Faculty Bibliography

Atypical Teratoid/Rhabdoid tumors (AT/RT) of the central nervous system are rare but aggressive tumors of childhood. Median survival with surgery and standard chemotherapy is less than 12 months. In an attempt to improve outcome, patients were treated with aggressive surgical resection and multi-agent chemotherapy, followed by high dose chemotherapy with autologous stem cell rescue. Nine consecutive children (median age 21 months) were diagnosed with AT/RT at the University of California San Francisco Childrens Hospital from 1997 to 2007 and treated with this aggressive approach. Diagnosis was confirmed using molecular markers. There are two long-term survivors (78 and 98 months from diagnosis). One additional patient is alive with disease. Three patients died of disease during therapy. Three patients died of disease after therapy was complete. There were no toxic deaths. Two of nine patients treated for AT/RT at our institution with high dose chemotherapy and autologous bone marrow transplant are long-term survivors, suggesting that a subset of patients can be cured with this approach.

We have shown previously that blockade of epidermal growth factor receptor (EGFR) cooperates with a pan-selective inhibitor of phosphoinositide-3-kinase (PI3K) in EGFR-driven glioma. In this communication, we tested EGFR-driven glioma differing in PTEN status, treating with the EGFR inhibitor erlotinib and a novel dual inhibitor of PI3Kalpha and mTOR (PI-103). Erlotinib blocked proliferation only in PTEN(wt) cells expressing EGFR. Although erlotinib monotherapy showed little effect in PTEN(mt) glioma, PI-103 greatly augmented the antiproliferative efficacy of erlotinib in this setting. To address the importance of PI3K blockade, we showed in PTEN(mt) glioma that combining PI-103 and erlotinib was superior to either monotherapy or to therapy combining erlotinib with either rapamycin (an inhibitor of mTOR) or PIK-90 (an inhibitor of PI3Kalpha). These experiments show that a dual inhibitor of PI3Kalpha and mTOR augments the activity of EGFR blockade, offering a mechanistic rationale for targeting EGFR, PI3Kalpha, and mTOR in the treatment of EGFR-driven, PTEN-mutant glioma.

BACKGROUND: Recurrent non-cerebellar primitive neuroectodermal tumors (PNETs) carry a dismal prognosis when treated with conventional chemotherapy alone. XSWe tested the efficacy of high-dose chemotherapy (HDC) followed by autologous stem-cell rescue (ASCR) in this setting. PROCEDURE: Eligibility mandated either minimal residual disease or evidence of chemosensitivity before HDC. Conditioning consisted of carboplatin (CBDCA) (500 mg/m(2) or AUC = 7 mg/ml min using the Calvert formula) on days -8 to -6, thiotepa (300 mg/m(2)), and etoposide (250 mg/m(2)) on days -5 to -3. Irradiation was given post HDC selectively. RESULTS: Among 17 patients treated in this study, there were eight pineoblastoma(s) (pineo), seven cortical PNETs, and two arising elsewhere. Relapse was either local (nine) or metastatic to the brain (four) or spine (four). Two patients received HDC as the sole therapy for recurrence; additionally, eight underwent surgical debulking before HDC, and nine received irradiation, including six after HDC. Median age at ASCR was 3.9 years. Two patients died of toxicity (11%) and ten experienced tumor relapse (range: 23-361 days post ASCR). Five patients with cortical PNETs remain alive disease-free (median follow-up: 8.3 years); four of them received irradiation post HDC. The difference in 5-year event-free survival (EFS) between patients with pineo and other supratentorial PNETs was significant (0 vs. 62.5 +/- 17%, P = 0.0065). Both surgery at relapse and irradiation post HDC were favorable prognostic factors (P = 0.006 and 0.01, respectively). CONCLUSIONS: Patients with recurrent cortical PNETs can be cured with this strategy. Surgical debulking before, and irradiation after HDC play an important role in treatment success