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Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
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Polyamine pathway metabolism as a novel therapeutic option for Diffuse Intrinsic Pontine Glioma
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

Diffuse intrinsic pontine glioma (DIPG) is the most aggressive of all childhood cancers. Standard treatment with radiotherapy is only palliative and chemotherapy has been found ineffective. Polyamines are organic compounds essential for key functions of living cells. They can be made by human cells but also generated from intestinal microorganisms and taken from dietary sources. Polyamines are produced at higher levels in cancer cells and contribute thus to aberrant growth of multiple adult and childhood tumours. Our preliminary experiments have shown that polyamines increase the growth of DIPG tumour cells. We have tested a specific combination of drugs that inhibit the production and cellular uptake of polyamines and found this to be highly active against DIPG cells but not in healthy cells. Furthermore, we have tested this combination in two separate orthotopic animal models of DIPG, which recapitulate the human disease, and found that the survival of these animals was significantly enhanced and tumour growth was reduced. This combination was also found to significantly reduce the growth of DIPG cells together with panobinostat, a targeted drug that is currently in a clinical trial for DIPG patients. This project will determine in animal models of DIPG whether polyamine inhibition therapy can enhance the effects of radiotherapy, which is the current standard treatment for DIPG patients. Furthermore, we intend to evaluate the combination of polyamine inhibitors together with panonbinostat, in animal models of DIPG.  Finally we also aim to determine the therapeutic efficacy of polyamine inhibition in other paediatric brain tumor animal models. Positive results from this study will provide the preclinical evidence required to urgently translate these novel discoveries to clinical trial to directly benefit children with DIPG and other aggressive brain tumours.

Executive Summary

Diffuse Intrinsic Pontine Gliomas (DIPGs) are the most aggressive of all childhood cancers.  They are a type of brain tumour that peak in incidence at 5-7 years of age and are the most common form of malignant glioma to affect children. There are absolutely no effective treatments and current therapeutic strategies are palliative only. Due to their location within the brainstem the tumours cannot be removed surgically, they do not respond to chemotherapy, and radiotherapy only slows their growth temporarily.  Novel and innovative treatment approaches are therefore urgently needed to counter these tumours.     

Polyamines are small intracellular polycations, indispensable for cells. They are especially important for the survival of cancer cells, due to their increased metabolic needs, since they affect a range of biological processes, including DNA synthesis, transcription and translation, ribosome bio-genesis, protein phosphorylation and cellular proliferation. Polyamines are synthesized endogenously from ornithine. Ornithine decarboxylase ODC is the rate-limiting enzyme in polyamine synthesis, it is expressed abundantly in mammalian cells and is upregulated in cancer cells. However polyamines can also be taken up from intestinal microorganisms and dietary sources.

Difluoromethylornithine (DFMO) is the best known and most well studied of all the polyamine synthesis inhibitors, and is an enzyme-activated, irreversible inhibitor of ODC. DFMO effectively crosses the blood-brain barrier with minimal toxicity, and is in a Phase I/II international clinical trial for neuroblastoma led by CI Ziegler. Our preliminary experiments have shown that DFMO significantly inhibits proliferation of DIPG neurospheres and formation of colonies. Furthermore we have found that a novel polyamine transport inhibitor AMXT-1501, which is currently in clinical development in adult phase 1 studies, synergistically increased the cytotoxicity of DFMO, reduced DIPG cell proliferation, colony formation and enhanced apoptosis. Treatment with AMXT-1501 led to reduced uptake of radiolabeled polyamine confirming the presence of an active polyamine transport system in DIPG cells. Most excitingly, and consistent with the in vitro results, combination of DFMO with AMXT-1501 significantly reduced tumour growth and led to unprecedented prolongation in the survival of mice bearing the SU-DIPG-VI and HSJD-DIPG007 orthografts. This combination represents the most effective combination treatment we have tested to date in our aggressive DIPG animal models with more than half of the mice surviving up to maximum holding time of 23 weeks post DIPG injection. These findings indicate that DIPG cells are sensitive to pharmacological inhibition of the polyamine pathway and that the combination of DFMO with AMXT-1501 represents an exciting new therapeutic strategy for DIPG.

We seek here to build upon these initial findings, and to develop the preclinical evidence required to urgently translate these novel discoveries to clinical trial to directly benefit children with DIPG and other aggressive brain tumours.  We aim to determine whether administration of DFMO/AMX-1501 directly inhibits polyamine synthesis in DIPG tumours. We also intend to evaluate whether the therapeutic efficacy of DFMO/AMXT-1501 combination can be further enhanced with radiotherapy and other anticancer drugs such histone deacetylase (HDAC) inhibitors, which are under clinical evaluation in DIPG patients. Our aims are to assess the efficacy of DFMO/AMXT-1501 combination together with irradiation and subsequently in combination with panobinostat.  Furthermore, in planning for a clinical trial, we intend to evaluate the therapeutic efficacy of DFMO with AMXT-1501 combination in three additional aggressive paediatric brain tumour orthtotopic animal models (GBM/HGG/Medulloblastoma).  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 paediatric patients diagnosed with the most aggressive brain tumours.

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 Maria Tsoli is a senior post-doctoral researcher with expertise in brain tumour and DIPG cell cultures and xenograft models, cancer cell biology and drug discovery and has been involved together with A/Prof Ziegler in the co-supervision of a PhD student who has provided the preliminary data described in this project. A/Prof Ziegler has preclinical expertise in paediatric malignant brain tumours 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 the 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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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.