Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

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

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Modulation of intra-tumor hypoxia to sensitize DIPG irradiation and initiate innovative therapeutic approaches
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

Malignant gliomas in specific region like brain pons are not curable as they cannot be surgically resected and are only transiently benefiting from local irradiation and in some cases from targeted therapies. These aggressive brain tumors are molecularly well known as they are characterized by a driver mutation. This abnormality is giving to these tumors a complete cell deregulation that is for instance hardly targetable or reversible. Therefore, there is a clear need to explore other way of therapies. Those tumors are growing fast and need a local adaptation to low levels of nutriments and oxygen. The mechanism that is regulating glucose use and low oxygen level adaptation is named hypoxia. Two main hypoxic actors are induced and give cell properties to resist to conventional treatments like radiotherapy, chemotherapy or drug targeting molecular abnormalities. To understand their role in these DIPG (diffuse intrinsic pontine gliomas), we plan to quantify their presence in DIPG cells and in animal models recreating these tumors. After, we will understand their link with other cell proteins and their role during irradiation to finally try to target them to see their impact on cell death and on energy metabolism. New treatment opportunities will be issued from this research and will be combined with the current standard of care that is irradiation.

Executive Summary

DIPGs remain the more aggressive brain tumor group with no current cure. They are resistant to all conventional treatments, except a transient sensitivity to irradiation. Currently, more and more targeted therapies are used in the dedicated protocols for those DIPGs, but they have limited effects. Since 2010, a mutation was described on histone H3 and considered as a driver even it is not recreating alone the pHGG development in mouse models. Above all, it is particularly difficult to target this extensive epigenetic deregulation, resulting from this driver mutation. Therefore, our team was focusing on a translational mechanism that is intra-tumor hypoxia. This mechanism was previously described by our team in DIPGs and described as a marker of therapeutic resistance and tumor progression. It was linked to a worst prognosis and a less response to irradiation. Its inhibition was a way to decrease clearly tumor cell proliferation and to obtain a tumor cell apoptosis. Nevertheless, some high grade gliomas were escaping this strategy through the overexpression of another hypoxic biomarkers that is HIF-2a. Therefore, there is a real need to understand the balanced expression of both HIF-1a and HIF-2a in DIPG cell and animal models at different oxygen gradients to recreate the differential hypoxic heterogeneity throughout tumors. We have to know their impact on DIPG cell state, specification or plasticity (culture with 2D more differentiated cells and in stem-like 3D cells), on cell metabolism and on cell mobility. To go further, we will combine this study of hypoxic biomarkers additionally to cells’ (PDCL cultures) and tumor (PDX models) irradiation and combine this treatment to specific targeted therapies. Nevertheless, we have also to explore and determine the activated genes of HIF-1 and HIF-2 induction by hypoxia in DIPG. After all, we will try to see the impact of their inhibition on tumor cell proliferation, tumor cell death, epigenetic status in DIPG cells, as well as on cell metabolism.

We will use different techniques to assess in 6 different patient-derived cell lines initiated from diagnostic DIPG and their paired PDX (patient derived xenograft) the role and modulation of HIF-1a and HIF-2a in several oxygen gradient from minimal to severe hypoxia representative of tumor hypoxia heterogeneity. Several techniques from RNAsequencing to metabolomics through western blot, clonogenic assay or spheroid migration assay, will be helpful to answer our questions around hypoxia and its key role in DIPG.

This research project will be feasible due to the availability of DIPG cell and PDX models in our Lab, as well as all techniques. We have already the expertise in hypoxic environment study and we acquired in the last years the Incucyte© technology that is allowing to automate all drug screening and to follow the cells in culture after drug exposure and/or irradiation in all oxygen conditions It is a live cell follow-up that can use fluorescent stains to assess proliferation and apoptotic cells. During the last months, we also acquired expertise in irradiation techniques and their follow-up in several cancer cells like adult glioblastomas or head and neck cancers. All the techniques are already developed and will be rapidly applied in all DIPG PDCLs. Furthermore, the expertise of the applicant in clinical and in translational research will be helpful to integrate all results for future clinical trials using combined approaches with irradiation plus hypoxia (HIF-1a/HIF-2a) targeting.

This prospective work that will be managed rapidly in the next 12 months and will be the starting point of new approaches combining the targeting of intra-tumor hypoxia and metabolism understanding. New drugs are currently developed to also block these cell adaptive metabolisms.

Description of Research Proposal

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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

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