US 2011/0257035 A1 · IDENTIFICATION OF SIGNATURE GENES ASSOCIATED WITH HEPATOCELLULAR CARCINOMA

Abstract

The present invention relates to, for example, (1) a novel method for identification of clinically useful serum and/or tumor biomarkers and expression signatures that can be used for detection, prognostication and guidance for the treatment of patients with hepatocellular carcinoma (HCC); and (2) discovery of an expression signature that can be used to monitor and/or study the efficacy of a chemotherapeutic regimen, such as, for example, sorafenib (solely or in combination with other agents). The present invention also provides a method for predicting clinical outcomes, such as, for example, overall survival (OS), time to progression (TTP) and/or likelihood of benefitting from a chemotherapeutic treatment (i.e., sorafenib) in HCC patients based on the analysis of such biomarkers.

Claims36

Dependent claims

A method of prognosticating the outcome of sorafenib treatment of hepatocellular carcinoma (HCC) in a patient comprising

detecting at least one biomarker from vascular endothelial growth factor (VEGF), soluble VEGF receptor 2 (s-VEGFR-2), soluble VEGF receptor 3 (VEGFR-3), soluble c-Kit (s-c-Kit), hepatocyte growth factor (HGF), Ras p 21, phosphorylated ERK (pERK), angiopoietin 2 (Ang2), basic fibroblast growth factor (bFGF), or insulin-like growth factor (IGF-2);
and
comparing said level of expression of said biomarkers in said patient test sample with a reference standard,
wherein differential levels of expression of said biomarker in said test sample compared to said reference standard is indicative of said outcome of sorafenib treatment.

1 more element

An antibody array or a kit which comprises of a plurality of antibody molecules, each of which specifically binds to an antigenic composition consisting of:

