Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

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

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Precision Therapy to Overcome Chemoresistance in Pediatric Glioblastoma
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

Glioblastoma (GBM) remains one of the most aggressive and lethal forms of cancer. Despite the best available treatment options including surgical resection, radiotherapy, and chemotherapy, prognosis is poor in glioblastoma, with a median overall survival of 14 months.1Currently, temozolomide (TMZ) is the preferred chemotherapeutic drug in the treatment of GBM following surgical resection and/or radiation.2 However, more than 90% of patients still die due to tumor recurrences due to intrinsic or acquired resistance to chemotherapy. Thus, there is an urgent need to identify ways to sensitizing tumor cells to chemotherapeutic alkylating agents (eg TMZ) while leaving normal cells unharmed- i.e., increasing therapeutic index while minimizing toxicity.

According to clinical observation, most of the patients were resistant to TMZ due to high expression of MGMT or loss of MMR (therefore preventing the initiation of apoptotic signaling). The correlation with MGMT status in response to chemotherapy is well known with adult patients GBM but is controversial in pediatric GBM patients. In pediatric GBM, TMZ seems to have little or no effect despite a lack of MGMT expression in many cases. Recent studies using an siRNA screen targeting over 240 DNA damage response genes identified a non–MGMT dependent base excision repair (BER) pathway enzyme called N-methylpurine DNA glycosylase (MPG) and its direct substrate ataxia telangiectasia mutated ATM are novel sensitizers to alkylating agents (e.g., TMZ).3Therefore, there is an urgent need to investigate alternate treatment options such as developing a novel specific MPG inhibitor for pediatric GBMpatients with TMZ-resistant tumors and adjuvant chemotherapy.

Executive Summary

The screening of existing chemical libraries has already provided many interesting candidate molecules that efficiently and selectively inhibit DNA repair pathways, including some that act synergistically with DNA-damaging drugs.4 In searching for novel specific MPG inhibitors, one of our collaborators performed high throughput screening on a small molecule library using a gel-based MPG activity assay for inhibition and identified a Morin Hydrate that inhibits MPG activity specifically. Detailed mechanism analysis showed that Morin Hydrate inhibited substrate DNA binding of MPG and subsequently enzymatic activity of MPG. Computational docking studies with an x-ray derived MPG structure as well as comparison studies with other structurally-related MPG analogs offer a rationale for the inhibitory activity of Morin Hydrate observed.5

To improve the potency and selectivity of this inhibitor against MPG, we have developed a fragment-based drug discovery approach based on in silicohomology modelling of MPG and Morin Hydrate. The newly designed small molecules have better CNS drug like properties  than Morin Hydrate and ultimately might increase the potency and selectivity towards MPG inhibition and chemosensitivity. Motivated by the persistent TMZ chemo resistance associated poor survival rate and limited therapeutic treatment options for patients with pediatric GBM, we will identify and characterize small molecule inhibitors that selectively inhibit MPG-directed BER pathway. Identification of drugs that inhibit BER would be a novel approach to increase sensitization to TMZ in pediatric GBM patients. Since there is strong clinical evidence correlating overexpression of BER directed protein (MPG) in patients with little or no response to TMZ treatment and poor survival rate, successful completion of this proposal would result in a new therapeutic option to improve the survival rate of pediatric GBM patients with TMZ treatment. 

 

This proposal to Cure fund snap grant is requesting discovery grant funding todevelop novel, potent, specific MPG inhibitors as sensitizers for chemo-resistant pediatric GBM cell lines. Therefore, the research proposed herein has the following Specific Aims:

 

Specific Aim1. Screening of selected hit leads for direct inhibition of MPG activity. We will screen selected Morin Hydrate analogs to identify potent MPG inhibitors against cell free and cell mediated MPG activity assay.

Specific Aim 2. Study the role of validated hits (SA1) in sensitizing TMZ chemotherapy in in vitro MPG overexpressing pediatric GBM tumor models.We will study the mechanism of action how identified MPG inhibitors are sensitizing tumor cells to TMZ in vitropatient derived GBM models. We will use three MPG overexpressing pediatric glioma cells, less or no MPG expressed pediatric glioma cells as control. We have long experience with both adult and pediatric patient-derived cell lines and have over 50 lines in the Department repository.

 

Description of Research Proposal

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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

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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.