Analysis of Chemopredictive Assay for Targeting Cancer Stem Cells in Glioblastoma Patients

Abstract

Introduction: The prognosis of glioblastoma (GBM) treated with standard-of-care maximal surgical resection and concurrent adjuvant temozolomide (TMZ)/radiotherapy remains very poor (less than 15 months). GBMs have been found to contain a small population of cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. The highly invasive nature of high-grade gliomas and their inherent resistance to therapy lead to very high rates of recurrence. For these reasons, not all patients with similar diagnoses respond to the same chemotherapy, schedule, or dose. Administration of ineffective anticancer therapy is not only costly but more importantly burdens the patient with unnecessary toxicity and selects for the development of resistant cancer cell clones. We have developed a drug response assay (ChemoID) that identifies the most effective chemotherapy against CSCs and bulk of tumor cells from of a panel of potential treatments, offering great promise for individualized cancer management. Providing the treating physician with drug response information on a panel of approved drugs will aid in personalized therapy selections of the most effective chemotherapy for individual patients, thereby improving outcomes. A prospective study was conducted evaluating the use of the ChemoID drug response assay in GBM patients treated with standard of care. Methods: Forty-one GBM patients (mean age 54 years, 59% male), all eligible for a surgical biopsy, were enrolled in an Institutional Review Board–approved protocol, and fresh tissue samples were collected for drug sensitivity testing. Patients were all treated with standard-of-care TMZ plus radiation with or without maximal surgery, depending on the status of the disease. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Odds ratio (OR) associations of 12-month recurrence, PFS, and OS outcomes were estimated for CSC, bulk tumor, and combined assay responses for the standard-of-care TMZ treatment; sensitivities/specificities, areas under the curve (AUCs), and risk reclassification components were examined. Results: Median follow-up was 8 months (range 3-49 months). For every 5% increase in in vitro CSC cell kill by TMZ, 12-month patient response (nonrecurrence of cancer) increased two-fold, OR = 2.2 (P = .016). Similar but somewhat less supported associations with the bulk tumor test were seen, OR = 2.75 (P = .07) for each 5% bulk tumor cell kill by TMZ. Combining CSC and bulk tumor assay results in a single model yielded a statistically supported CSC association, OR = 2.36 (P = .036), but a much attenuated remaining bulk tumor association, OR = 1.46 (P = .472). AUCs and [sensitivity/specificity] at optimal outpoints (>40% CSC cell kill and >55% bulk tumor cell kill) were AUC = 0.989 [sensitivity = 100/specificity = 97], 0.972 [100/89], and 0.989 [100/97] for the CSC only, bulk tumor only, and combined models, respectively. Risk categorization of patients w...

The Clinical Impact of Cancer Stem Cells

“…This assay uses patient biopsies to test the chemosensitivity of individual patient bulk tumor cells and CSCs to currently available therapies to predict tumor response. This assay could potentially determine which therapies are most likely to kill both bulk tumor cells and CSCs in an individual patient .…”

The methods of in vitro selection of chemotherapeutic druds for individual chemotherapy of maligant tumors in patinets

“…Метод ChemoID, разработанный американскими учеными из медицинского центра при университете Миссиссипи, позволяет провести определение химиочувствительности раковых стволовых клеток и клеток глиобластомы для индивидуализации выбора химиотерапии у пациентов [70]. Тест ChemoID включает комбинирование методов оценки химиочувствительности опухолевых клеток по их жизнеспособности при окрашивании трипановым синим, флуоресцентно-меченными антителами к маркерам CD133, CXCR4, CD44, Oct3/4, Nanog и WST8 анализа (Water-soluble tetrazolium salts analysis).…”

“…Медиана возникновения рецидива составила 20 мес для пациентов, у которых в ChemoID тесте погибало более 40% раковых стволовых клеток по сравнению с 3 мес для больных, имеющих меньший процент погибших клеток. Таким образом, ChemoID дает возможность 2,2 раза повысить ответ опухоли у пациентов на химиотерапию по сравнению с группой больных, терапию которым назначают без применения данного метода [70].…”

New Advances and Challenges of Targeting Cancer Stem Cells

“…CSC-targeting ChemoID drug response assays served as correlative endpoints and stratification variables for glioblastoma (Pier Paolo Claudio, University of Mississippi, Oxford, MS; ref. 15), which could lead to more efficient and personalized anticancer therapy in the future. FABP5 drives self-renewal of triple-negative breast CSCs by enhancing the transcriptional activity of PPARδ to induce NANOG, SOX2, and OCT4 (Dr. Liraz Levi, Cleveland Clinic Foundation, Cleveland, OH).…”