Our collaborative proposal is highly innovative in the following aspects:  Strong preliminary data indicating the efficacy of TAK228 for targeting DIPG tumor   Robust data indicating TAK228 administration more than doubles the median survival of mice bearing a well-accepted murine DIPG orthotopic model   Ability to target both mTORC1 and mTORC2 pathways using TAK228   mTORC1 inhibition by commonly used drugs (e.g. rapamycin and everolimus) often leads to upregulation of mTORC2, which may contribute to the relative lack of effectiveness of mTORC1 inhibitors. TAK228, which is a dual mTORC kinase inhibitor may have broader therapeutic use than rapalogs, due to its ability to inhibit both mTORC1 and mTORC2.  Ability to inhibit DIPG growth and induce apoptosis at nanomolar concentrations.  The agent is available for clinical trials in the United States through the CTEP program at NCI.    Collaborative proposal between two leading institutions in childhood brain tumor research.  Access to robust and rare xenograft, allograft, and in vitro models of DIPG avenues.  Potential to assess and identify combinatorial therapy of TAK228 for direct translational application of this agent.   Potential for identification of tumorigenic pathways and thus further allowing for novel therapeutic combinations. 
 
Feasibility. The proposed project is a highly feasible project as shown by our robust preliminary data and published manuscript (Cancer Letters, 2017). Our collaborative team of basic researchers and clinicians have the expertise and the resources to fully execute the proposed project.                                                     
 
Expertise. Dr. Nazarian (PI) at CNHS has extensive expertise studying the molecular profiling (mRNA, methylation, proteomics) of DIPGs. Dr. Raabe (Co-PI) a pediatric oncologist at Johns Hopkins University School has extensive experience in cell culture, molecular biology, immunochemical analysis and xenografting. Dr. Raabe’s laboratory had developed a primary DIPG line (JHH DIPG1) extensively used for preclinical testing across many laboratories.  . 
 
Requested Budget.  $200,000 

 
 

Executive Summary

Validation of TAK228 as an Effective Drug for Treating Children Diagnosed with DIPG Diffuse intrinsic pontine glioma (DIPG) is an untreatable childhood cancer.  DIPGs develop in pons making them surgically unresectable.  We and others have identified mutations in histone and their obligate partner mutations that seem to drive tumorigenicity. While epigenetic drugs targeting histone mutation have shown positive outcome in preclinical setting, these drugs have yet to show effectiveness in the clinic.  Moreover, >70% of DIPGs are driven by AKT gain or PTEN loss.  Our collaborative team at Children’s National and Johns Hopkins School of Medicine have achieved robust preliminary success in targeting AKT and PTEN pathways using TAK228, also known as sapanisertib, MLN0128 and INK128. We also find that TAK228 in combination with radiation leads to increased DIPG apoptosis. We also find preliminary evidence of synergy between panobinostat and TAK228, consistent with findings in other tumor types that mTOR inhibition in combination with panobinostat leads to improved cell killing (20, 21). We hypothesize that combinatorial regimen of TAK228, radiation, and panobinostat can effectively target H3.3 and H3.1K27M mutant cells in vitro and in vivo and that any mechanism of drug resistance are identifiable using cutting edge protein and gene studies. In this study, two Specific Aims will be tested: Specific Aim 1. Assess TAK228 efficacy in H3.3 and H3.1 DIPG models, alone and in combination with radiation and panobinostat.   Specific Aim 2. Determine mechanisms of cellular resistance to TAK228.  Our collaborative team has all necessary resources to carry the outlines experiments. The experiments detailed here will provide the pre-clinical justification of a phase I/II clinical trial of TAK228 in patients with newly diagnosed DIPG. 
 
Innovation. Our collaborative proposal is highly innovative in the following aspects:  Strong preliminary data indicating the efficacy of TAK228 for targeting DIPG tumor   Robust data indicating TAK228 administration more than doubles the median survival of mice bearing a well-accepted murine DIPG orthotopic model   Ability to target both mTORC1 and mTORC2 pathways using TAK228   mTORC1 inhibition by commonly used drugs (e.g. rapamycin and everolimus) often leads to upregulation of mTORC2, which may contribute to the relative lack of effectiveness of mTORC1 inhibitors. TAK228, which is a dual mTORC kinase inhibitor may have broader therapeutic use than rapalogs, due to its ability to inhibit both mTORC1 and mTORC2.  Ability to inhibit DIPG growth and induce apoptosis at nanomolar concentrations.  The agent is available for clinical trials in the United States through the CTEP program at NCI.    Collaborative proposal between two leading institutions in childhood brain tumor research.  Access to robust and rare xenograft, allograft, and in vitro models of DIPG avenues.  Potential to assess and identify combinatorial therapy of TAK228 for direct translational application of this agent.   Potential for identification of tumorigenic pathways and thus further allowing for novel therapeutic combinations. 
 
Feasibility. The proposed project is a highly feasible project as shown by our robust preliminary data and published manuscript (Cancer Letters, 2017). Our collaborative team of basic researchers and clinicians have the expertise and the resources to fully execute the proposed project.                                                     
 
Expertise. Dr. Nazarian (PI) at CNHS has extensive expertise studying the molecular profiling (mRNA, methylation, proteomics) of DIPGs. Dr. Raabe (Co-PI) a pediatric oncologist at Johns Hopkins University School has extensive experience in cell culture, molecular biology, immunochemical analysis and xenografting. Dr. Raabe’s laboratory had developed a primary DIPG line (JHH DIPG1) extensively used for preclinical testing across many laboratories.  . 
 
Requested Budget.  $200,000 

 

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.