RGD Reference Report - XPO1 Inhibition Enhances Radiation Response in Preclinical Models of Rectal Cancer. - Rat Genome Database

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XPO1 Inhibition Enhances Radiation Response in Preclinical Models of Rectal Cancer.

Authors: Ferreiro-Neira, Isabel  Torres, Nancy E  Liesenfeld, Lukas F  Chan, Carlos H F  Penson, Tristan  Landesman, Yosef  Senapedis, William  Shacham, Sharon  Hong, Theodore S  Cusack, James C 
Citation: Ferreiro-Neira I, etal., Clin Cancer Res. 2016 Apr 1;22(7):1663-73. doi: 10.1158/1078-0432.CCR-15-0978. Epub 2015 Nov 24.
RGD ID: 151665795
Pubmed: PMID:26603256   (View Abstract at PubMed)
DOI: DOI:10.1158/1078-0432.CCR-15-0978   (Journal Full-text)


PURPOSE: Combination of radiation with radiosensitizing chemotherapeutic agents improves outcomes for locally advanced rectal cancer. Current treatment includes 5-fluorouracil-based chemoradiation prior to surgical resection; however pathologic complete response varies from 15% to 20%, prompting the need to identify new radiosensitizers. Exportin 1 (XPO1, also known as chromosome region 1, CRM1) mediates the nuclear export of critical proteins required for rectal cancer proliferation and treatment resistance. We hypothesize that inhibition of XPO1 may radiosensitize cancer cells by altering the function of these critical proteins resulting in decreased radiation resistance and enhanced antitumoral effects.
EXPERIMENTAL DESIGN: To test our hypothesis, we used the selective XPO1 inhibitor, selinexor, to inhibit nuclear export in combination with radiation fractions similar to that given in clinical practice for rectal cancer: hypofractionated short-course radiation dosage of 5 Gy per fraction or the conventional long-course radiation dosage of 1 Gy fractions. Single and combination treatments were tested in colorectal cancer cell lines and xenograft tumor models.
RESULTS: Combination treatment of radiotherapy and selinexor resulted in an increase of apoptosis and decrease of proliferation compared with single treatment, which correlated with reduced tumor size. We found that the combination promoted nuclear survivin accumulation and subsequent depletion, resulting in increased apoptosis and enhanced radiation antitumoral effects.
CONCLUSIONS: Our findings suggest a novel therapeutic option for improving radiation sensitivity in the setting of rectal cancer and provide the scientific rationale to evaluate this combination strategy for clinical trials.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
XPO1Humancolorectal cancer amelioratesIMP human cell line in a mouse modelRGD 
Xpo1Ratcolorectal cancer amelioratesISOXPO1 (Homo sapiens)human cell line in a mouse modelRGD 
Xpo1Mousecolorectal cancer amelioratesISOXPO1 (Homo sapiens)human cell line in a mouse modelRGD 

Objects Annotated

Genes (Rattus norvegicus)
Xpo1  (exportin 1)

Genes (Mus musculus)
Xpo1  (exportin 1)

Genes (Homo sapiens)
XPO1  (exportin 1)


Additional Information