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Patent Application Titled "Correlation of Molecular Markers with Clinical Outcome in Gbm Patients Radiation Treated with Or without Gefitinib"...

June 12, 2014



Patent Application Titled "Correlation of Molecular Markers with Clinical Outcome in Gbm Patients Radiation Treated with Or without Gefitinib" Published Online

By a News Reporter-Staff News Editor at Politics & Government Week -- According to news reporting originating from Washington, D.C., by VerticalNews journalists, a patent application by the inventors CHAKRAVARTI, Arnab (Dublin, OH); Pinard, Robert (Andover, MA); Waldron, Donald (Fairfield, CT); Ang, Agnes (Newbury Park, CA); Dolled-Filhart, Marisa P. (New Haven, CT); Molinaro, Annette (New Haven, CT), filed on October 14, 2013, was made available online on May 29, 2014.

The assignee for this patent application is Radiation Therapy Oncology Group of the Americal College of Radiology.

Reporters obtained the following quote from the background information supplied by the inventors: "Glioblastoma Multiforme (GBM) is the most common malignant brain tumor of adults and is among the most lethal of all cancers. Analysis of large clinical databases demonstrates clinical prognostic groups of glioblastoma patients, suggesting considerable biological heterogeneity(Curran W J, 1993 J Natl Cancer Ins 85:704-710;Scott C B, 1998 Int J Radiat Oncol Biol Phys. 1998 Jan. 1; 40(1):51-5. Recent data suggest that morphologically indistinguishable glioblastomas have distinct classes of causal oncogene activation and downstream signaling pathway deregulation that may affect survival and response to therapy (Mischel P S, 2003 Cancer Biol Ther 2(3)242-7; Mischel P S, 2003 Brain Pathol 13(1)52-61; Mischel P S, 2003 Oncogene 22(15)2361-73; Mischel, 2003 #3120; Shai, 2003 #3161; Chakravarti, 2001 Clin Cancer Res (1)2387-2395. Deregulation of the PI3K/Akt pathway signaling, which promotes malignant transformation, tumor progression and radiation-resistance in pre-clinical models, is common in glioblastomas (Choe, 2003 Cancer Res 63:2742-2746; Chakravarti, 2003 #3229; Chakravarti, 2004 Oncogene 23(45)7494-506; J Clin Oncol 22(10)1926-33; Int J Radiat Oncol Biol Phys 58(3)927-31).

"It is an object of the present invention, therefore, to identify biomarkers that have prognostic value for GBM and to develop assays useful for identifying patients that may be suitable for targeted therapies."

In addition to obtaining background information on this patent application, VerticalNews editors also obtained the inventors' summary information for this patent application: "The present invention is directed to a method of determining a prognosis of a patient comprising assessing the concentration of one or more protein biomarkers selected from the group consisting of PTEN, EGFRvIII, EGFR, IGF-1R, and NFkB in a tissue specimen obtained from the patient in which high levels of PTEN, EGFRvIII, EGFR, IGF-1R, and/or NFkB indicate a relatively poor prognosis for the patient when treated with radiation therapy alone. In a particular embodiment of the invention the patient suffers from brain cancer, and the brain cancer may be glioblastoma.

"The invention is further directed to a method of determining a prognosis of a patient comprising: assessing the relative concentrations of two or more protein biomarkers selected from the group consisting of PTEN, EGFRvIII, EGFR, IGF-1R, and NFkB in a tissue specimen obtained from the patient in which high levels of PTEN, EGFRvIII, EGFR, IGF-1R and/or NFkB indicate a relatively poor prognosis for the patient when treated with radiation therapy alone.

"The invention is also directed to a method of determining a prognosis of a patient comprising: assessing the concentration (or relative concentration) of one or more protein biomarkers selected from the group consisting of pAKT, pmTOR, and pMAPK in a tissue specimen obtained from the patient in which high levels of nuclear pAKT, nuclear pMAPK, and/or low levels of nuclear pmTOR indicate a relatively poor prognosis for the patient when treated with radiation therapy in combination with gefitinib.

