Rationale and Objective for the Proposed Work
Cholangiocarcinoma (CCA) is an aggressive cancer that arises from the cells that line the bile duct. It is a rare cancer impacting 1.20 persons/100,000/year in the United States. It is very difficult to diagnose and treat, because CCA generally does not cause symptoms in the early stages. As a result, approximately 70% of patients present with advanced CCA, when surgical treatment is unlikely to increase survival or improve quality-of-life. CCA is also resistant to current chemotherapies meaning that these drugs offer limited help for CCA patients. The molecular aberrations that drive CCA and could be the targets of new diagnostic approaches and effective drug treatments are also poorly understood. These factors contribute to only about 10% of CCA patients surviving longer than 5 years.
To address these issues, this study will examine the cellular receptor CDCP1 as a key molecular contributor to CCA that could serve as a target for early detection and improved treatment of this aggressive cancer. Thus, the Fiscal Year 2021 Rare Cancers Research Program Focus Area(s) the project addresses are “Biology and Etiology” and Therapy.
Evidence supporting that CDCP1 is important in CCA and is a strong target for detection and treatment of CCA can be found in our unpublished experiments. These experiments show that CDCP1 is a molecular driver of CCA by strongly promoting growth of CCA tumors in mice. CDCP1 likely promotes CCA by activating another protein called EGFR that is already known to be a key driver of CCA. As well as contributing to the growth of CCA, our results indicate that CDCP1 could be a biomarker for detection of CCA as well as a target for drugs to treat CCA. We have tested this possibility by developing drugs, called antibody-drug conjugates, that bind very strongly and specifically to CDCP1. When injected into the blood of mice, the antibody-drug-conjugates are very effective at treating CCA tumors, blocking tumor growth while also markedly increasing the survival of the mice. An important property of antibody-drug conjugates is that they have limited contact with the patient’s normal organs, meaning that they generally have many fewer toxic effects compared to chemotherapies. We have already engineered the antibodies that are the key components of antibody-drug conjugates to be ready for testing in humans.
The Ultimate Applicability of the Research
This study will generate critical new knowledge and advancements about the role of the receptor CDCP1 in CCA that will underpin future research that could lead to earlier diagnosis and/or effective treatments for CCA. A central task that is being pursued is evaluation of the effectiveness of CDCP1-directed antibody-drug conjugates to treat preclinical models of CCA. Another task is to test radioactive tracers, developed by us, that are linked to antibodies directed to CDCP1, for their ability to be used in molecular imaging (PET-CT) scans to detect tumors in mouse models of CCA.
Because we have already developed human-ready antibodies against CDCP1, we are well placed in the short- term to move our research from the laboratory into clinical trials. Our radioactive engineered CDCP1-directed antibodies will be able to be tested in clinical trials for their ability in PET-CT scans to detect CCA in patients. Earlier diagnosis of CCA will mean earlier treatment offering significant potential to allow many more CCA patients the opportunity to undergo potentially curative treatments. This would be a major advancement, because currently, about 70% of CCAs are too advanced for treatments to offer significant benefits to patients. These patients currently receive palliative treatments.
In addition, our antibody-drug conjugates are available to be tested in clinical trials for their safety in patients and their efficacy in treating CCA. A major finding from our laboratory experiments is that our CDCP1-directed antibody-drug conjugates are much more effective at impeding tumor growth in mice than the chemotherapy gemcitabine, which is currently used to treat CCA. In fact, we saw the best effects against CCA by combining gemcitabine with our CDCP1-targeted antibody-drug conjugates. Similar to potential applications for early CDCP1-directed detection of CCA by PET-CT scans, the availability of our human-ready antibodies means that in the short-term, CDCP1-directed antibody-drug conjugates could be trialled against CCA, including when used in combination with gemcitabine, offering significant opportunity to markedly improve survival of CCA patients above the current abysmal 5-year rate of about 10%. | 
