Search

EP-3444359-B1 - METHODS OF IDENTIFICATION OF NON-SMALL CELL LUNG CANCER

EP3444359B1EP 3444359 B1EP3444359 B1EP 3444359B1EP-3444359-B1

Inventors

  • IZBICKA, ELZBIETA
  • BAEK, SUNG H.
  • STREEPER, ROBERT T.

Dates

Publication Date
20260513
Application Date
20100312

Claims (10)

  1. An ex vivo method of physiological characterization in a subject comprising determining the extent of expression of all of the following three biomarkers MPO, MMP-9, and MMP-7, and, optionally, one or more of the biomarkers selected from the group consisting of HGF, SAA, Resistin, IL-5, IL12 (p70), IL-8, IL-4, IL-7, MIF, sCD40 ligand, sICAM-1, IL-13, 1-TAC, MMP-1, Eotaxin, IP-10, sVCAM-1, Adiponectin, CRP, C-Peptide, MMP-3, SAP, IL-1ra, IL-15, EGF, MMP-8, IL-6, MMP-12, PAI-1, Amylin (Total), IL-1α, sFSI, MIP-1β, SE-selectin, IL-17, GM-CSF, G-CSF, TGF-α, IFN-y, Fractalkine, VEGF, IL-12 (p40), Sfas, IL-1β, IL-2, MIP-1α, Insulin, GLP-1, TNF-α, MMP-2, MMP-13, I-TAC, or a combination thereof, in a physiological sample of the subject, wherein the extent of expression of the biomarkers is indicative of non-small cell lung cancer.
  2. The method of claim 1, wherein said method comprises determining the extent of expression of at least four of said biomarkers in a physiological sample of said subject.
  3. The method of claim 1 or claim 2, wherein said biomarker is a polypeptide.
  4. The method of any preceding claim, wherein the physiological sample is biological fluid.
  5. The method of claim 4, wherein the biological fluid is blood serum or plasma.
  6. The method of any preceding claim, wherein the subject is a mammal.
  7. The method of claim 6, wherein the mammal is a human.
  8. The method of any preceding claim, wherein the method of determining the extent of expression comprises performing a quantitative multiplex immunoassay.
  9. The method of any preceding claim, wherein said method comprises determining the extent of expression of at least five of said biomarkers in a physiological sample of said subject.
  10. The method of any preceding claim, wherein said method comprises determining the extent of expression of at least six of said biomarkers in a physiological sample of said subject.

Description

BACKGROUND OF THE INVENTION (a) Field of the Invention The invention relates to the detection, identification, assessment, prevention, diagnosis, and treatment of lung disease using biomarkers. More specifically, the invention relates to the diagnosis of non-small cell lung cancers by measuring and quantifying expression levels of specific biomarkers. The invention is at least partly based on the identification of biomarkers present in human serum or other biological fluids, which, when found to be expressed at levels different from those found in the normal population, are indicative of pathologies associated with human lung tissues and the human respiratory system. By identifying the biomarkers associated with such pathologies, quantifying the expression levels of those biomarkers, and comparing the expression levels with those levels generally expected to present in a normal person's serum, it is possible to detect the presence of the pathologies early on in their progression through simple blood tests and characterize the progression of the pathology, as well as to differentiate among the pathologies. (b) Description of the Related Art Pathologies of the respiratory system, such as asthma and lung cancer, affect millions of Americans. In fact, the American Lung Association® reports that almost 20 million Americans suffer from asthma. The American Cancer Society, Inc. estimated 229,400 new cancer cases of the respiratory system and 164,840 deaths from cancers of the respiratory system in 2007 alone. While the five year survival rate of all cancer cases when the cancer is detected while still localized is 46%, the five year survival rate of lung cancer patients is only 13%. Correspondingly, only 16% of lung cancers are discovered before the disease has spread. Lung cancers are generally categorized as two main types based on the pathology of the cancer cells. Each type is named for the types of cells that were transformed to become cancerous. Small cell lung cancers are derived from small cells in the human lung tissues, whereas non-small-cell lung cancers generally encompass all lung cancers that are not small-cell type. Non-small cell lung cancers are grouped together because the treatment is generally the same for all non-small-cell types. Together, non-small-cell lung cancers, or NSCLCs, make up about 75% of all lung cancers. A major factor in the low survival rate of lung cancer patients is the fact that lung cancer is difficult to diagnose early. Current methods of diagnosing lung cancer or identifying its existence in a human are restricted to taking X-rays, Computed Tomography (CT) scans and similar tests of the lungs to physically determine the presence or absence of a tumor. Therefore, the diagnosis of lung cancer is often made only in response to symptoms which have presented for a significant period of time, and after the disease has been present in the human long enough to produce a physically detectable mass. Lizasa et al. Clin Cancer Research 1999, 5(1), 149-53 describes elevated levels of matrix metalloproteinase-9 in non-small cell lung cancer patients.Voorzanger-Rousselot Cancer Treat Rev 2007, 33(3), 230-83 discloses various biochemical markers that can be used for predicting tumor recurrence, progression and development of metastases. US 2006/024692 A1 describes methods of diagnosing non-small cell lung cancer comprising determining the expression levels of certain genes. There does not exist in the art a simple, reliable method of diagnosing pathologies of human lung tissues early in their development. Furthermore, there is not a blood test available today which is capable of indicating the presence of a particular lung tissue pathology. It is therefore desirable to develop a method to determine the existence of lung cancers early in the disease progression. It is likewise desirable to develop methods to diagnose asthma and non-small cell lung cancer, and to differentiate them from each other and from other lung diseases such as infections, at the earliest appearance of symptoms. It is further desirable to identify specific proteins present in human blood which, when altered in terms of relative intensities of expression, are indicative of the presence of non-small cell lung cancers and/or reactive airway disease. SUMMARY OF THE INVENTION The present inventors have identified a number of biomarkers which are useful for characterizing the physiologic state of a subject with regard to lung diseases, such as non-small cell lung cancer or reactive airway disease. These biomarkers are presented in Tables 1-23. Table 1A lists biomarkers whose expression level has been found to be different from the level in normal individuals when measured in individuals with one or more lung diseases. Table IB lists biomarkers whose expression level has been found to be different from the level in normal individuals when measured in individuals with either non-small cell lung cancer or reactive airway dise