(a) Combinations comprising one biomarker from Group A and one biomarker from Group B
(i) HGF and VEGF;
(ii) s-c-Kit and VEGF;
(iii) s-VEGFR-3 and VEGF;
(iv) HGF and s-VEGFR-2;
(v) s-c-Kit and s-VEGFR-2;
(vi) s-VEGFR-3 and s-VEGFR-2;
(vii) Ang2 and VEGF;
(viii) Ang2 and sVEGFR2;
(ix) Ang2 and Ras p 21;
(x) IGF-2 and VEGF;
(xi) IGF-2 and sVEGFR2;
(xii) IGF-2 and Ras p21;
or
(b) Combinations comprising one biomarker from Group A and two biomarkers from Group B
(i) HGF and VEGF plus s-VEGFR-2;
(ii) s-c-Kit and VEGF plus s-VEGFR-2;
(iii) s-VEGFR-3 and VEGF plus s-VEGFR-2;
(iv) Ang2 and VEGF plus sVEGFR2;
(v) Ang2 and sVEGFR2 plus Ras p21;
(vi) Ang2 and Ras p21 plus VEGF;
(vii) IGF-2 VEGF and sVEGFR2;
(viii) IGF-2, sVEGFR2 and Ras p21;
(ix) IGF-2, VEGF and Ras p21;
or
(c) Combinations comprising two biomarkers from Group A and one biomarker from Group B
(i) HGF, s-c-Kit and VEGF;
(ii) HGF, s-c-Kit and s-VEGFR-2;
(iii) HGF, s-VEGFR-3 and VEGF;
(iv) HGF, s-VEGFR-3 and s-VEGFR-2;
(v) s-c-Kit, s-VEGFR-3 and VEGF;
(vi) s-c-Kit, s-VEGFR-3 and s-VEGFR-2;
(vii) HGF, Ang2 and VEGF;
(viii) HGF, Ang2 and s-VEGFR-2;
(ix) s-c-Kit, Ang2 and VEGF;
(x) s-c-Kit, s-VEGFR-3 and s-VEGFR-2;
(xi) s-VEGFR-3, Ang2 and VEGF;
(xii) s-VEGFR-3, Ang2 and s-VEGFR-2;
(xiii) IGF-2, HGF and VEGF;
(xiv) IGF-2, HGF and sVEGFR2;
(xv) IGF-2, HGF and Ras p21;
(xvi) IGF-2, Ang2 and VEGF;
(xvii) IGF-2, Ang2 and sVEGFR2;
(xviii) IGF-2, Ang2 and Ras p21;
(xix) IGF-2, s-c-Kit and VEGF;
(xx) IGF-2, s-c-Kit and sVEGFR2;
(xxi) IGF-2, s-c-Kit and Ras p21;
or
(d) Combinations comprising two biomarkers from Group A and two biomarkers from Group B
(i) HGF, s-c-Kit and VEGF plus s-VEGFR-2;
(ii) HGF, s-VEGFR-3 and VEGF plus s-VEGFR-2;
(iii) s-c-Kit, s-VEGFR-3 and VEGF plus s-VEGFR-2;
(iv) HGF, Ang2 and VEGF plus s-VEGFR-2;
(v) s-c-Kit, Ang2 and VEGF plus s-VEGFR-2;
(vi) s-VEGFR-3, Ang2 and VEGF plus s-VEGFR-2;
(vii) IGF-2, HGF and VEGF plus sVEGFR2;
(viii) IGF-2, HGF and sVEGFR2 plus Ras p21;
(ix) IGF-2, HGF and VEGF plus Ras p21;
(x) IGF-2, Ang2 and VEGF plus sVEGFR2;
(xi) IGF-2, Ang2 and sVEGFR2 plus Ras p21;
(xii) IGF-2, Ang2 and VEGF plus Ras p21;
(xiii) IGF-2, s-c-Kit VEGF plus sVEGFR2;
(xiv) IGF-2, s-c-Kit and sVEGFR2 plus Ras p21;
(xv) IGF-2, s-c-Kit and VEGF plus Ras p21;
or
(e) Combinations comprising three biomarkers from Group A and one biomarker from Group B
(i) HGF, s-c-Kit, s-VEGFR-3 and VEGF;
(ii) HGF, s-c-Kit, s-VEGFR-3 and s-VEGFR-2;
(iii) HGF, s-c-Kit, Ang2 and VEGF;
(iv) HGF, s-c-Kit, Ang2 and s-VEGFR-2;
(vi) s-c-Kit, s-VEGFR-3, Ang2 and VEGF;
(vi) s-c-Kit, s-VEGFR-3, Ang2 and s-VEGFR-2;
(vii) HGF, s-VEGFR-3, Ang2 and VEGF;
(viii) HGF, s-VEGFR-3, Ang2 and s-VEGFR-2;
(ix) HGF, s-c-Kit, IGF-2 and VEGF;
(x) HGF, s-c-Kit, IGF-2 and s-VEGFR-2;
