Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>Background: Most chemotherapeutic agents kill via the mitochondrial pathway of apoptosis, but unfortunately there is a lack of effective predictive biomarkers to assess the optimal treatment for each patient. When effective death signaling is initiated by a targeted therapy, an increase in mitochondrial apoptotic sensitivity (or ‘priming for death’) can be observed within hours. We developed a new technique, Dynamic BH3 Profiling, that measures changes in priming induced by chemotherapy in cancer cells, without the requirement for prolonged ex vivo culture, and we assessed if it could be used as predictive assay to personalize cancer therapy in patients.</jats:p>
<jats:p>Hypothesis : Early apoptotic signaling detected via Dynamic BH3 Profiling can predict later cytotoxic cellular response.</jats:p>
<jats:p>Results: Our first test was whether dynamic BH3 profiling performed following only 16 hours of drug exposure could predict cytotoxicity at a much later (72-96 hours) time point. We initiated our studies on a diverse panel of human cancer cell lines treated with a wide range of kinase inhibitors. These cell lines included solid tumors: NSCLC, breast cancer, melanoma and colon carcinoma; and hematological malignancies: multiple myeloma, CML, diffuse large B cell lymphoma and AML. We used different treatments (primary targets): Gefitinib (EGFR inh), Imatinib (BCR-ABL inh), Lapatinib (HER2 inh), TAE-684 (ALK inh), MK-2206 (Akt inh), PLX-4032 (BRaf V600E inh), AZD6244 (MEK inh), BEZ235 (PI3K/mTOR inh) and others. We observed a significant correlation between the increase in priming following short-term exposure to the agents and cell death at 72-96 hours, demonstrating the predicting capacity of dynamic BH3 profiling in different cancer cells.</jats:p>
<jats:p>We then tested if dynamic BH3 profiling can predict clinical response in cancer patients. For that purpose, we used samples from stable phase CML and ovarian adenocarcinoma patients of known clinical outcome to imatinib or carboplatin treatment respectively. In both cases we found that the induction of mitochondrial priming caused by short term (16 hr) ex vivo exposure to treatment predicted clinical response.</jats:p>
<jats:p>Moreover, the ROC curve analysis demonstrated that Dynamic BH3 profiling is an excellent binary predictor of response in vitro and in the clinic.</jats:p>
<jats:p>Conclusions: Our cell line and clinical experiments demonstrate the potential for Dynamic BH3 profiling to be used as a powerful real-time tool to predict chemotherapy response across many cancers and many agents, including combinations of agents. It is an excellent binary predictor in multiple cell lines and different types of primary samples. and could be used to recognize the best agent from a list of possible therapies for an individual tumor and improve cancer therapy.</jats:p>
<jats:p>Citation Format: Joan Montero, Kris A. Sarosiek, Joe D. DeAngelo, Huiying Piao, Neil Horowitz, Ross Berkowitz, Ursula Matulonis, Ronny Drapkin, Anthony Letai. Hitting the target: Dynamic BH3 profiling, a novel functional assay to predict chemotherapy response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2837. doi:10.1158/1538-7445.AM2014-2837</jats:p>