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TIM-3 as a Biomarker of Ovarian Cancer

T cell immunoglobulin and mucin protein 3 (TIM-3) is a type I cell surface protein that was originally identified as a marker for murine T helper type 1 cells. TIM-3 was found to negatively regulate murine T cell responses and galectin-9 was described as a binding partner that mediates T cell inhibitory effects of TIM-3. A study has shown that expression of TIM-3 is significantly increased in both CD4+ and CD8+ T cells in ovarian cancer patients than in controls (Wu et al. 2013). Patients who had recurrent ovarian cancer had a higher proportion of TIM-3+CD4+ T cells than when they were newly diagnosed. Patients with a higher tumor grade demonstrated further augmented TIM-3 expression in CD4+ and CD8+ T cells compared to those with lower tumor grades. These findings suggest that TIM-3 may participate in the development and progression of ovarian cancer by its negative regulation on various T cell subsets, and TIM-3 expression in CD4+ T cells could serve as a predictive biomarker for anticancer therapies.

Since no single biomarker is adequate for detection of ovarian cancer, attempts have been made to use multiplex assays. Univariate and multivariate statistical analyses applied to protein-profiling data obtained from serum samples of patients with ovarian cancer using protein biochips has led to the discovery of biomarker protein panels, which can distinguish serum samples from healthy controls and patients with either benign or malignant ovarian neoplasia. Two tumor biomarkers, CA125 and HE4 (approved by FDA), are used to track whether chemotherapy is working or ovarian cancer is recurring. A one-time CA125 test can not screen seemingly healthy women because levels rise with benign cysts, endometriosis, even normal menstruation, but Fujirebio’s triage test uses HE4 and CA125 to assess who most likely has a benign cyst and whose has cancer.

OvaSure (LabCorp) measures concentrations of leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA-125 by using a multiplex, bead-based, immunoassay system. OvaSure is a screening test for women at high risk of ovarian cancer that was developed by Yale University under a law that allows a single laboratory to offer testing without FDA review. Used on blood samples stored from cancer patients and healthy women, the test correctly identified cancer a sensitivity of 95.3% and a specificity of 99.4% (Visintin et al. 2008). However, this does not prove that OvaSure can detect when cancer is forming. Yale is working to validate OvaSure.

MS pattern analysis is a potentially rewarding approach in that it is based on power of combined multiple biomarkers so that discrimination accuracy is higher. Having reliable, discriminatory patterns obviates the need to identify and purify the biomarkers of interest and develop molecular assays for them. This process can be quite tedious, especially if the biomarkers are in low concentration. Furthermore, MS pattern assays take advantage of the high resolving power and small sample volume requirement of mass spectrometry. MS pattern analysis requires laboratories to develop new ways to continually affirm platform and sample integrity in the absence of biology-based means. Essay variability could arise from potential heterogeneity of molecules within a spot, which is why SELDI-TOF employs multiple desorptions from different positions within a spot.

Various studies have shown that a 3-biomarker panel could classify stage I/II ovarian cancer samples healthy control samples with 97% specificity and 74% sensitivity, compared to 97% specificity and 54% sensitivity when CA-125 alone was used to classify. Even though it is considerably better than use of CA-125, it does not meet the requirements for a screening test. The 3-biomarker panel would have greater value if used in conjunction with another complementary test. OvPlex™ (HealthLinx, Australia) first generation ovarian cancer 3-biomarker panel was launched in Australia with diagnostic efficiency of 92.9%. In the second generation product two new novel biomarkers were been added (HTX005 and HTX010). A phase II biomarker trial on the second generation 5-biomarker panel OvPlex™ increased the diagnostic efficiency of the panel to 98% for early stage diagnosis as compared with CA125 with diagnostic efficiency of <60% for early stage detection.

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