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Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

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

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Developing Novel Combination theraputic approaches for DIPG targeting Polo-like Kinase 1
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

Whole genome sequencing on DIPG biopsy and autopsy samples have identified specific mutations in Histone H3, ACVRI, TP53 and ATRX causing heterochromatin silencing, genetic instability and alterations in DNA damage response pathways. Using a unique panel of patient derived DIPG cultures, we have further examined the molecular profile of DIPG to understand key oncogenic drivers within these tumours and identify novel therapeutic targets. Excitingly, we have found overexpression of multiple regulators which control the cell cycle. Of these, Polo-like Kinase 1 (PLK1) represents the most promising cell cycle factor for targeting in DIPG. PLK1 not only activates the key intermediaries which promote tumour cell growth and division, but also controls cellular response to DNA damage, inducing cell cycle arrest to promote DNA repair and avoid cell death while regulating the mechanisms used to escape arrest and continue tumour growth. Importantly, we hypothesise the rapid repair of DNA and recovery from cell cycle arrest controlled by PLK1 may account for the resistance to radiotherapy commonly seen in children with DIPG. We propose that inhibiting PLKI activity may impede cell cycle progression, block DNA repair and recovery following cell cycle arrest, radiosensitise the tumour and increase the levels of single stranded DNA above the threshold required to induce DNA lethality resulting in tumour cell death. We also hypothesise that the activity of PLK1 inhibitors may be synergistically enhanced through the development of rational combination therapies.

Our data shows PLKl is essential for DIPG tumour cell growth and that PLKl inhibition provides one of the most promising potential treatment applications for children with DIPG to date. We have found single agent PLK1 inhibition using clinically available therapies has extremely potent cytotoxic effects against DIPG cultures in vitro, with near complete eradication of DIPG cells, inhibition of colony formation and a significant induction of G2 cell cycle arrest all at exceptionally low nanomolar potency (IC50 <10nM). Using our most aggressive patient-derived in vivo model of DIPG, we have examined the activity of 2 different PLKl inhibitors as single agents and found that both therapies significantly and potently enhanced the survival of all treated animals (P=<0.0005). Importantly, PLKl inhibitors have shown the most potent anti-DIPG effect in vitro and in vivo compared with any other therapy we have tested in our models to date. We have also found that PLKI inhibition targets one of the major oncogenic drivers in DIPG, the Phosphoinositide 3-kinase (Pl3K) pathway. We have preliminary evidence PLK 1 inhibition is synergistically enhanced upon addition of the Pl3K inhibitor BKM120, providing a highly potent combination therapy for DIPG (Combination Index 0.0004). We have seen a similar effect of PLK1 inhibitors in combination with Temsirolimus (an inhibitor of Mechanistic Target of Rapamycin). As a result, we seek to conduct an analysis of PLK1 inhibitors in combination with inhibitors which target key oncogenic pathways in DIPG to identify the two most potent and synergistic combinations, their mechanism of action and their efficacy in our two orthotopic models of DIPG, providing the necessary quantum of data to move these treatments to the clinic.

Our team has the necessary skills and expertise to ensure success of the proposed project and successful clinical translation. PI Franshaw is an early career Research Officer at the Children's Cancer Institute with expertise in establishing and maintaining DIPG cultures, drug discovery, in vivo models of DIPG, advanced imaging and cancer cell biology. Since joining the Institute late 2012, she has helped establish multiple DIPG cultures, 2 in vivo models of DIPG and identified multiple novel treatments against DIPG currently under investigation. Her most recent discovery of the potency of PLKI inhibitors against DIPG is one of the most promising findings in the field to date. Co-PI Ziegler is a paediatric oncologist and director of the clinical trials unit at the Kids Cancer Centre (Sydney Children's Hospital), Group Leader at the Children's Cancer Institute and a Conjoint Associate Professor at the University of New South Wales. He is a national leader in early phase clinical trials in paediatric oncology, testing novel therapeutic agents in children with relapsed and refractory malignancies for whom there are no known effective treatment strategies. Support by A/Prof Ziegler will ensure success of the project and the rapid movement of effective therapies to the clinic to directly benefit children with DIPG.

