Lorem Sit Amet Dolor
123 abc lane, Townsville, ZZ 00000, USA
Funding Progress: $§ / $§§§§§
Photodynamic therapy of diffuse intrinsic pontine glioma in combination with radiation.
TranslationalDIPG, Childhood (Brain Cancer)
Lay Summary
Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brain tumor and a leading cause of pediatric brain tumor-related mortality. Even with treatment, the median survival of patients with DIPG is 9–11 months. Despite a number of clinical trials, no treatments have proven more effective than radiation therapy (RT) for children with DIPG. 5-aminolevulinic acid photodynamic therapy (5-ALA PDT) is an innovative, targeted treatment for patients with high grade gliomas (HGGs). Recently, 5-ALA PDT has been found to have a significant antitumor effect in malignant pediatric brain tumor preclinical studies. Our preliminary studies with patient-derived DIPG cells revealed that 5-ALA PDT has a pronounced antitumor effect and additionally enhanced the effects of RT. Based on these novel findings, we hypothesize that the application of 5-ALA PDT in children harboring DIPG tumors could lead to better patient outcomes and quality of life when combined with RT. To that end, we are initiating preclinical studies to determine the safety and efficacy of PDT in combination with RT and translate this treatment modality to children suffering from this devastating tumor.
Executive Summary
Despite a number of clinical trials, the standard of care for children harboring diffuse intrinsic pontine glioma (DIPG) consists of radiation therapy (RT) and even with treatment the median overall survival is 9-11 months. In search of effective therapeutic strategies, we are investigating 5-aminolevulinic acid (5-ALA) photodynamic therapy (PDT), a highly targeted treatment which is being studied in adults with high grade gliomas (HGGs) in combination with adjuvant therapies. PDT may permit radiosensitivity enhancement of HGGs and may enhance innate antitumor immune responses. 5-ALA PDT involves the oral administration of 5-ALA, which is currently approved by the US Food and Drug administration (FDA) for HGG fluorescence-guided surgery (FGS). 5-ALA is metabolized to protoporphyrin IX (PpIX), which selectively accumulates in glioma cells due to a defect in enzymatic conversion of PpIX to heme. The application of light (635 nm) to cells with PpIX generates cytotoxic reactive oxygen species (ROS) resulting in selective glioma cell death. In vitro 5-ALA PDT studies in pediatric malignant brain tumor cells lines, including medulloblastoma (DAOY/UW228), primitive neuroectodermal tumor (PNET) (PFSK-1), and rhabdoid tumor BT16, have demonstrated a significant antitumor effect.
We hypothesize that 5-ALA PDT will permit the targeted radiosensitivity enhancement of DIPG tumors enabling more effective treatment of these invasive, therapy-resistant tumors. Our preliminary fluorescence microscopy studies have shown a pronounced increase in accumulation of intracellular 5-ALA-derived PpIX levels in cells of the previously characterized patient-derived DIPG cell line, SU-DIPG-XIII. Specifically, the PpIX fluorescence increase within 5-ALA treated cells was 470 times higher compared to the non-treated SU-DIPG-XIII cells. Moreover, we have found a significant anti-tumor effect after 5-ALA PDT in combination with RT of SU-DIPG-XIII. Our laboratory has recently developed a rodent 5-ALA PDT model with intra-tumoral placement of a cylindrical-diffuser optical laser fiber for 635nm light excitation of DIPG tumors (Figure 1). We propose to study the antitumor effects of 5-ALA PDT in combination with RT in multiple patient derived H3-K27M-mutant DIPG cell cultures in vitro. Additionally, we propose to study the safety and efficacy of this combination treatment on two patient-derived H3-K27M+ DIPG orthotopic xenograft models, a murine DIPG model and in healthy mice aiming to provide data that will guide the translation of this highly promising combination therapy. We expect to enhance the effects of RT with DIPG, determine the optimal dose scheme that will permit safe and effective treatment, and characterize the 5-ALA PDT mediated tumor-specific immune response. The characterization of the 5-ALA PDT mediated tumor-specific immune response may guide the future use of adjuvant immunotherapies that may further enhance the tumor-specific 5-ALA PDT treatment.
The PI is a neurosurgeon-scientist whose focus is on the surgical management of glioma patients. He has been involved with the stereotactic biopsy and management of DIPG patients. He is also the Sponsor and IND holder (#112246) of a Multicenter Phase II studying the use of 5-ALA (Gleolan) and fluorescence-guided surgery (FGS) for the resection of gliomas. Dr. Hadjipanayis was the first to use Gleolan and perform FGS on a GBM patient in the US in 2011 and led the FDA effort for approval of 5-ALA (Gleolan) in the US in June 2017.6 He has also been involved in preclinical 5-ALA studies involving rodent glioma models.9 He recently initiated a 5-ALA PDT study in canines who develop spontaneous gliomas.
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.