New MEMS Device for Cancer Diagnosis
Next phase of research seeks to validate prostate cancer applications for CTC analysis similar to those already shown for lung cancer

Friday, October 10 -- A novel microfluidic MEMS device, developed by Drs. Daniel Haber and Mehmet Toner of Harvard/Massachusetts General Hospital Cancer Center, enables a simple blood test to detect and characterize the circulating tumor cells (CTCs) responsible for metastasis, the process through which an initial cancerous tumor forms remote, and ultimately lethal, secondary tumors. Although it is not yet approved for clinical use, the inventors believe the device will eventually play a key role in numerous aspects of cancer diagnosis and treatment, including detecting and evaluating metastatic disease, selecting and individualizing initial surgical and medical therapies, monitoring disease progression, detecting the occurrence of therapy-induced mutations and the consequent development of resistance, and understanding the fundamental biology of metastasis.

CTCs are present at very low levels in the bloodstream, as low as one in a billion cells. Current detection methods successfully detect CTC's in only half of samples known to contain them. Typically, they capture only one CTC per ml of blood and CTCs constitute only 0.1% of all captured cells. The presence of so many non-CTC cells interferes with characterization, and the detection process usually kills the cells, preventing culture.

The new device consists of approximately 80,000 micro posts covered with antibodies against the epithelial cell adhesion molecule (EpCAM), permitting them to selectively bind CTC's. The bound cells are visualized with fluorescent staining and optical microscopy. Similar technology has been employed for cell enrichment in other contexts, such as the isolation of fetal cells circulating in maternal blood. The novelty of the CTC chip lies in its application of a BioMEMs cell sorting platform to address unmet needs of cancer clinicians and scientists.

The device has been used to detect CTCs from prostate, lung, breast and gastrointestinal cancers. Staining techniques for specific molecules, such as prostate specific antigen (PSA), provide reliable confirmation of the source of the CTC. In a recent study looking at lung cancer CTCs, it successfully detected CTCs in 92% of samples known to contain them, capturing 50 to 100 cells per ml of blood with 50% purity. Significantly, captured cells remain viable.

The lung cancer results also demonstrated several useful applications of CTC characterization in cancer diagnosis and treatment. It provides a minimally invasive technique for early detection of tumors and metastasis. Analysis of CTCs can indicate the type of cancer, its aggressiveness, and its susceptibility to particular treatments. Although the absolute number of CTCs did not correlate to tumor size, variations in CTC levels over the course of treatment do correlate with radiographic evaluations of progression and remission, providing an important and responsive means of monitoring the efficacy of standard or experimental regimens. Equally important, genetic analysis of CTCs was able to detect the occurrence of mutations that are the result of and reduce the effectiveness of certain therapies, allowing clinicians to respond to changes as they occur.

The Prostate Cancer Foundation (PCF), the world's largest philanthropic source of support for advanced prostate cancer research, is funding the next phase of research being conducted with the MEMS device developed by Drs. Haber and Toner. Using the device, Drs. Rick Lee and Matthew Smith at the Massachusetts General Hospital Cancer Center are directing clinical trials to analyze CTCs in prostate cancer patients.

The research seeks to validate prostate cancer applications for CTC analysis similar to those already shown for lung cancer. The clinical trials include correlating CTCs with borderline or rising PSA levels, pathological and histological analysis, and the likelihood of post-operative recurrence; rapidly measuring therapeutic responses; detecting the development of resistance and genetic changes, such as translocation and androgen receptor mutation; and understanding the disease process to identify diagnostic markers and novel therapeutic targets. Prostate cancer is the most common non-skin cancer in America. One in six men will be diagnosed with it.

"The discovery of biomarkers that predict disease progression or provide a signal for effectiveness of experimental medications for prostate cancer is a priority for the foundation," comments Howard Soule, Ph.D., chief science officer for the PCF. "These markers will accelerate new medication development and signal physicians earlier when prostate cancer is progressing. Enumeration of these cells provides an early signal of disease progression and will be clinically validated.

"We have given a high priority to supporting Dr. Haber's efforts, in collaboration with oncologists, biologists and engineers, to refine a system that measures tumor cells in patient blood," adds Soule.

Existing CTC capture systems limit the ability to perform biological analysis on the cells retrieved. Cells are often not viable after isolation. Cells that are viable are often mixed with white blood cells that taint analytical findings. This project will enable scientists to isolate and characterize viable CTCs from a patient's blood samples, with a goal of gaining insight into the fundamental biology of prostate cancer.

"A second objective is more clinical," says Soule. "CTC counts have been shown in patients with breast and gastrointestinal tumors to correlate with the aggressiveness of their disease, tumor progression, and survival. The BioMEMs approach outlined by Haber and Toner may increase the sensitivity and specificity of CTC counts as compared to existing techniques. Our hope is the enhanced counting may enable the development of CTC counts in prostate cancer patients as a diagnostic tool to predict disease progression and treatment outcomes." 

Figure 1 Blood flows through an array of 80,000 micro posts, each covered with antibodies that bind to a molecule found on the surface of CTC’s. Other cells and components of the blood pass unimpeded through the array.

Figure 2 A CTC is bound to one of the micro posts.