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Oct 3rd, 2012
 
CTC microfluidic chip test to solve cancer treatment issues
 
There are two common dilemmas in the treatment of cancer today: the first is that many therapies, including chemotherapies and radiation can debilitate healthy cells, to the point of killing the person before defeating the cancer.
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The second problem is that many cancer cells, responding to a prevention drug, can quickly mutate to become immune and more resilient. Recent advances in circulating tumor cell technology (CTC) however, headed by Dr. Daniel Haber, Director at Massachusetts General Hospital Cancer Center and Dr. Mehmet Toner, Director of the Center for BioMicroElectroMechanical Systems, address this mutation problem head on. Their research has also found support from The American Association of Cancer Research, the American Cancer Society and The Jeffrey Epstein VI Foundation, which supports cutting edge medical research around the world.

CTC is a simple blood test to detect circulating cancer cells. Using a microfluidic chip, the test isolates cancer cells in the blood and allows them to be purified to analyze their genetic structure. Although many challenges remain in the test, the advantages have already made a huge impact on the treatment of cancer. To date, the test has identified more than 1,200 cancer-causing genetic mutations, the largest collection in the world. The findings have led to a host of mutation specific targeted therapies including the use of reversible and irreversible inhibitors, which have been highly effective in tumor reduction. For instance, Dr. Haber's team recently found that gastric adenocarcinomas, stemming from amplification of the growth factor receptor gene c-MET, only respond to novel inhibitors of the MET tyrosine kinase, leading to the initiation of a genotype-directed clinical trial.

Critically, the CTC test also addresses the major problem of secondary and tertiary genetic mutation to treatment. For while targeted inhibitors can be highly effective in tumor shrinkage, almost all cancer cells quickly mutate to be resistant, reversing tumor reduction within six to eight months. Furthermore, resistance becomes effective from the slightest evolution. For example, approximately half of non-small cell lung cancer cases with mutations to EGFR TK inhibitors became resistant from a single mutation of T790M within the EGFR kinase domain. Indeed, the bulkier methionine residue at position T790M hinders interaction with the inhibitor, preventing binding to the EGFR kinase domain while preserving catalytic activity. An analogous mutation (T315I) in the BCR-ABL fusion kinase in chronic myelogenous leukemia cells renders them resistant to ABL kinase inhibitors, gleevec and dasatinib.

By extracting cancer cells from a CTC blood test however, a patient can be analyzed in genetic real time, meaning a continual genetic analysis to determine the first line of treatment and then a secondary or third line of treatment, as soon as any resistive mutations occur. In fact, since treatment can be tested on the patient's cells in vitro—and from a blood sample relatively quickly and accurately—as compared to a biopsy, any secondary or tertiary mutations detected in the cell culture, can be treated preemptively as part of the first line of attack, as a cocktail with the primary treatment or in immediate sequence. Unlike a blood test however, tumor biopsies can be hugely debilitating, costly, genetically outdated, not always easy to locate and can encourage metastasis of the tumor.

By using the microfluidic test, Dr. Haber's team has a growing catalog of secondary and tertiary mutations and has shown how several irreversible inhibitors produce significant, if not permanent anti-tumor activity on a variety of secondary mutations such as the EGFR receptor double mutation, L858R/T790M. Some of these irreversible inhibitors, namely HKI-272, EKB-569, BIBW2992, and PF00299804, are currently undergoing clinical testing.

Technically, the CTC microfluidic chip test works by taking only 10 milliliters of blood, containing about 80 billion cells. Magnetic beads on the chip are coated with antibodies that bind to both EpCAM positive and EpCAM negative cells (epithelial cell adhesion molecules), a common marker present on CTCs originating from epithelial cancers. The binding of antibodies, makes the CTC cells detectable and ready for extraction via purification.

The toxic effect of genetic therapies are significantly less than standard chemotherapy drugs, due to their receptor specificity, however toxicity is still a major hurdle and can cause heart disease, gastrointestinal damage and the development of other cancers."The CTC test is not only increasingly specific to the mutation driving the cancer," Jeffrey Epstein countered, whose foundation supports cutting edge medical and science research around the world,"but doses can be closely minimized to tumor reduction and secondary treatments can be given in tandem or immediately thereafter."


 
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