(xi) HGF, IGF-2, Ang2 and VEGF;
(xii) HGF, IGF-2, Ang2 and s-VEGFR-2;
or
(f) Combination comprising three biomarkers from Group A and two biomarkers from Group B
(i) HGF, s-c-Kit, s-VEGFR-3 and VEGF plus s-VEGFR-2;
(ii) HGF, s-c-Kit, Ang2 and VEGF plus s-VEGFR-2;
(iii) HGF, Ang2, s-VEGFR-3 and VEGF plus s-VEGFR-2;
(iv) s-c-Kit, s-VEGFR-3, Ang2 and VEGF plus s-VEGFR-2;
(v) HGF, s-c-Kit, IGF-2 and VEGF plus s-VEGFR-2;
(vi) HGF, s-c-Kit, IGF-2 and VEGF plus s-VEGFR-2;
(vii) HGF, IGF-2, Ang2 and VEGF plus s-VEGFR-2;
(viii) HGF, IGF-2, Ang2 and VEGF plus s-VEGFR-2;
or
(g) Combination comprising four biomarkers from Group A and one biomarker from Group B
(i) HGF, s-c-Kit, s-VEGFR-3, Ang2 and VEGF;
(ii) HGF, s-c-Kit, s-VEGFR-3, Ang2 and s-VEGFR-2;
(iii) HGF, s-c-Kit, IGF-2, Ang2 and VEGF;
(iv) HGF, s-c-Kit, IGF-2, Ang2 and s-VEGFR-2;
or
(h) Combination comprising four biomarkers from Group A and two biomarkers from Group B
(i) HGF, s-c-Kit, s-VEGFR-3, Ang2 and VEGF plus s-VEGFR-2;
(ii) HGF, s-c-Kit, IGF-2, Ang2 and VEGF plus s-VEGFR-2;
or
(i) Combinations comprising all of the aforementioned biomarkers;
Aspect 37. An oligonucleotide array or a kit which comprises a plurality of oligonucleotide molecules, each of which specifically hybridize, under stringent hybridization conditions, with a combination consisting of the following genes:
(a) Combinations comprising one biomarker from Group A and one biomarker from Group B
(i) HGF and VEGF;
(ii) s-c-Kit and VEGF;
(iii) s-VEGFR-3 and VEGF;
(iv) HGF and s-VEGFR-2;
(v) s-c-Kit and s-VEGFR-2;
(vi) s-VEGFR-3 and s-VEGFR-2;
(vii) Ang2 and VEGF;
(viii) Ang2 and sVEGFR2;
(ix) Ang2 and Ras p 21;
(x) IGF-2 and VEGF;
(xi) IGF-2 and sVEGFR2;
(xii) IGF-2 and Ras p21;
or
(b) Combinations comprising one biomarker from Group A and two biomarkers from Group B
(i) HGF and VEGF plus s-VEGFR-2;
(ii) s-c-Kit and VEGF plus s-VEGFR-2;
(iii) s-VEGFR-3 and VEGF plus s-VEGFR-2;
(iv) Ang2 and VEGF plus sVEGFR2;
(v) Ang2 and sVEGFR2 plus Ras p21;
(vi) Ang2 and Ras p21 plus VEGF;
(vii) IGF-2 VEGF and sVEGFR2;
(viii) IGF-2, sVEGFR2 and Ras p21;
(ix) IGF-2, VEGF and Ras p21;
or
(c) Combinations comprising two biomarkers from Group A and one biomarker from Group B
(i) HGF, s-c-Kit and VEGF;
(ii) HGF, s-c-Kit and s-VEGFR-2;
(iii) HGF, s-VEGFR-3 and VEGF;
(iv) HGF, s-VEGFR-3 and s-VEGFR-2;
(v) s-c-Kit, s-VEGFR-3 and VEGF;
(vi) s-c-Kit, s-VEGFR-3 and s-VEGFR-2;
(vii) HGF, Ang2 and VEGF;
(viii) HGF, Ang2 and s-VEGFR-2;
(ix) s-c-Kit, Ang2 and VEGF;
(x) s-c-Kit, s-VEGFR-3 and s-VEGFR-2;
(xi) s-VEGFR-3, Ang2 and VEGF;
(xii) s-VEGFR-3, Ang2 and s-VEGFR-2;
(xiii) IGF-2, HGF and VEGF;
(xiv) IGF-2, HGF and sVEGFR2;
(xv) IGF-2, HGF and Ras p21;
(xvi) IGF-2, Ang2 and VEGF;
(xvii) IGF-2, Ang2 and sVEGFR2;
