Molecular mechanisms of GBM radioresistance and strategies for radiosensitization View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2011-2017

FUNDING AMOUNT

1618204 USD

ABSTRACT

DESCRIPTION (provided by applicant): Glioblastoma Multiforme (GBM) tumors are the third leading cause of cancer-related death among adults aged 30 - 50 years, even though they account for less than 1.5% of all new cancer cases reported in the United States each year. The very high mortality rate of GBMs (>90% at 2 years) has remained relatively unchanged over the past 40 years despite aggressive therapy that includes surgical resection, radiotherapy and chemotherapy. However, a clear survival advantage of post-resection radiation has been established by randomized trials, showing that the median survival of GBM patients was improved, from approximately 6 months to 10-12 months, following near-maximal brain-tolerated doses of ionizing radiation. The central role that radiation plays in treating GBM is also illustrated by the landmark Stupp study showing that concurrent radiation and Temozolomide can further increase median survival from 12.1 to 14.6 months. Thus, radiation remains the mainstay of GBM therapy, and the success of the Stupp study, though modest, offers hope that radiotherapy of GBMs can be further improved. Any improvement in therapy would require a more mechanistic understanding of the basis of GBM radioresistance. The lack of improvement in GBM treatment is partly due to a paucity of appropriate genetic models that can be used to delineate the effects of genetic changes that occur in GBMs on radioresistance. The recent mapping of the GBM genome by the Cancer Genome Atlas Network revealed that these tumors have radically altered genomes with many mutations, gene copy number gains and losses, and methylation changes. Amongst the myriad genetic alterations that populate the GBM genomic landscape, 5 key genetic alterations dominate: loss of Ink4a, Arf, p53, or PTEN and amplification of EGFR (especially, the constitutively active EGFRvIII). Which of these key genetic aberrations may confer therapeutic resistance remains unclear. Understanding the contribution of these lesions, singly and in combination, to GBM radioresistance along with the underlying mechanism(s) will be of paramount importance in developing more effective therapeutic modalities. Towards this goal, we plan to use conditional knock out mouse models wherein these key genetic lesions can be introduced in astrocytes and neural stem cells (NSCs) both in culture and in the mouse brain using the Cre-ERT2 system. We propose to examine how these genetic changes impact on mechanisms for the repair of radiation-induced DNA double-strand breaks (DSBs). Based upon our preliminary results, we hypothesize that cross talk between the EGFRvIII-PI3K-Akt axis and the DNA repair enzyme, DNA-PKcs, underlies the radioresistance of GBMs and that this connection can be targeted for effective radiotherapy. Specifically, we propose: 1. To confirm that GBM radioresistance is conferred by interactions between key GBM-specific genetic lesions. 2. To validate that phosphorylation of DNA-PKcs by Akt promotes the repair of radiation-induced DNA breaks. 3. To test whether Akt-DNA-PKcs is a vulnerable node that can be targeted to improve radiotherapy of GBMs. More... »

URL

http://projectreporter.nih.gov/project_info_description.cfm?aid=8795699

JSON-LD is the canonical representation for SciGraph data.

TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

[
  {
    "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
    "about": [
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/2211", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "type": "DefinedTerm"
      }
    ], 
    "amount": {
      "currency": "USD", 
      "type": "MonetaryAmount", 
      "value": "1618204"
    }, 
    "description": "DESCRIPTION (provided by applicant): Glioblastoma Multiforme (GBM) tumors are the third leading cause of cancer-related death among adults aged 30 - 50 years, even though they account for less than 1.5% of all new cancer cases reported in the United States each year. The very high mortality rate of GBMs (>90% at 2 years) has remained relatively unchanged over the past 40 years despite aggressive therapy that includes surgical resection, radiotherapy and chemotherapy. However, a clear survival advantage of post-resection radiation has been established by randomized trials, showing that the median survival of GBM patients was improved, from approximately 6 months to 10-12 months, following near-maximal brain-tolerated doses of ionizing radiation. The central role that radiation plays in treating GBM is also illustrated by the landmark Stupp study showing that concurrent radiation and Temozolomide can further increase median survival from 12.1 to 14.6 months. Thus, radiation remains the mainstay of GBM therapy, and the success of the Stupp study, though modest, offers hope that radiotherapy of GBMs can be further improved. Any improvement in therapy would require a more mechanistic understanding of the basis of GBM radioresistance. The lack of improvement in GBM treatment is partly due to a paucity of appropriate genetic models that can be used to delineate the effects of genetic changes that occur in GBMs on radioresistance. The recent mapping of the GBM genome by the Cancer Genome Atlas Network revealed that these tumors have radically altered genomes with many mutations, gene copy number gains and losses, and methylation changes. Amongst the myriad genetic alterations that populate the GBM genomic landscape, 5 key genetic alterations dominate: loss of Ink4a, Arf, p53, or PTEN and amplification of EGFR (especially, the constitutively active EGFRvIII). Which of these key genetic aberrations may confer therapeutic resistance remains unclear. Understanding the contribution of these lesions, singly and in combination, to GBM radioresistance along with the underlying mechanism(s) will be of paramount importance in developing more effective therapeutic modalities. Towards this goal, we plan to use conditional knock out mouse models wherein these key genetic lesions can be introduced in astrocytes and neural stem cells (NSCs) both in culture and in the mouse brain using the Cre-ERT2 system. We propose to examine how these genetic changes impact on mechanisms for the repair of radiation-induced DNA double-strand breaks (DSBs). Based upon our preliminary results, we hypothesize that cross talk between the EGFRvIII-PI3K-Akt axis and the DNA repair enzyme, DNA-PKcs, underlies the radioresistance of GBMs and that this connection can be targeted for effective radiotherapy. Specifically, we propose: 1. To confirm that GBM radioresistance is conferred by interactions between key GBM-specific genetic lesions. 2. To validate that phosphorylation of DNA-PKcs by Akt promotes the repair of radiation-induced DNA breaks. 3. To test whether Akt-DNA-PKcs is a vulnerable node that can be targeted to improve radiotherapy of GBMs.", 
    "endDate": "2017-09-30T00:00:00Z", 
    "funder": {
      "id": "https://www.grid.ac/institutes/grid.48336.3a", 
      "type": "Organization"
    }, 
    "id": "sg:grant.2480880", 
    "identifier": [
      {
        "name": "dimensions_id", 
        "type": "PropertyValue", 
        "value": [
          "2480880"
        ]
      }, 
      {
        "name": "nih_id", 
        "type": "PropertyValue", 
        "value": [
          "R01CA149461"
        ]
      }
    ], 
    "inLanguage": [
      "en"
    ], 
    "keywords": [
      "mechanism(s", 
      "loss", 
      "GBM treatment", 
      "strategies", 
      "GBM genome", 
      "years", 
      "randomized trial", 
      "p53", 
      "phosphorylation", 
      "Cancer Genome Atlas Network", 
      "cross", 
      "EGFR", 
      "chemotherapy", 
      "key GBM-specific genetic lesions", 
      "Stupp study", 
      "cancer", 
      "DNA-PKcs", 
      "basis", 
      "appropriate genetic model", 
      "lesions", 
      "paramount importance", 
      "myriad genetic alterations", 
      "DSBs", 
      "recent mapping", 
      "DNA breaks", 
      "Cre-ERT2 system", 
      "preliminary results", 
      "amplification", 
      "key genetic aberrations", 
      "new cancer cases", 
      "genetic changes impact", 
      "PKCs", 
      "concurrent radiation", 
      "effect", 
      "methylation changes", 
      "months", 
      "strand breaks", 
      "maximal brain", 
      "therapy", 
      "cause", 
      "improvement", 
      "Akt", 
      "radiosensitization", 
      "post-resection radiation", 
      "death", 
      "many mutations", 
      "active EGFRvIII", 
      "aggressive therapy", 
      "United States", 
      "applicants", 
      "DNA", 
      "genetic changes", 
      "description", 
      "GBM therapy", 
      "clear survival advantage", 
      "combination", 
      "mouse model", 
      "ARF", 
      "median survival", 
      "glioblastoma multiforme", 
      "radiotherapy", 
      "paucity", 
      "molecular mechanisms", 
      "gene copy number gain", 
      "Akt axis", 
      "radioresistance", 
      "radiation", 
      "mouse brain", 
      "key genetic alterations", 
      "vulnerable nodes", 
      "GBM patients", 
      "mainstay", 
      "connection", 
      "goal", 
      "success", 
      "INK4a", 
      "mechanistic understanding", 
      "GBM genomic landscape", 
      "PTEN", 
      "DNA repair enzymes", 
      "culture", 
      "astrocytes", 
      "interaction", 
      "GBM radioresistance", 
      "high mortality rate", 
      "landmark Stupp study", 
      "tumor", 
      "contribution", 
      "central role", 
      "adults", 
      "key genetic lesions", 
      "effective therapeutic modality", 
      "lack", 
      "neural stem cells", 
      "temozolomide", 
      "doses", 
      "repair", 
      "surgical resection", 
      "mechanism", 
      "therapeutic resistance", 
      "EGFRvIII-PI3K", 
      "Akt-DNA", 
      "genome"
    ], 
    "name": "Molecular mechanisms of GBM radioresistance and strategies for radiosensitization", 
    "recipient": [
      {
        "id": "https://www.grid.ac/institutes/grid.267313.2", 
        "type": "Organization"
      }, 
      {
        "affiliation": {
          "id": "https://www.grid.ac/institutes/grid.267313.2", 
          "name": "UT SOUTHWESTERN MEDICAL CENTER", 
          "type": "Organization"
        }, 
        "familyName": "BURMA", 
        "givenName": "SANDEEP", 
        "id": "sg:person.01142321463.18", 
        "type": "Person"
      }, 
      {
        "member": "sg:person.01142321463.18", 
        "roleName": "PI", 
        "type": "Role"
      }
    ], 
    "sameAs": [
      "https://app.dimensions.ai/details/grant/grant.2480880"
    ], 
    "sdDataset": "grants", 
    "sdDatePublished": "2019-03-07T12:14", 
    "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
    "sdPublisher": {
      "name": "Springer Nature - SN SciGraph project", 
      "type": "Organization"
    }, 
    "sdSource": "s3://com.uberresearch.data.processor/core_data/20181219_192338/projects/base/nih_projects_7.xml.gz", 
    "startDate": "2011-01-01T00:00:00Z", 
    "type": "MonetaryGrant", 
    "url": "http://projectreporter.nih.gov/project_info_description.cfm?aid=8795699"
  }
]
 

Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

JSON-LD is a popular format for linked data which is fully compatible with JSON.

curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/grant.2480880'

N-Triples is a line-based linked data format ideal for batch operations.

curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/grant.2480880'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/grant.2480880'

RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/grant.2480880'


 

This table displays all metadata directly associated to this object as RDF triples.

147 TRIPLES      19 PREDICATES      125 URIs      117 LITERALS      5 BLANK NODES

Subject Predicate Object
1 sg:grant.2480880 schema:about anzsrc-for:2211
2 schema:amount N12c1cf40e47c4c8ab22162ecf619e169
3 schema:description DESCRIPTION (provided by applicant): Glioblastoma Multiforme (GBM) tumors are the third leading cause of cancer-related death among adults aged 30 - 50 years, even though they account for less than 1.5% of all new cancer cases reported in the United States each year. The very high mortality rate of GBMs (>90% at 2 years) has remained relatively unchanged over the past 40 years despite aggressive therapy that includes surgical resection, radiotherapy and chemotherapy. However, a clear survival advantage of post-resection radiation has been established by randomized trials, showing that the median survival of GBM patients was improved, from approximately 6 months to 10-12 months, following near-maximal brain-tolerated doses of ionizing radiation. The central role that radiation plays in treating GBM is also illustrated by the landmark Stupp study showing that concurrent radiation and Temozolomide can further increase median survival from 12.1 to 14.6 months. Thus, radiation remains the mainstay of GBM therapy, and the success of the Stupp study, though modest, offers hope that radiotherapy of GBMs can be further improved. Any improvement in therapy would require a more mechanistic understanding of the basis of GBM radioresistance. The lack of improvement in GBM treatment is partly due to a paucity of appropriate genetic models that can be used to delineate the effects of genetic changes that occur in GBMs on radioresistance. The recent mapping of the GBM genome by the Cancer Genome Atlas Network revealed that these tumors have radically altered genomes with many mutations, gene copy number gains and losses, and methylation changes. Amongst the myriad genetic alterations that populate the GBM genomic landscape, 5 key genetic alterations dominate: loss of Ink4a, Arf, p53, or PTEN and amplification of EGFR (especially, the constitutively active EGFRvIII). Which of these key genetic aberrations may confer therapeutic resistance remains unclear. Understanding the contribution of these lesions, singly and in combination, to GBM radioresistance along with the underlying mechanism(s) will be of paramount importance in developing more effective therapeutic modalities. Towards this goal, we plan to use conditional knock out mouse models wherein these key genetic lesions can be introduced in astrocytes and neural stem cells (NSCs) both in culture and in the mouse brain using the Cre-ERT2 system. We propose to examine how these genetic changes impact on mechanisms for the repair of radiation-induced DNA double-strand breaks (DSBs). Based upon our preliminary results, we hypothesize that cross talk between the EGFRvIII-PI3K-Akt axis and the DNA repair enzyme, DNA-PKcs, underlies the radioresistance of GBMs and that this connection can be targeted for effective radiotherapy. Specifically, we propose: 1. To confirm that GBM radioresistance is conferred by interactions between key GBM-specific genetic lesions. 2. To validate that phosphorylation of DNA-PKcs by Akt promotes the repair of radiation-induced DNA breaks. 3. To test whether Akt-DNA-PKcs is a vulnerable node that can be targeted to improve radiotherapy of GBMs.
