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C. Presant



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    MO20 - Preclinical Therapeutic Models II (ID 93)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO20.07 - Identification of New Chemotherapeutic Strategies in Mesothelioma and Non-Small Cell Lung Cancer Using a Drug-Induced Apoptosis Assay (MiCK Assay) (ID 3158)

      11:10 - 11:15  |  Author(s): C. Presant

      • Abstract
      • Presentation
      • Slides

      Background
      Given limited progress in developing novel chemotherapies for mesothelioma and multi-negative NSCLC, new technology is needed to identify promising drug strategies. A drug-induced apoptosis assay has been developed that has been applied in acute myelocytic leukemia, ovarian cancer, and a variety of solid tumors including breast cancer (Cancer Research 2012; 72:3901). We explored the use of the MiCK assay in mesothelioma and NSCLC tumor specimens.

      Methods
      Fresh tumor specimens from resected tissue or malignant effusions were processed in a central laboratory. Cell separation techniques were used to prepare >95% tumor cell suspensions for the MiCK assay (as described in Cancer 2012; 118: 4877). Over 48 hours in short term culture, optical techniques based on Mie light scattering measured apoptosis in control wells and test wells containing different chemotherapy drugs or combinations. Significant apoptosis gave results over 1.0 kinetic units (KU). Drugs or combinations producing the highest KU +/- 1 SD compared to other drugs were defined as best regimens. Differences of over 0.57 KU correlated with clinically significant better responses.

      Results
      15 specimens have been submitted with 9 successfully assayed to date. Mean numbers of drugs or combinations assayed successfully were 32 in mesothelioma and 20 in NSCLC. New treatment strategies in individual patients with mesothelioma were: epirubicin 5.0 and 9 KU, idarubicin 4.0 KU, pemetrexed+doxorubicin 4.9 and 4.6 KU, ifosfamide 3.4 and 2.2 KU, bendamustine 4.0 KU, dactinomycin 4.7 and 3.4 KU, vinorelbine 4.7 KU, asacytidine 3.8 KU, bortezomib 3.0 KU, doxorubicin 3.9 KU, cyclophosphamide+doxorubicin+vincristine 3.0 KU and cisplatin+irinotecan 3.1 KU. New treatment strategies in individual patients with NSCLC were: doxorubicin 2.0, 1.7 and 1.7 KU, epirubicin 1.6 KU, 5-fluorouracil+leucovorin 1.3 KU, and cyclophosphamide+doxorubicin+vincristine 2.3 KU. In class differences in drug activity were apparent in individual patients: cisplatin>carboplatin, epirubicin>doxorubicin, and docetaxel>paclitaxel. In one mesothelioma patient with paired specimens from malignant effusion and solid tumor the most active (pemetrexed+doxorubicin) and least active regimens (cisplatin+paclitaxel) were concordant. In mesothelioma, the most active chemotherapy regimens in individual patients were epirubicin, idarubicin, pemetrexed+doxorubicin, vinorelbine, cisplatin+etoposide, cisplatin+irinotecan, cyclophosphamide+doxorubicin+vincristine, and dactinomycin. In NSCLC, the most active regimens were doxorubicin, cisplatin, docetaxel, irinotecan, and cyclophosphamide+doxorubicin+vincristine.

      Conclusion
      Use of the MiCK assay in mesothelioma and NSCLC can identify unexpected new leads for innovative therapeutic strategies for individual patients, and for candidate enrollment in phase II and III studies. The MiCK assay may play a role in designing precision therapeutics for patients with mesothelioma and NSCLC. Marked differences between patients in individual drug activities, and discordant in-class drug effectiveness indicate the need for individualized patient tumor testing of drug-induced apoptosis. Since use of the MiCK assay has correlated with improved clinical outcomes in prior studies, clinical trials of drugs with unexpected activity may be warranted in mesothelioma and NSCLC patients.

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