Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
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Targeting the thioredoxin system as a novel strategy for DIPG
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

Diffuse intrinsic pontine glioma (DIPG) is the most aggressive of all childhood brain cancers. Radiotherapy treatment is palliative, and chemotherapy is ineffective. We have found that both DIPG cells and DIPG animal models are exquisitely sensitive to auranofin. Auranofin is a gold containing anti-inflammatory compound previously used to treat rheumatoid arthritis. Auranofin has potential anticancer activities and is in phase I/II clinical trial for adults with ovarian cancer and pediatric leukemia. Auranofin blocks thioredoxin reductase (TrxR) function eventually leading to cancer cell death. TrxR is overexpressed in many cancer types and is thought to promote cell growth and survival. High-throughput screening identified potential auranofin combinations for examination including marizomib (proteasome inhibitor), temsirolimus (mTOR inhibitor), SAHA (epigenetic modifier) and mefloquine (anti-malarial). In this project, we will preclinically develop auranofin combinations as a therapeutic strategy for DIPG and obtain the necessary data to begin translation of auranofin therapy from the bench-to-bedside to directly benefit children with this devastating and currently incurable tumor.

Executive Summary

DIPG is the most aggressive of all childhood cancers. It is a type of brain tumor that peaks in incidence at 5-7 years of age and is the most common form of malignant glioma to affect children. There are no effective treatments and current therapeutic strategies are palliative only. Due to its location within the brainstem, the tumor cannot be removed surgically, it does not respond to chemotherapy, and radiotherapy only slows their growth temporarily. Novel and innovative treatment approaches are therefore urgently needed to counter this tumor1.

Auranofin was FDA approved in 1985 for the treatment of rheumatoid arthritis. Auranofin is an orally available, lipophilic, organogold compound, with anti-inflammatory and potential antineoplastic activities. Auranofin blocks thioredoxin reductase (TrxR) activity by interacting with selenocysteine residue within the redox-active domain of mitochondrial TrxR. This results in the induction of mitochondrial oxidative stress leading to apoptosis. TrxR is overexpressed in many cancer types such as lung2,3, colorectal, hepatocellular carcinoma4 and gastric carcinoma5,6 as well as cancer cell lines7 and is thought to promote cell growth and survival through a range of mechanisms including directly removing apoptotic inducers8 and indirectly activating anti-apoptotic activity of NF-KB and reduced Trx9,10.  Auranofin is well tolerated in children and adults and previous studies suggest it crosses the blood brain barrier11. Auranofin is currently in clinical trial for ovarian cancer (Phase I/II), lung cancer (Phase I/II) and GBM (Phase I/II).

Previous high throughput screening (HTS) experiments performed in our laboratory have shown that auranofin is highly active against DIPG cells in vitro. Cytotoxicity assays showed that auranofin decreased cell viability in a dose dependent manner when examined across a panel of DIPG neurosphere cultures. Treatment with auranofin led to a dose dependent decrease colony formation when examined in a soft agar colony forming assay. Excitingly, we found that treatment with auranofin led to a sustained and significantly increased survival in an orthotopic DIPG mouse model in vivo.

Four candidate drugs for combination with auranofin have been selected through a high-throughput combination drug screen. Two candidate therapeutics will be selected based on preliminary in vitro combination experiments. The candidate auranofin combinations that will be examined include marizomib (proteasome inhibitor), temsirolimus (mTOR inhibitor), SAHA (epigenetic modifier) and mefloquine (anti-malarial). All aforementioned drugs are already clinically approved pharmaceutical compounds. This will help us to develop them further for translation from bench to bedside and into pediatric clinical trials. We seek to build upon our initial in vitro and in vivo findings, and to develop further preclinical evidence required to urgently translate these novel discoveries to clinical trials to directly benefit children with DIPG and other aggressive brain tumors. We aim to determine whether the combination of auranofin with drug candidates will be effective in DIPG tumors and high-grade gliomas (HGGs). In doing so, we aim to develop the quantum of preclinical data required to rapidly translate this therapy from the bench to the bedside for pediatric patients diagnosed with the most aggressive brain tumors.

Our team has all the necessary expertise that will ensure the success of the proposed project and ultimately the implementation of the discoveries into the clinic. Dr Dannielle Upton is a post-doctoral scientist with particular expertise in DIPG cell cultures and xenograft models, drug combinations and mechanistic studies and with the support of A/Prof Ziegler and Dr Tsoli has generated the background data described in this project. A/Prof Ziegler has preclinical expertise in pediatric malignant brain tumors and his clinical focus on early phase clinical trials will facilitate translation of positive results to the bedside. The support of A/Prof Ziegler and Prof Haber at Children’s Cancer Institute provides an invaluable environment to ensure the success of this novel research program, and with the ultimate goal of improving outcomes for children diagnosed with DIPG.

Description of Research Proposal

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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.