Ratio based biomarkers and methods of use thereof

Abstract

Compositions, methods and kits are described for identifying biomolecules (e.g., proteins and nucleic acids) expressed in a biological sample that are associated with the presence, development, or progression of a disease (such as cancer), or more generally determination of the etiology or risk factors associated with a disease. Sample types analyzed by the disclosed methods include but are not limited to archival tissue blocks that have been preserved in a fixative, tissue biopsy samples, tissue microarrays, and so forth. The methods disclosed herein correlate expression profiles of biomolecules with various disease types, and allow for the determination of relative survival rates; in some embodiments, the methods permit determination of survival rates for a subject with cancer. In other embodiments, the disclosure relates to methods for evaluating therapeutic regimes for the treatment, such as treatment of cancer.

Description

REFERENCE TO RELATED APPLICATION(S)[0001]This application claims the benefit of U.S. provisional application No. 61 / 144,501, filed Jan. 14, 2009, the entire content of which is incorporated herein in its entirety.FIELD OF THE DISCLOSURE[0002]This disclosure relates to identification of ratio-based biomarkers for the detection, progression and prognosis of disease, such as cancer, in a subject. Also provided are similar methods for determination of the etiology or risk associated with a disease or condition. This disclosure also relates to methods of predicting survival probabilities and prognosis for a subject, and to methods of stratifying patient therapeutic regimes.BACKGROUND[0003]Tumors are characterized by their extensive heterogeneity and histopathologic variability. Currently, more than 250 malignant tumors and thousands of subtypes and histologic variants have been described in humans. Nevertheless, the classic pathologic criteria, such as tumor size, grade of malignancy, an...

AI Technical Summary

Benefits of technology

[0015]In a further embodiment, the disclosure provides a method of determining relative cancer survival rates (or more generally prognosis) for a subject with a solid tumor by obtaining a biomarker indicator, the biomarker indicator being obtained by acquiring a solid tumor sample from the subject, extracting a first cancer associated protein from the solid tumor to produce a fraction comprising the first cancer associated protein, calculating the content of the first cancer associated protein in the fraction, normalizing the first cancer associated protein content against total cellular content in the fraction, extracting a second cancer associated protein from the solid tumor sample, calculating the content of the second cancer associated protein in the fraction, normalizing the second cancer associated protein content against total cellular protein content in the fraction, and correlating the normalized first cancer associated protein content against the normalized second cancer associated protein content to obtain a biomarker indicator, and comparing the biomarker indicator with relative survival rates, thereby determining the relative cancer survival rate for the subject with the solid tumor.

[0016]The present disclosure is further directed to methods for predicting relative cancer survival rates for a subject with a solid tumor by detecting the presence of an antibody to a tumor antigen in the solid tumor, wherein the tumor antigen involves increased expression of p-AKT and p-mTOR or decreased expression of PTEN as compared to a normal non-cancerous sample, thereby detecting the cancer in the subject, and correlating decreased expression of the tumor antigen in the subject as compared to a normal non-cancerous sample with a lower survival rate in the subject with the solid tumor. In another embodiment, the calculated tumor antigen involves increased HER2 relative to and / or along with decreased HER3 expression. Thus, the absolute value of the level of individual tumor (or other disease / condition) antigen is not necessarily determinative—rather, it is the relative amount compared to one or more other antigens that provides the predictive biomarker described herein.

Problems solved by technology

In addition to the variability of histopathologic subtypes, molecular study of tumors is even more complex.

However in practice, rates of success for the treatment of tumors or responsiveness of tumors after administration with such non-cytotoxic agents have been erratic.

Currently, there is no simple answer to the question of which cellular proteins or signaling pathways are responsible for making a cell cancerous.

While LCM does provide the capacity to perform a directed western blot on a tissue section, the methodology is time consuming and does not provide a global expression view of a targeted protein.

Immunohistochemistry while providing excellent localization, lacks quantification without sophisticated equipment such as high resolution tandem mass spectrometry, and lacks a normalization component.

Other “grind and bind” techniques for protein expression profiling provide quantification, but fail to provide a histo-morphological perspective of protein expression.

Although these techniques are generally superior in expression profiling and quantification of protein changes associated with disease states, each has significant limitations.

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