Funding Status: Funded!

This grant has been fully funded!

Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
Funding Progress: $§ / $§§§§§

Signup to see this grant's details

Targeting DIPG through combining a super-activator (MCB-613) of steroid receptor coactivators with radiation
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

The objective of this application is to demonstrate that combining MCB-613, a small molecule stimulator of the oncogenic steroid receptor co-activator (SRC), with ionizing radiation would synergistically kill tumor cells of diffuse intrinsic pontine glioma (DIPG) in vivo and significantly prolong survival times in patient tumor-derived orthotopic (intra-brain stem) xenograft (PDOX) mouse models. This proposal is a follow-up study from a preclinical analysis of MCB-613 on DIPGs that was generously funded by the Cure Starts Now Foundation and DIPG Collective (2015-2017). Our goal is to establish strong preclinical rational to support a rapid initiation of MCB-613 clinical trials in children with DIPG.  DIPG is the most lethal childhood cancer, and virtually all children with this disease die within 1-2 years of diagnosis. In our previous study that was generously funded by the Cure Starts Now Foundation and the DIPG Collective, we have shown that MCB-613 can overcome some major challenges for the development of new therapies for DIPG using our panel of intra-brain stem PDOX models of DIPG, including 1) strong antiproliferative activities in vitro in traditional monolayer cells as well as in neurospheres (enriched with the putative cancer stem cells), 2) low toxicity to normal cells in NOD/SCID mice that were treated for 4 weeks;  3)  capability of passing through the blood brain barrier (BBB) to reach xenograft tumor cells in vivo in mouse brain stems; 4) significant prolongation of animal survival times (the gold standard of therapeutic efficacy) in a DIPG PDOX model acting as single agent; and 5) synergistic killing of DIPG xenograft cells and significant prolongation of animal survival times when combined with fractionated radiation. There were, however, some missing data that are critically needed to move MCB-613 into clinical trials. When administered as single agent, MCB-613 was active only in 1/4 DIPG models and the synergistic cell killing was only demonstrated in one DIPG model. Fortunately, it was also during the previous funding period that we have identified the “under treatment” (i.e., short and insufficient drug exposure time of 14 days) as one of the causes of tumor progression.  Our central hypothesis for this proposal is that 1) Increase the length of  MCB-613 treatment time and in combination with clinically relevant fractionated ionizing radiation will  synergistically kill DIPG cells in vivo in intra-brain stem DIPG xenograft models and significantly prolong animal survival times compared to mice treated with MCB-613 and with radiation alone; and 2) analyzing multiple DIPG xenografts that exhibited differential responses would facilitate the discovery of new diagnostic marker(s) for patient selection.   To test our hypothesis, we will utilize our established PDOX models of DIPG to accomplish the following Specific Aims: 1) Demonstrate that the combined treatment of intra-brain stem DIPG xenografts with extended MCB-613 treatment (> 4 weeks) and fractionated radiation (2 Gy/day x 5 days) will synergistic improve therapeutic efficacy and significantly prolonged animal survival times. 2) Understand mechanisms of the synergistic cell killing induced by the combination of MCB-613 and XRT in DIPG cells. 3) Identify the cellular and molecular cause of therapy resistance toward the combined MCB-613 and XRT treatment.    This proposal is innovative on several levels.  Firstly, our panel of intra-brain stem DIPG PDOX mouse models is derived from terminal-stage DIPG patients; consequently, they represent therapy-resistant disease, which is in desperate need of new therapies.  These models provide us with unprecedented opportunities to study tumor biology and test new therapies in vivo in a microenvironment closest to human DIPGs.  Secondly, our research proposal is the evaluating the therapeutic efficacy of MCB-613, a novel compound with a novel mechanism of action.  This drug crosses the BBB and accumulates in brain tissue, thus allowing MCB-613 to research the tumor site. Indeed, MCB-613 has already shown promising anti-tumor activities against DIPG cells both in vitro and in vivo. Most importantly, since our treatment approach combines MCB-613 with radiotherapy, the standard treatment for DIPGs, our chances of rapid translation of the drug into clinical trials are greatly improved.  