"In a particular embodiment of the invention a method is described for determining a prognosis of a patient by assessing the relative concentration of one or more biomarkers in a tissue sample comprising: (a) incubating the tissue sample with a first stain that specifically labels a first marker defined subcellular compartment, a second stain that specifically labels a second marker defined subcellular compartment, and a third stain that specifically labels a biomarker; (b) obtaining a high resolution image of each of the first, the second and the third stain in the tissue sample; assigning a pixel of the image to a first compartment based on the first stain intensity, a second compartment based on the second stain intensity, or to neither a first nor second compartment; (d) measuring the intensity of the third stain in each of the pixels assigned to either the first or the second compartment or both; (e) determining a staining score indicative of the concentration of the biomarker in the first or the second compartment or both; and (f) plotting the biomarker concentration in relationship to a second biomarker concentration thereby providing a determination of the patient's prognosis. Typically, the tissue sample is obtained from a patient suffering from brain cancer, most likely, glioblastoma multiforme. Also the one or more biomarkers may be selected from the group consisting of pAKT, PTEN, EGFRvIII, EGFR, IGF-1R, pmTOR, pMAPK, survivin, or NFkB. One of the subcellular compartments may be cytoplasm, for which GFAP can be used as a stain that specifically labels this subcellular compartment.

"The invention also provides a kit comprising: (a) a first stain specific for pAKT, PTEN, EGFRvIII, EGFR, IGF-1R, pmTOR, pMAPK, survivin, and/or NFkB; (b) a second stain specific for a first subcellular compartment of a cell; and instructions for using the kit. The second stain is preferably GFAP.

"Another aspect of the invention relates to a method of identifying a patient suitable for treatment with gefitinib in combination with radiation therapy, comprising: assessing the relative concentration of one or more biomarkers in a tissue specimen obtained from the patient wherein high levels of one or more biomarkers indicates the patient is likely to benefit from treatment. The term 'relative concentration' means that the protein biomarker expression levels of a particular patient are compared with a plurality of patients. The overall results can be separated in most cases to relatively 'high' expression levels, relatively 'low' expression levels, and 'intermediate' levels. Individual patients can then be assigned to one group or one of the other groups. Preferably, the one or more biomarkers, whose expression levels are assessed, are chosen from the group consisting of pAKT, PTEN, EGFRvIII, EGFR, IGF-1R, pmTOR, pMAPK, survivin, and/or NFkB.

"It is also an objective of the invention to provide a method of determining a prognosis of a patient comprising: assessing the concentration (or the relative concentration) of one or more protein biomarkers selected from the group consisting of pAKT, PTEN, EGFRvIII, EGFR, IGF-1R, pmTOR, pMAPK, survivin, and/or NFkB in a tissue specimen obtained from the patient in which an intermediate level of expression of IGF-1R or NFkB or a high cytoplasmic to nuclear ratio of pAKT indicate a relatively poor prognosis for the patient when treated with radiation therapy alone.

"It is a further objective of the invention to provide a method of determining a prognosis of a patient comprising: assessing the concentration (or the relative concentration) of one or more protein biomarkers selected from the group consisting of pAKT, PTEN, EGFRvIII, EGFR, IGF-1R, pmTOR, pMAPK, survivin, and/or NFkB in a tissue specimen obtained from the patient in which a high nuclear pMAPK or intermediate cytopslasm to nuclear PTEN ratio indicate a relatively good prognosis for the patient when treated with radiation therapy alone.

"Yet another objective of the invention is to provide a method of determining a prognosis of a patient comprising: assessing the concentration (or the relative concentration) of one or more protein biomarkers selected from the group consisting of Src, pAKT, PTEN, EGFRvIII, EGFR, IGF-1R, pmTOR, pMAPK, survivin, and/or NFkB in a tissue specimen obtained from the patient in which an intermediate level of EGFR, high level of NFkB and/or intermediate to high Src level indicate a relatively poor prognosis for the patient when treated with radiation therapy combined with gefitinib.

"Yet another objective of the invention is to provide a method of determining a prognosis of a patient comprising: assessing the concentration (or the relative concentration) of one or more protein biomarkers selected from the group consisting of Src, pAKT, PTEN, EGFRvIII, EGFR, IGF-1R, pmTOR, pMAPK, survivin, and/or NFkB in a tissue specimen obtained from the patient in which relatively high or low EGFR levels, low Src levels and/or low to intermediate NFkB indicate a relatively good prognosis for the patient when treated with radiation therapy combined with gefitinib.

