SBIR-STTR Award

The overall goal of this proposal is to develop a novel early detection diagnostic for hepatocellular carcinoma based on the detection of glycoproteins that have increased levels of fucosylation in the sera of patients. With our colleagues at Drexel University, we have shown that there is an increase in the level of core fucosylation associated with the development of liver cancer. The observation that changes in glycosylation patterns occur with cancer has been reported earlier by others as well, however, currently, no novel fucosylated glycoprotein is being developed as diagnostics. In our earlier studies, we identified a number of glycoproteins with elevated levels of fucosylation and validated 3 such proteins for further diagnostics development. The objectives of this phase I is to develop a Lectin-ELISA assay and validate the assay with a small cohort of patients diagnosed with HCC. In phase II, the specificity and sensitivity of the assay will be evaluated using a large serial and cross sectional patient population and compared with the existing diagnostic assay for HCC to generate clinical data needed for an approval of a new in vitro diagnostic test for HCC. Accomplishments of these aims will permit the introduction of a highly sensitive and specific diagnostic tool for the early detection of HCC. Given the need for early diagnosis for HCC to facilitate early intervention that can lead to a cure, the introduction of a new non-invasive, high through put and highly sensitive and specific diagnostic based on hyperfucosylated serum markers as described here is extremely important. Hepatocellular carcinoma (HCC) is one of the most common solid malignancies worldwide and the incidence in the United States is increasing. Approximately two-thirds of all liver cancers are HCC, one of the most common aggressive malignancies. The number of cases of HCC will continue to increase primarily due to the hepatitis C (HCV) epidemic. Despite advances in medical technology, the 5-year survival between 1981 and 1998 improved only 3%, likely due to the fact that the majority of patients with HCC are diagnosed at advanced stages leading to an overall 1-year survival of 25% in the United States. In this setting of a significant increase in the number of patients with HCC, early detection and treatment are vital to improve outcome.

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Our over-all goal has been to develop a diagnostic test for the early detection of liver cancer (hepatocellular carcinoma (HCC)) that is more specific and sensitive than existing, approved diagnostic tests and procedures. Using glycoproteomic discovery methods, we identified several glycoproteins whose serum amounts and degree of fucosylation appear to correlate with a diagnosis of HCC. In Phase I, as planned, we conducted extensive evaluations of three of the most promising detection markers which were selected based on their out-performance of AFP, the standard of care, in their ability to detect early-stage HCC. In addition, as planned, we have succeeded in developing a high throughput- compatible, lectin-ELISA for the highly promising marker Fuccosylated (Fc)-Kininogen. In phase I, we developed and validated a lectin-ELISA for Fc-Kininogen and generated preliminary, pre-validation data that demonstrate that this is a highly sensitive and selective marker for early-stage HCC. In pre-validation studies, our Fc-Kininogen lectin-ELISA assay had a sensitivity of 93%, a specificity of 90%, a positive predictive value (PPV) of 93% and a negative predictive value (NPV) of 90%, far exceeding the performance of the standard AFP assay. These results satisfied the criteria for our "Go" decision to proceed to Phase II. In phase II, larger scale validation studies will be performed using a large serial and cross sectional patient population, and data generated with the Fc-Kininogen assay will be compared with the existing AFP diagnostic assay to generate the clinical data needed for pre-market approval of a new in vitro diagnostic test for HCC. We intend to work with a commercial partner that can manufacture, market and distribute the commercial assay for us and have already initiated commercialization discussions with a major U.S. diagnostics company. Accomplishing these aims will permit the introduction of a highly sensitive and specific diagnostic tool for the early detection of HCC. Given the need for early diagnosis for HCC to facilitate early and efficacious intervention, the introduction of a new non-invasive, high throughput, highly sensitive and specific diagnostic based serum assay is extremely important.HCC Diagnostics defined by fucosylated serum biomarkers. Diagnosis and intervention at an early stage is critical to reducing the number of liver cancer-related deaths. We have discovered novel biomarkers and completed the assay development work in our phase I application. In this phase II, we propose to develop and validate a noninvasive, highly sensitive and selective early diagnostic test for liver cancer that can potentially be applicable to HBV or HCV positive and negative patients. Our ultimate goal is to develop an early detection diagnostics that can be used as a routine clinical screen in patients with high risk for developing liver cancer.

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