Executive Summary

The objective of this application is to demonstrate that combining MCB-613, a small molecule stimulator of the oncogenic steroid receptor co-activator (SRC), with ionizing radiation would synergistically kill tumor cells of diffuse intrinsic pontine glioma (DIPG) in vivo and significantly prolong survival times in patient tumor-derived orthotopic (intra-brain stem) xenograft (PDOX) mouse models. This proposal is a follow-up study from a preclinical analysis of MCB-613 on DIPGs that was generously funded by the Cure Starts Now Foundation and DIPG Collective (2015-2017). Our goal is to establish strong preclinical rational to support a rapid initiation of MCB-613 clinical trials in children with DIPG.  DIPG is the most lethal childhood cancer, and virtually all children with this disease die within 1-2 years of diagnosis. In our previous study that was generously funded by the Cure Starts Now Foundation and the DIPG Collective, we have shown that MCB-613 can overcome some major challenges for the development of new therapies for DIPG using our panel of intra-brain stem PDOX models of DIPG, including 1) strong antiproliferative activities in vitro in traditional monolayer cells as well as in neurospheres (enriched with the putative cancer stem cells), 2) low toxicity to normal cells in NOD/SCID mice that were treated for 4 weeks;  3)  capability of passing through the blood brain barrier (BBB) to reach xenograft tumor cells in vivo in mouse brain stems; 4) significant prolongation of animal survival times (the gold standard of therapeutic efficacy) in a DIPG PDOX model acting as single agent; and 5) synergistic killing of DIPG xenograft cells and significant prolongation of animal survival times when combined with fractionated radiation. There were, however, some missing data that are critically needed to move MCB-613 into clinical trials. When administered as single agent, MCB-613 was active only in 1/4 DIPG models and the synergistic cell killing was only demonstrated in one DIPG model. Fortunately, it was also during the previous funding period that we have identified the “under treatment” (i.e., short and insufficient drug exposure time of 14 days) as one of the causes of tumor progression.  Our central hypothesis for this proposal is that 1) Increase the length of  MCB-613 treatment time and in combination with clinically relevant fractionated ionizing radiation will  synergistically kill DIPG cells in vivo in intra-brain stem DIPG xenograft models and significantly prolong animal survival times compared to mice treated with MCB-613 and with radiation alone; and 2) analyzing multiple DIPG xenografts that exhibited differential responses would facilitate the discovery of new diagnostic marker(s) for patient selection.   To test our hypothesis, we will utilize our established PDOX models of DIPG to accomplish the following Specific Aims: 1) Demonstrate that the combined treatment of intra-brain stem DIPG xenografts with extended MCB-613 treatment (> 4 weeks) and fractionated radiation (2 Gy/day x 5 days) will synergistic improve therapeutic efficacy and significantly prolonged animal survival times. 2) Understand mechanisms of the synergistic cell killing induced by the combination of MCB-613 and XRT in DIPG cells. 3) Identify the cellular and molecular cause of therapy resistance toward the combined MCB-613 and XRT treatment.    This proposal is innovative on several levels.  Firstly, our panel of intra-brain stem DIPG PDOX mouse models is derived from terminal-stage DIPG patients; consequently, they represent therapy-resistant disease, which is in desperate need of new therapies.  These models provide us with unprecedented opportunities to study tumor biology and test new therapies in vivo in a microenvironment closest to human DIPGs.  Secondly, our research proposal is the evaluating the therapeutic efficacy of MCB-613, a novel compound with a novel mechanism of action.  This drug crosses the BBB and accumulates in brain tissue, thus allowing MCB-613 to research the tumor site. Indeed, MCB-613 has already shown promising anti-tumor activities against DIPG cells both in vitro and in vivo. Most importantly, since our treatment approach combines MCB-613 with radiotherapy, the standard treatment for DIPGs, our chances of rapid translation of the drug into clinical trials are greatly improved.  

Description of Research Proposal

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.

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.