Abstract
Administration of ineffective anticancer therapy is associated with unnecessary toxicity and development of resistant clones. Cancer stem-like cells (CSLCs) resist chemotherapy, thereby causing relapse of the disease. Thus, development of a test that identifies the most effective chemotherapy management offers great promise for individualized anticancer treatments. We have developed an ex vivo chemotherapy sensitivity assay (ChemoID), which measures the sensitivity of CSLCs as well as the bulk of tumor cells to a variety of chemotherapy agents. Two patients, a 21-year old male (patient 1) and a 5-month female (patient 2), affected by anaplastic WHO grade-III ependymoma were screened using the ChemoID assay. Patient 1 was found sensitive to the combination of irinotecan and bevacizumab, which resulted in a prolonged disease progression free period of 18 months. Following recurrence, the combination of various chemotherapy drugs was tested again with the ChemoID assay. We found that benzyl isothiocyanate (BITC) greatly increased the chemosensitivity of the ependymoma cells to the combination of irinotecan and bevacizumab. After patient 1 was treated for two months with irinotecan, bevacizumab and supplements of cruciferous vegetable extracts containing BITC, we observed over 50% tumoral regression in comparison with pre-ChemoID scan as evidenced by MRI. Patient 2 was found resistant to all treatments tested and following 6 cycles of vincristine, carboplatin, cyclophosphamide, etoposide, and cisplatin in various combinations, the tumor of this patient rapidly progressed and proton beam therapy was recommended. As expected animal studies conducted with patient derived xenografts treated with ChemoID screened drugs recapitulated the clinical observation. This assay demonstrates that patients with the same histological stage and grade of cancer may vary considerably in their clinical response, suggesting that ChemoID testing which measures the sensitivity of CSLCs as well as the bulk of tumor cells to a variety of chemotherapy agents could lead to more effective and personalized anticancer treatments in the future.
Highlights
Ependymomas are the third most common type of brain tumor in children, they are relatively rare, with approximately 200 cases diagnosed in the US each year [1,2]
We found with the ChemoID assay that increasing concentrations of benzyl isothiocyanate (BITC) ranging from 2.5 mM to 20 mM decreased the viability of CD133(+) ependymoma cells of Patient 1 from 90% to 62% in a statistically significant manner (Figure 5A)
Chemotherapy has been used extensively in the treatment management of ependymomas, this therapeutic modality is often reserved for patients with residual tumor after surgery and for children younger than 3 years of age in an attempt to delay radiation therapy
Summary
Ependymomas are the third most common type of brain tumor in children (following astrocytoma and medulloblastoma), they are relatively rare, with approximately 200 cases diagnosed in the US each year [1,2]. They account for 60% of all intramedullary tumors and 50% arise in the filum terminale [3]. The initial standard treatment for ependymoma is surgery often followed by radiation therapy, and chemotherapy. Chemotherapy is often reserved for patients with residual tumor after surgery and for children younger than 3 years of age in an attempt to delay radiation therapy [4]
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