We kindly request US$185,706 to fund the proposed project.

Executive Summary

Whole genome sequencing on DIPG biopsy and autopsy samples have identified specific mutations in Histone H3, ACVRI, TP53 and ATRX causing heterochromatin silencing, genetic instability and alterations in DNA damage response pathways. Using a unique panel of patient derived DIPG cultures, we have further examined the molecular profile of DIPG to understand key oncogenic drivers within these tumours and identify novel therapeutic targets. Excitingly, we have found overexpression of multiple regulators which control the cell cycle. Of these, Polo-like Kinase 1 (PLK1) represents the most promising cell cycle factor for targeting in DIPG. PLK1 not only activates the key intermediaries which promote tumour cell growth and division, but also controls cellular response to DNA damage, inducing cell cycle arrest to promote DNA repair and avoid cell death while regulating the mechanisms used to escape arrest and continue tumour growth. Importantly, we hypothesise the rapid repair of DNA and recovery from cell cycle arrest controlled by PLK1 may account for the resistance to radiotherapy commonly seen in children with DIPG. We propose that inhibiting PLKI activity may impede cell cycle progression, block DNA repair and recovery following cell cycle arrest, radiosensitise the tumour and increase the levels of single stranded DNA above the threshold required to induce DNA lethality resulting in tumour cell death. We also hypothesise that the activity of PLK1 inhibitors may be synergistically enhanced through the development of rational combination therapies.

Our data shows PLKl is essential for DIPG tumour cell growth and that PLKl inhibition provides one of the most promising potential treatment applications for children with DIPG to date. We have found single agent PLK1 inhibition using clinically available therapies has extremely potent cytotoxic effects against DIPG cultures in vitro, with near complete eradication of DIPG cells, inhibition of colony formation and a significant induction of G2 cell cycle arrest all at exceptionally low nanomolar potency (IC50 <10nM). Using our most aggressive patient-derived in vivo model of DIPG, we have examined the activity of 2 different PLKl inhibitors as single agents and found that both therapies significantly and potently enhanced the survival of all treated animals (P=<0.0005). Importantly, PLKl inhibitors have shown the most potent anti-DIPG effect in vitro and in vivo compared with any other therapy we have tested in our models to date. We have also found that PLKI inhibition targets one of the major oncogenic drivers in DIPG, the Phosphoinositide 3-kinase (Pl3K) pathway. We have preliminary evidence PLK 1 inhibition is synergistically enhanced upon addition of the Pl3K inhibitor BKM120, providing a highly potent combination therapy for DIPG (Combination Index 0.0004). We have seen a similar effect of PLK1 inhibitors in combination with Temsirolimus (an inhibitor of Mechanistic Target of Rapamycin). As a result, we seek to conduct an analysis of PLK1 inhibitors in combination with inhibitors which target key oncogenic pathways in DIPG to identify the two most potent and synergistic combinations, their mechanism of action and their efficacy in our two orthotopic models of DIPG, providing the necessary quantum of data to move these treatments to the clinic.

Our team has the necessary skills and expertise to ensure success of the proposed project and successful clinical translation. PI Franshaw is an early career Research Officer at the Children's Cancer Institute with expertise in establishing and maintaining DIPG cultures, drug discovery, in vivo models of DIPG, advanced imaging and cancer cell biology. Since joining the Institute late 2012, she has helped establish multiple DIPG cultures, 2 in vivo models of DIPG and identified multiple novel treatments against DIPG currently under investigation. Her most recent discovery of the potency of PLKI inhibitors against DIPG is one of the most promising findings in the field to date. Co-PI Ziegler is a paediatric oncologist and director of the clinical trials unit at the Kids Cancer Centre (Sydney Children's Hospital), Group Leader at the Children's Cancer Institute and a Conjoint Associate Professor at the University of New South Wales. He is a national leader in early phase clinical trials in paediatric oncology, testing novel therapeutic agents in children with relapsed and refractory malignancies for whom there are no known effective treatment strategies. Support by A/Prof Ziegler will ensure success of the project and the rapid movement of effective therapies to the clinic to directly benefit children with DIPG.

We kindly request US$185,706 to fund the proposed project.

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.