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November 20, 2017

A Cancer Cell’s Weight Predicts Its Therapeutic Opponent

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    Multiple myeloma [NIH]

    Scientists in the U.S. have shown how measuring changes in the weight of individual living cancer cells taken from multiple myeloma (MM) patients can accurately predict whether their cancer will respond to different drug treatments. The microfluidic device, known as a suspended microchannel resonator (SMR), is capable of weighing cells 10 to 100 times more accurately than any other existing method, making it possible to measure changes in the growth, or mass accumulation rate (MAR), of single cells over periods of just 10 to 20 minutes.

    Last year, the Massachusetts Institute of Technology (MIT) team that developed the SMR instrument demonstrated in different cancer cell models that a decrease in cancer cell MAR following drug treatment indicates that cells are sensitive to the drug, whereas their MAR doesn’t change if the cells are resistant. Working with colleagues at the Dana-Farber Cancer Institute, the team has now used the technique to predict drug sensitivity in nine MM patients who were either sensitive or resistant to a range of therapies.“When the clinical biomarkers showed that the patients should be sensitive to a drug, we also saw sensitivity by our measurement,” comments co-researcher Mark Stevens, Ph.D., a research scientist at the Dana-Farber Cancer Institute. “ …in cases where the patients were resistant, we saw that in the clinical biomarkers as well as our measurement."

    Reporting their studies in Nature Communications, the authors write, “…we demonstrate that our MAR assay, without the need for extended culture ex vivo, correctly defines the response of nine patients to standard-of-care drugs according to their clinical diagnoses.” The paper is entitled “Determining Therapeutic Susceptibility in Multiple Myeloma by Single-Cell Mass Accumulation.”

    Multiple myeloma is an incurable bone marrow cancer characterized by high rates of drug resistance and relapse, despite the development of targeted drugs, antibodies, chemotherapeutics, and stem cell transplants. For many cancers, therapeutic decision-making is based largely on identifying genetic or epigenetic markers, but  for MM, there is no way to predict, whether using genetic markers or other means, how a patient will respond to a particular drug.

    In an ideal world, in vitro functional assays would be available to directly measure how cells are going to respond to different therapeutic approaches before deciding on the best treatment for each patient. For many years, functional assays have been used in vitro studies, but there hasn’t yet been a prospective in vitro functional assay applied routinely in the clinic, the researchers note. “Historically, functional assays are limited by a variety of factors including requirements for large tissue samples, artifact-inducing long-term cell culture, and bulk measurement approaches,” they point out.

    In the infectious disases field, cell proliferation has been used effectively for years to test for antibiotic susceptibility. But its not an approach that lends itself to cancer testing, explains Scott Manalis, Ph.D., the Andrew and Erna Viterbi professor in the MIT departments of biological engineering and mechanical engineering, and a member of MIT’s Koch Institute for Integrative Cancer Research. “Unlike bacteria, analogous tests for tumor cells have been challenging, in part because the cells don't always proliferate upon removal from the patient."

    In contrast with existing cell proliferation approaches, the high-throughput method developed by the MIT researchers instead directly measures changes in the mass of individual cells in response to therapy. The latest version of the serial SMR device, which can measure 50 to 100 cells per hour, comprises multiple sensors that weigh cells as they flow through tiny channels. The device can measure 50 to100 cells per hour and weigh each cell 10 times over a 20-minute period, which is sufficient for an accurate MAR measurement. Encouragingly, the technique can be used with the relatively limited numbers of cells obtained from bone marrow biopsies, which makes it suitable for applications in MM.

    The researchers first used the device to determine MAR as a measure of the sensitivity of single cells from well-characterized MM cell lines to standard-of-care (SOC) treatments, including bortezomib, dexamethasone, lenalidomide, and combinations of therapy. In each case, the MAR of the cells decreased if they were sensitive to therapy, and remained roughly the same if the cells were resistant to their given treatment.The approach also allowed the researchers to evaluate experimental MM therapies, including the BET inhibitor JQ1 and a peptide therpaetic targeting the E2F/DP1 interaction, “highlighting the potential of functional MAR measurements to assess therapeutic response in research setting,” they write.

    The researchers then went on to confirm their findings in a clinical setting to predict the responses to therapy of primary cancer cells from nine MM patients. The SMR device was used to assess cells from patients who had already undergone treatment and also from patients who had yet to start their treatment. Again, in each case, the MARs dropped in cells from patients whose cancers were sensitive to the treatment and stayed the same if their cancers were resistant to therapy. “In both cases, MAR response was consistent with clinical outcomes, suggesting that this assay can be used to prospectively determine treatment decisions,” the authors state. Interestingly, in both the cell line tests and the tests on patient-derived cells, there was a greater reduction in MAR in response to combinations of therapies, compared with response to single therapies.

    “Due to its unique characteristics, the MAR assay shows promise to make distinctive contributions to clinical practice as well as research," the authors conclude. "Reduction of MAR in myeloma cells occurs in less than 4 h following treatment, precedes loss of viability and does not require proliferation, making MAR measurements uniquely suited to working within the constraints of MM primary samples.”

    The researchers can see the technology having particular utility when a patient's disease relapses because tumors have developed resistance to some therapies. "At this time of relapse, we would take a bone marrow biopsy from a patient, and we would test each therapy individually or in combinations that are typically used in the clinic,” Stevens suggests. “At that point, we'd be able to inform the clinician as to which therapy or combinations of therapies this patient seems to be most sensitive or most resistant to.”



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