The coming generation of personalized anti-cancer treatments will increasingly require companion diagnostic tests to ascertain the presence of specific genetic mutations for which drug targets are available. Cancer tissue or disseminated cancer cells in the circulation or other bodily fluids will be required to carry out these assays. Tissue directly from the tumor is ideal because it is highly pure and can yield sensitive mutational analyses, but this is not available in certain cases as the primary tumor may have already been resected, micrometastases are too small to biopsy, or tumor is present near sensitive anatomical sites thus preventing safe surgical access. In such cases, disseminated tumor cells present in the blood can be highly useful as this is an easily accessible source. A major problem with using cells from blood in companion diagnostics is the presence of a large background of white blood cells within unprocessed samples;these cells prevent the counting and overpower the molecular signal from rare cancer cells and must therefore be removed for accurate diagnosis. We are developing the """"""""Centrifuge on a Chip"""""""" technology to address this challenge and enrich rare circulating cancer cells from blood samples to high purity. This device innovatively utilizes inertial fluid physics at high fluid flow rates to generate microscale vortics which size-selectively and passively isolate larger cells and releases them into a small volume of fluid off chip. We have conducted a pilot study with this device in which we have isolated putative tumor cells from patients with advanced malignancies of the prostate and bladder and these cells can be processed for downstream molecular assays. This technology is easy to use and an order of magnitude faster than current microfluidic cell separation technologies.
We aim to validate the Centrifuge Chip technology to enumerate circulating tumor cells as a function of cancer stage and to evaluate whether cells purified with this approach yield higher quality genetic and mutational analyses. Ultimately, such a device may provide a cost-effective and rapid 'liquid biopsy'sample which can be utilized for downstream genetic analyses in order to more effectively personalize anti-cancer therapy.

Public Health Relevance

Determining if a patient's cancer will respond to next generation targeted anti-cancer drugs requires access to tumor sample for genetic testing. In many cases this may not be possible because the primary tumor has been removed and recurrence is in a difficult to access site, or direct biopsy would be too risky. The Centrifuge o a Chip microtechnology that we are developing will allow for concentration and enrichment of rare tumor cells which are present within the patient's bloodstream which can provide genetic information that will more appropriately direct anti-cancer treatment and thus potentially improve overall outcome and survival.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants Phase II (R33)
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Special Emphasis Panel (ZCA1-SRLB-Q (M1))
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Ossandon, Miguel
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University of California Los Angeles
Biomedical Engineering
Schools of Engineering
Los Angeles
United States
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Dhar, Manjima; Lam, Jeffrey Nam; Walser, Tonya et al. (2018) Functional profiling of circulating tumor cells with an integrated vortex capture and single-cell protease activity assay. Proc Natl Acad Sci U S A 115:9986-9991
Dhar, Manjima; Wong, Jessica; Che, James et al. (2018) Evaluation of PD-L1 expression on vortex-isolated circulating tumor cells in metastatic lung cancer. Sci Rep 8:2592
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Dhar, Manjima; Pao, Edward; Renier, Corinne et al. (2016) Label-free enumeration, collection and downstream cytological and cytogenetic analysis of circulating tumor cells. Sci Rep 6:35474
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