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Oct 28, 2011

Studies Outline Mitochondrial Approach to Predicting Cancer Response to Chemotherapy

  • The likely effectiveness of chemotherapy can be predicted before treatment starts by evaluating how close the cancer cells’ mitochondria are to an apoptotic threshold that results in cell death, researches claim. The observation has been made by a team led by investigators at the Dana-Farber Cancer Institute, using a mitochondrial profiling assay. The cellular assay essentially measured mitochondrial priming in cancer cells from patients with different forms of leukemia and an ovarian cancer before treatment was started, to see whether there was a correlation between how close cancer cell mitochondria were to the apoptotic threshold, with subsequent clinical outcome after chemotherapy.

    In each case the results indicated that the higher the prechemotherapy priming levels, the more likely the cancer was to respond to chemotherapy. The same trend was subsequently confirmed in cancer cell lines derived from a range of tumor types. Reporting their findings in Science Express, the authors claim the results suggest that manipulating mitochondrial priming might provide a way of boosting the efficacy of chemotherapy. Their paper is titled “Pretreatment Mitochondrial Priming Correlates with Clinical Response to Cytotoxic Chemotherapy.”

    Predicting whether any particular cancer will respond to chemotherapy is fraught with uncertainty. Tumors that respond well to one type of chemotherapy will often also respond positively to another form that displays a very different mechanism of action. Conversely, cancers that respond poorly to one type of chemotherapy will typically similarly respond poorly to another cytotoxic agent, the researchers explain. And although cell proliferation rate has been identified as an important determinant of chemosensitivity, there are, nevertheless, some rapidly dividing tumors that remain resistant to chemotherapy, while other types of slowly dividing tumors are chemosensitive.

    The Dana Farber-led team hypothesized that many different types of chemotherapy might impact on a central signaling node, and that variations in this node might determine the likelihood of drug response. They centered on the mitochondrial apoptosis pathway, through which a number of chemotherapeutic agents act, and investigated whether differences in cancer cells’ readiness to undergo apoptosis—before cancer treatment is started—impacts on their response to subsequently administered cytotoxic agents.

    Chemotherapy triggers cell death-signaling pathways that ultimately lead to either activation of proapoptotic, or inactivation of antiapoptotic BCL-2 proteins, and activation of the proapoptotic proteins BAX and BAK, which cause mitochondrial outer membrane permeabilization (MOMP) and inevitable cell death, the team notes. To measure MOMP in pretreatment cancers, they used a functional assay called BH3 profiling, which uses peptides derived from the BH3 domains of proapoptotic BH3-only proteins of the BCL2 family.

    The BH3 peptides are administered to whole cells, and interact with antiapoptotic proteins already present, effectively pushing the mitochondria past the apoptotic point of no return. The ease with which the cells are triggered to undergo apoptosis indicates the level of mitochondrial priming, and is measured using a fluorescent dye that can detect MOMP as a change in potential across the mitochondrial inner membrane. The aim of the tests was to determine whether cancer cells that were already "primed" (i.e., already close to the threshold) before treatment was started, provided an indication of how well the cancer would respond to subsequent chemotherapy.

    The investigators studied cells from 85 multiple myeloma, acute myelogenous and lymphoblastic leukemia, and ovarian cancer. For 51 of the cancers individual clinical follow-up was available. What they found was that for each type of cancer assayed, the level of mitochondrial priming in the tumor cells before therapy consistently correlated with better response to chemotherapy and clinical outcome, “suggesting a fundamental relationship between mitochondria and response to cytotoxic chemotherapy in vivo,” the authors state.

    To see if priming was actually a determinant of chemosensitivity, rather than just a correlate, the researchers then artificially increased priming in a myeloid leukemia cell line by treating the cells with a BH3 mimetic drug that binds to the antiapoptotic proteins BCL-2, BCL-XL, and BCL2. This resulted in an increase in sensitivity of the cells to the chemotherapeutic agents doxorubicin, vincristine, and etoposide, adding weight to the notion that mitochondrial priming may be a determinant of chemosensitivity, they remark.

    Finally, they tested a typically chemosensitive childhood acute lymphoblastic leukemia, a typically chemoresistant endometrial cancer, serous borderline ovarian tumor, and renal cell carcinoma samples, for which individual clinical response data weren’t available. The results confirmed that the mitochondria from the chemosensitive cancers were consistently more primed than those from chemoresistant cancers.

    “One implication of these results is that agents that selectively increase priming in cancer cells, even if they do not cause cell death by themselves, might enhance the response of tumors to conventional chemotherapy,” the authors conclude. “A tool like BH3 profiling, which can detect changes in priming, might be useful in identifying such agents.”

    The next stage will be to test whether the correlation between mitochondrial priming and chemotherapy efficacy is valid for other types of cancers. If so, BH3 profiling could be used to help decide on the best treatment approach for individual cancer patients. “One of the goals of personalized medicine is to know, in advance, which agents are likely to be effective in a given patient and which are not,” the authors comment. “This research highlights that potential.” 


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