4 schema:endDate 2017-09-30T00:00:00Z
5 schema:funder https://www.grid.ac/institutes/grid.48336.3a
6 schema:identifier N3c1da7ecbfb44269a4dfad153e66a2e4
7 N87e71bb9e5114cd0aed31d2fc3edfb2c
8 schema:inLanguage en
9 schema:keywords ARF
10 Akt
11 Akt axis
12 Akt-DNA
13 Cancer Genome Atlas Network
14 Cre-ERT2 system
15 DNA
16 DNA breaks
17 DNA repair enzymes
18 DNA-PKcs
19 DSBs
20 EGFR
21 EGFRvIII-PI3K
22 GBM genome
23 GBM genomic landscape
24 GBM patients
25 GBM radioresistance
26 GBM therapy
27 GBM treatment
28 INK4a
29 PKCs
30 PTEN
31 Stupp study
32 United States
33 active EGFRvIII
34 adults
35 aggressive therapy
36 amplification
37 applicants
38 appropriate genetic model
39 astrocytes
40 basis
41 cancer
42 cause
43 central role
44 chemotherapy
45 clear survival advantage
46 combination
47 concurrent radiation
48 connection
49 contribution
50 cross
51 culture
52 death
53 description
54 doses
55 effect
56 effective therapeutic modality
57 gene copy number gain
58 genetic changes
59 genetic changes impact
60 genome
61 glioblastoma multiforme
62 goal
63 high mortality rate
64 improvement
65 interaction
66 key GBM-specific genetic lesions
67 key genetic aberrations
68 key genetic alterations
69 key genetic lesions
70 lack
71 landmark Stupp study
72 lesions
73 loss
74 mainstay
75 many mutations
76 maximal brain
77 mechanism
78 mechanism(s
79 mechanistic understanding
80 median survival
81 methylation changes
82 molecular mechanisms
83 months
84 mouse brain
85 mouse model
86 myriad genetic alterations
87 neural stem cells
88 new cancer cases
89 p53
90 paramount importance
91 paucity
92 phosphorylation
93 post-resection radiation
94 preliminary results
95 radiation
96 radioresistance
97 radiosensitization
98 radiotherapy
99 randomized trial
100 recent mapping
101 repair
102 strand breaks
103 strategies
104 success
105 surgical resection
106 temozolomide
107 therapeutic resistance
108 therapy
109 tumor
110 vulnerable nodes
111 years
112 schema:name Molecular mechanisms of GBM radioresistance and strategies for radiosensitization
113 schema:recipient Nffb141b2c0334926b6bc791489fa825c
114 sg:person.01142321463.18
115 https://www.grid.ac/institutes/grid.267313.2
116 schema:sameAs https://app.dimensions.ai/details/grant/grant.2480880
117 schema:sdDatePublished 2019-03-07T12:14
118 schema:sdLicense https://scigraph.springernature.com/explorer/license/
119 schema:sdPublisher N9e3953629fac4b03af3c673b4a3486df
120 schema:startDate 2011-01-01T00:00:00Z
121 schema:url http://projectreporter.nih.gov/project_info_description.cfm?aid=8795699
122 sgo:license sg:explorer/license/
123 sgo:sdDataset grants
124 rdf:type schema:MonetaryGrant
125 N12c1cf40e47c4c8ab22162ecf619e169 schema:currency USD
126 schema:value 1618204
127 rdf:type schema:MonetaryAmount
128 N3c1da7ecbfb44269a4dfad153e66a2e4 schema:name nih_id
129 schema:value R01CA149461
130 rdf:type schema:PropertyValue
131 N87e71bb9e5114cd0aed31d2fc3edfb2c schema:name dimensions_id
132 schema:value 2480880
133 rdf:type schema:PropertyValue
134 N9e3953629fac4b03af3c673b4a3486df schema:name Springer Nature - SN SciGraph project
135 rdf:type schema:Organization
136 Nffb141b2c0334926b6bc791489fa825c schema:member sg:person.01142321463.18
137 schema:roleName PI
138 rdf:type schema:Role
139 anzsrc-for:2211 schema:inDefinedTermSet anzsrc-for:
140 rdf:type schema:DefinedTerm
141 sg:person.01142321463.18 schema:affiliation https://www.grid.ac/institutes/grid.267313.2
142 schema:familyName BURMA
143 schema:givenName SANDEEP
144 rdf:type schema:Person
145 https://www.grid.ac/institutes/grid.267313.2 schema:name UT SOUTHWESTERN MEDICAL CENTER
146 rdf:type schema:Organization
147 https://www.grid.ac/institutes/grid.48336.3a schema:Organization
 




Preview window. Press ESC to close (or click here)


...