(xviii) IGF-2, Ang2 and Ras p21;
(xix) IGF-2, s-c-Kit and VEGF;
(xx) IGF-2, s-c-Kit and sVEGFR2;
(xxi) IGF-2, s-c-Kit and Ras p21;
or
(d) Combinations comprising two biomarkers from Group A and two biomarkers from Group B
(i) HGF, s-c-Kit and VEGF plus s-VEGFR-2;
(ii) HGF, s-VEGFR-3 and VEGF plus s-VEGFR-2;
(iii) s-c-Kit, s-VEGFR-3 and VEGF plus s-VEGFR-2;
(iv) HGF, Ang2 and VEGF plus s-VEGFR-2;
(v) s-c-Kit, Ang2 and VEGF plus s-VEGFR-2;
(vi) s-VEGFR-3, Ang2 and VEGF plus s-VEGFR-2;
(vii) IGF-2, HGF and VEGF plus sVEGFR2;
(viii) IGF-2, HGF and sVEGFR2 plus Ras p21;
(ix) IGF-2, HGF and VEGF plus Ras p21;
(x) IGF-2, Ang2 and VEGF plus sVEGFR2;
(xi) IGF-2, Ang2 and sVEGFR2 plus Ras p21;
(xii) IGF-2, Ang2 and VEGF plus Ras p21;
(xiii) IGF-2, s-c-Kit VEGF plus sVEGFR2;
(xiv) IGF-2, s-c-Kit and sVEGFR2 plus Ras p21;
(xv) IGF-2, s-c-Kit and VEGF plus Ras p21;
or
(e) Combinations comprising three biomarkers from Group A and one biomarker from Group B
(i) HGF, s-c-Kit, s-VEGFR-3 and VEGF;
(ii) HGF, s-c-Kit, s-VEGFR-3 and s-VEGFR-2;
(iii) HGF, s-c-Kit, Ang2 and VEGF;
(iv) HGF, s-c-Kit, Ang2 and s-VEGFR-2;
(vi) s-c-Kit, s-VEGFR-3, Ang2 and VEGF;
(vi) s-c-Kit, s-VEGFR-3, Ang2 and s-VEGFR-2;
(vii) HGF, s-VEGFR-3, Ang2 and VEGF;
(viii) HGF, s-VEGFR-3, Ang2 and s-VEGFR-2;
(ix) HGF, s-c-Kit, IGF-2 and VEGF;
(x) HGF, s-c-Kit, IGF-2 and s-VEGFR-2;
(xi) HGF, IGF-2, Ang2 and VEGF;
(xii) HGF, IGF-2, Ang2 and s-VEGFR-2;
or
(f) Combination comprising three biomarkers from Group A and two biomarkers from Group B
(i) HGF, s-c-Kit, s-VEGFR-3 and VEGF plus s-VEGFR-2;
(ii) HGF, s-c-Kit, Ang2 and VEGF plus s-VEGFR-2;
(iii) HGF, Ang2, s-VEGFR-3 and VEGF plus s-VEGFR-2;
(iv) s-c-Kit, s-VEGFR-3, Ang2 and VEGF plus s-VEGFR-2;
(v) HGF, s-c-Kit, IGF-2 and VEGF plus s-VEGFR-2;
(vi) HGF, s-c-Kit, IGF-2 and VEGF plus s-VEGFR-2;
(vii) HGF, IGF-2, Ang2 and VEGF plus s-VEGFR-2;
(viii) HGF, IGF-2, Ang2 and VEGF plus s-VEGFR-2;
or
(g) Combination comprising four biomarkers from Group A and one biomarker from Group B
(i) HGF, s-c-Kit, s-VEGFR-3, Ang2 and VEGF;
(ii) HGF, s-c-Kit, s-VEGFR-3, Ang2 and s-VEGFR-2;
(iii) HGF, s-c-Kit, IGF-2, Ang2 and VEGF;
(iv) HGF, s-c-Kit, IGF-2, Ang2 and s-VEGFR-2;
or
(h) Combination comprising four biomarkers from Group A and two biomarkers from Group B
(i) HGF, s-c-Kit, s-VEGFR-3, Ang2 and VEGF plus s-VEGFR-2;
(ii) HGF, s-c-Kit, IGF-2, Ang2 and VEGF plus s-VEGFR-2;
or
(i) an oligonucleotide array comprising all of the aforementioned biomarker genes.

198 more elements

Dependencies are inferred from the claim text.

Identification of signature genes associated with hepatocellular carcinoma

Life of this patent

Identification of signature genes associated with hepatocellular carcinoma

Life of this patent

Abstract

Claims36