The mathematical model developed here can be applied to virtually any solid cancer and associated biomarkers shed to help identify better candidate biomarkers and other strategies for early cancer detection.
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Detecting Cancers Through Tumor-Activatable Minicircles that Lead to a Detectable Blood Biomarker
New work from the Gambhir Lab published in PNAS uses a unique strategy to force tumor cells (if they exist) to produce a blood biomarker that would otherwise not be present.
This approach holds significant promise as a new way to tackle the early detection of cancer because it is not dependent on molecules that cancer cells naturally shed that enter the blood.
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Circulating Tumor Cells for Lung Cancer Early Detection
Lung cancer kills more people than any other cancer in this country. Although imaging and surgery are the mainstay for identifying and treating early cancers for the most common type, non-small cell lung cancer (NSCLC), recurs in 30 to 40 percent of these patients despite treatment.
Therefore, more effective tools are required to improve survival early in a lung cancer’s history. Blood biomarkers are one potential and promising approach, particularly Circulating Tumor Cells (CTCs), which detect micrometastatic disease in peripheral blood. We know that CTCs are abundant in late-stage cancers of diverse forms, and we know now that they are abundant in its early stages as well using next-generation molecular technologies based on morphologic characterization, nanofluidics, magnetic sifting, and filtration. Over the past three years, Dr. Carlssson A. Nair, with support from the Canary Foundation, has worked with a team of leading investigators to demonstrate that CTCs are a novel diagnostic tool for detecting early-stage disease using a next-generation CTC platform. He continues to carry forward those initial observations of CTCs into an ongoing and maturing observational cohort of lung cancer patients to explore the role of CTCs for surveillance and prognosis of early lung cancers over time.
Circulating tumor microemboli diagnostics for patients with non-small-cell lung cancer. Carlsson A, Nair VS, Luttgen MS, Keu KV, Horng G, Vasanawala M, Kolatkar A, Jamali M, Iagaru AH, Kuschner W, Loo BW Jr, Shrager JB, Bethel K, Hoh CK, Bazhenova L, Nieva J, Kuhn P, Gambhir SS. J Thorac Oncol. 2014 Aug;9(8):1111-9. doi: 10.1097/JTO.0000000000000235. PMID: 25157764
An observational study of circulating tumor cells and (18)F-FDG PET uptake in patients with treatment-naive non-small cell lung cancer.
Nair VS, Keu KV, Luttgen MS, Kolatkar A, Vasanawala M, Kuschner W, Bethel K, Iagaru AH, Hoh C, Shrager JB, Loo BW Jr, Bazhenova L, Nieva J, Gambhir SS, Kuhn P. PLoS One. 2013 Jul 5;8(7):e67733. doi: 10.1371/journal.pone.0067733. Print 2013. PMID: 23861795
Early Detection of Pancreatic Cancer
Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer-related death, with an average five- year survival rate of six percent.
Since less than 20 percent of patients can undergo potentially curative surgery and current therapies are not efficient, our only hope to improve survival from this disease is earlier detection.
The Translational Molecular Imaging Lab (TMIL) has shown substantial progress in developing a novel imaging approach, ultrasound molecular imaging, using contrast agents specifically designed to attach to early pancreatic cancer. We have employed two different approaches. First, we utilized the expression of the angiogenesis receptor VEGFR2 within the tumor vasculature as a molecular target for imaging pancreatic cancer with a novel clinical grade contrast microbubble. We showed that small developing tumors in the 2-7 mm size range expressed high VEGFR2 levels to allow detection with a high signal to noise ratio (1). Second, in collaboration with the University of Washington, we identified a new vascular marker of pancreatic cancer, Thy1\CD90 that is differentially expressed in pancreatic cancer but not in benign pancreatic tissue or patients with chronic pancreatitis. We developed a pre-clinical microbubble specific for this protein and were able to identify small foci of pancreatic cancers with this molecular imaging technique (2). We are currently creating a clinical-grade version of this targeted microbubble for detecting small pancreatic cancers in patients.
(1) Pysz, M. A., S. B. Machtaler, E. S. Seeley, J. J. Lee, T. A. Brentnall, J. Rosenberg, F. Tranquart and J. K. Willmann (2015). Vascular Endothelial Growth Factor Receptor Type 2–targeted Contrast-enhanced US of Pancreatic Cancer Neovasculature in a Genetically Engineered Mouse Model: Potential for Earlier Detection. Radiology 2015; 274(3): 790-799.
(2) Foygel, K*., H. Wang*, S. Machtaler*, A. M. Lutz, R. Chen, M. Pysz, A. W. Lowe, L. Tian, T. Carrigan, T. A. Brentnall and J. K. Willmann. Detection of pancreatic ductal adenocarcinoma in mice by ultrasound imaging of thymocyte differentiation antigen 1. Gastroenterology 2013; 145(4): 885-894 e883.
Early Detection of Pancreatic Cancer
Ultrasound molecular imaging is a highly sensitive imaging modality that plays a major role in the field of cancer imaging by contributing to earlier detection and characterization of focal lesions (1).
Using the first clinical-grade, molecularly targeted ultrasound contrast agent (BR55), targeted against human VEGFR2, has enabled us to assess tumor progression and differentiating normal from cancer tissue with high diagnostic accuracy in transgenic mouse models of breast cancer (FVB/N-Tg (MMTV-PyMT) 634Mul) that resemble tumor progression in patients (2). In this mouse model in vivo imaging signal significantly increased as the mammary gland tissue progressed from normal to hyperplasia, ductal carcinoma in situ (precursor lesions) and invasive breast cancer due to an increase in the number of tumor vessels and the magnitude of VEGFR2 expression levels per tumor vessel.
Recently, we detected and validated a novel breast cancer associated molecular marker, B7-H3 (CD276, a member of B7 family of immunomodulators) to be differentially expressed in breast cancer compared to benign lesions and normal breast tissue in a large scale IHC analysis of patient breast tissues (2). We also designed a new contrast agent targeted at B7-H3 and tested it in a breast cancer and ovarian cancer mouse model (3).
(1) Bachawal SV, Jensen KC, Lutz AM, Gambhir SS, Tranquart F, Tian L, et al. Earlier detection of breast cancer with ultrasound molecular imaging in a transgenic mouse model. Cancer Res 2013;73:1689-98.
(2) Bachawal SV, Jensen KC, Wison K, Tian L, Lutz AM, Willmann JK. Breast cancer detection by B7-H3 targeted ultrasound molecular imaging. Cancer Research 2015 (in press)
(3) Lutz AM, Bachawal SV, Drescher CW, Pysz MA, Willmann JK, Gambhir SS. Ultrasound molecular imaging in a human CD276 expression-modulated murine ovarian cancer model. Clin Cancer Res 2014;20:1313-22.