Linked Life Data

14566853

Source:http://linkedlifedata.com/resource/pubmed/id/14566853

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2003-10-20
pubmed:abstractText
The work of Al Knudson created the paradigm in which we see cancer as a result of the accumulation of multiple mutations. Our goal has been to exploit these mutations to develop strategies to enhance therapy for cancer by targeting the malignant cell while sparing the normal tissue. In studying the RAS oncogene, we observed that its expression when activated resulted in enhanced radioresistance. Conversely, inhibition of RAS made cells with activated RAS more radiosensitive. Hence, we postulated that it would be possible to sensitize tumors with RAS mutations to radiation without affecting the sensitivity of the normal tissue in patients with such tumors. This proved to be the case in animal models and has led to current clinical trials. These studies raised the question of identifying the downstream effectors of RAS that are responsible for altering the radiosensitivity of cells. We have found that phosphoinositide-3-kinase (PI3 kinase) is a critical component of this pathway. Blocking PI3 kinase enhanced the radiation response in vitro or in vivo of cells actively signaling through that pathway, but did not affect cells not actively signaling through PI3 kinase at the time of irradiation. Identification of tumors with active signaling in this pathway by immunohistochemical staining for phosphorylated AKT, the downstream target of PI3 kinase correlated with those patients for which radiation failed to achieve local control. Thus, characterization of the active signaling pathways in a given tumor might enable the selection of patients likely to respond to radiation. Pathways upstream from RAS may also be useful targets to consider for enhancing radiation therapy. Epidermal growth factor receptor (EGFR), which is upstream of PI3 kinase, may also mediate resistance through a common pathway. In addition to EGFR and RAS, PTEN can also regulate the PI3 kinase pathway. Identifying a common signal for EGFR, RAS, and PTEN that results in radiation resistance may uncover targets for developing molecular-based radiosensitization protocols for tumors resistant to radiation and thus lead to improvement of local control.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1045-2257
pubmed:author
pubmed:copyrightInfo
Copyright 2003 Wiley-Liss, Inc.
pubmed:issnType
Print
pubmed:volume
38
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
330-8
pubmed:dateRevised
2005-11-16
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
Targeting tumor cells by enhancing radiation sensitivity.
pubmed:affiliation
Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
pubmed:publicationType
Journal Article, Review