"Still another objective of the invention is to provide a method of determining a prognosis of a patient comprising: assessing the concentration (or the relative concentration) of one or more protein biomarkers selected from the group consisting of Src, pAKT, PTEN, EGFRvIII, EGFR, IGF-1R, pmTOR, pMAPK, survivin, and/or NFkB in a tissue specimen obtained from the patient in which expression or AQUA.RTM. score of each biomarker on a continuous scale is put into a Cox regression model for continuous variables resulting in a calculation of overall patient risk.

"Another objective of the invention is to provide a method of determining a prognosis of a patient comprising: assessing the concentration (or the relative concentration) of one or more protein biomarkers selected from the group consisting of Src, pAKT, PTEN, EGFRvIII, EGFR, IGF-1R, pmTOR, pMAPK, survivin, and/or NFkB in a tissue specimen obtained from the patient in which expression or AQUA.RTM. score of each biomarker is first categorized based on optimal univariate cutpoints, then applied to a Cox regression model for categorical variables resulting in a calculation of overall patient risk.

"Still another objective of the invention is to provide a method of determining prognosis or relative survival risk of a patient treated with radiation therapy combined with gefitinib comprising assessing the concentration, or the relative concentration of EGFR, NFkB and SRC in a tissue specimen obtained from the patient, wherein positive expression of all biomarkers is indicative of a high survival risk; no expression of all biomarkers is indicative of low survival risk; and positive expression of any two biomarkers is indicative of moderate survival risk

BRIEF DESCRIPTION OF THE FIGURES

"FIG. 1 is a summary of detection reagents used for determining biomarker AQUA.RTM. scores.

"FIG. 2 is a Kaplan-Meier analysis of survival based on PTEN scores from Array 8.

"FIG. 3 is a summary table of survival analysis based on PTEN analysis of Array 8.

"FIG. 4 is a Kaplan-Meier analysis of survival based on EGFRvIII scores from Array 8.

"FIG. 5 is a summary table of survival analysis based on EGFRvIII analysis of Array 8.

"FIG. 6 is a Kaplan-Meier analysis of survival based on total EGFR scores from Array 8.

"FIG. 7 is a summary table of survival analysis based on EGFR analysis of Array 8.

"FIG. 8 is a Kaplan-Meier analysis of survival based on survivin scores from Array 8.

"FIG. 9 is a Kaplan-Meier analysis of survival based on IGF-1R scores from Array 8.

"FIG. 10 is a Kaplan-Meier analysis of progression free survival based on pMAPK scores from Array 19.

"FIG. 11 is a Kaplan-Meier analysis of overall survival based on pMAPK scores from Array 19.

"FIG. 12 is a Kaplan-Meier analysis of survival based on pAKT scores from Array 19.

"FIG. 13 is a multivariate model combining PTEN and AKT scores from Array 19.

"FIG. 14 is a multivariate risk model for overall survival based on biomarker scores from Array 8.

"FIG. 15 is a multivariate progression free survival risk model based on biomarker scores from Array 8.

"FIG. 16 is a multivariate risk model for overall survival based on biomarker scores from Array 19.

"FIG. 17 is a multivariate risk model for progression free survival based on biomarker scores from Array 19.

"FIG. 18 is a Kaplan-Meier analysis of survival based on Src scores from Array 19.

"FIG. 19 is a multivariate risk model for overall survival based on biomarker scores from Array 19."

For more information, see this patent application: CHAKRAVARTI, Arnab; Pinard, Robert; Waldron, Donald; Ang, Agnes; Dolled-Filhart, Marisa P.; Molinaro, Annette. Correlation of Molecular Markers with Clinical Outcome in Gbm Patients Radiation Treated with Or without Gefitinib. Filed October 14, 2013 and posted May 29, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1823&p=37&f=G&l=50&d=PG01&S1=20140522.PD.&OS=PD/20140522&RS=PD/20140522

Keywords for this news article include: Cancer, Genetics, Glioblastoma, Legal Issues, Radiation Therapy Oncology Group of the Americal College of Radiology.

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