Phase II Study of Temozolomide in Relapsed or Refractory High-Risk Neuroblastoma: A Joint Société Française des Cancers de l’Enfant and United Kingdom Children Cancer Study Group–New Agents Group Study

Rubie, H; Chisholm, Julia; Defachelles, Anne‐Sophie; Morland, Bruce; Munzer, Caroline; Valteau‐Couanet, Dominique; Mosseri, Véronique; Bergeron, Christophe; Weston, Clare E.; Coze, Carole; Auvrignon, Anne; Djafari, L.; Hobson, Rachel; Baunin, C.; Dickinson, Fiona; Brisse, H.; McHugh, Kieran; Biassoni, Lorenzo; Giammarile, Francesco; Vassal, Gilles

doi:10.1200/jco.2006.06.1572

Cited by 58 publications

(62 citation statements)

References 31 publications

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“…We investigated whether these effects would enhance the cytotoxicity in the treatment of cancers with commonly used chemotherapeutic agents. We combined LB1.2 with temozolomide (TMZ), a DNA-methylating chemotherapeutic drug, to treat glioblastoma multiforme (GBM) (11) and neuroblastoma (NB) (12) xenografts in the mouse models. We also combined LB 1.2 with Doxorubicin (DOX), a DNA intercalating chemotherapeutic drug, (13) in GBM xenografts to study whether the effect depends on the specific mechanism of the cytotoxic agent.…”

Section: Medical Sciencesmentioning

confidence: 99%

Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms

Lü

Kovach

Johnson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

148

168

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A variety of mechanisms maintain the integrity of the genome in the face of cell stress. Cancer cell response to chemotherapeutic and radiation-induced DNA damage is mediated by multiple defense mechanisms including polo-like kinase 1 (Plk-1), protein kinase B (Akt-1), and/or p53 pathways leading to either apoptosis or cell cycle arrest. Subsequently, a subpopulation of arrested viable cancer cells may remain and recur despite aggressive and repetitive therapy. Here, we show that modulation (activation of Akt-1 and Plk-1 and repression of p53) of these pathways simultaneously results in paradoxical enhancement of the effectiveness of cytotoxic chemotherapy. We demonstrate that a small molecule inhibitor, LB-1.2, of protein phosphatase 2A (PP2A) activates Plk-1 and Akt-1 and decreases p53 abundance in tumor cells. Combined with temozolomide (TMZ; a DNA-methylating chemotherapeutic drug), LB-1.2 causes complete regression of glioblastoma multiforme (GBM) xenografts without recurrence in 50% of animals (up to 28 weeks) and complete inhibition of growth of neuroblastoma (NB) xenografts. Treatment with either drug alone results in only short-term inhibition/regression with all xenografts resuming rapid growth. Combined with another widely used anticancer drug, Doxorubicin (DOX, a DNA intercalating agent), LB-1.2 also causes marked GBM xenograft regression, whereas DOX alone only slows growth. Inhibition of PP2A by LB-1.2 blocks cell-cycle arrest and increases progression of cell cycle in the presence of TMZ or DOX. Pharmacologic inhibition of PP2A may be a general method for enhancing the effectiveness of cancer treatments that damage DNA or disrupt components of cell replication.

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Section: Medical Sciencesmentioning

confidence: 99%

Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms

Lü

Kovach

Johnson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

148

168

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“…TEM has recently been evaluated as a single-agent for neuroblastoma (3,13). Similar to the case with high-grade glioma, responses and prolonged stable disease are seen in a subset of patients.…”

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confidence: 99%

“…One potentially promising regimen is the combination of the DNA methylating agent temozolomide with the topoisomerase I inhibitor irinotecan. Both drugs have single-agent activity against neuroblastoma (2,3), and preclinical studies have shown that administration of TEM followed by IRN results in schedule-dependent synergy against mouse models of this disease (4). Based on encouraging preliminary reports of this combination in children with relapsed solid tumors (5 -7), the Children's Oncology Group is now conducting a national phase II trial of this drug pair to define its activity for neuroblastoma in first relapse.…”

mentioning

confidence: 99%

Targeting Methylguanine-DNA Methyltransferase in the Treatment of Neuroblastoma

Wagner

McLendon

Yoon

et al. 2007

Clinical Cancer Research

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Purpose: The combination of temozolomide and irinotecan has preclinical schedule-dependent synergy against neuroblastoma but is not curative for relapsed high-risk patients. We hypothesized that the DNA repair protein methylguanine-DNA methyltransferase (MGMT) is an important resistance factor, and that inactivation of MGMT would sensitize neuroblastoma cells to these agents. Experimental Design: MGMT protein expression was assessed in 74 primary neuroblastoma tumors. Growth inhibition assays were done to determine the IC 50 and the extent of synergy observed with various concentrations of temozolomide, irinotecan, and the MGMT-inactivating agent O 6 -benzylguanine, using cultured syngeneic neuroblastoma cells with either low or high levels of MGMT expression. We then assessed efficacy in a mouse xenograft model of metastatic neuroblastoma. Results: MGMT was expressed by all 74 tumors evaluated. Pretreatment of neuroblastoma cells with O 6 -benzylguanine reduced the IC 50 of temozolomide by 10-fold regardless of level of MGMT expression, and pretreatment with BG followed by temozolomide + irinotecan further reduced the IC 50 in cells with high MGMT expression another 10-fold, to well below clinically achievable concentrations.The combination index was 0.27 to 0.30 for all three drugs in both cell lines, indicating strong synergy. Survival at 100 days for mice with metastatic neuroblastoma was 56% with three-drug treatment, compared with untreated controls (0%, P < 0.001) or temozolomide + irinotecan (10%, P = 0.081). Conclusions: MGMT is widely expressed in primary neuroblastoma tumors, and is a relevant therapeutic target. Both in vitro and in vivo studies suggest inactivation of MGMT with O 6 -benzylguanine may increase the activity of temozolomide and irinotecan against neuroblastoma.Neuroblastoma is the most common extracranial solid tumor of childhood, and accounts for 15% of all pediatric cancer deaths. Fewer than half of all children diagnosed with high-risk neuroblastoma will survive 5 years after diagnosis (1). The identification of new active agents or drug combinations is essential to improving the prognosis for these patients. One potentially promising regimen is the combination of the DNA methylating agent temozolomide with the topoisomerase I inhibitor irinotecan. Both drugs have single-agent activity against neuroblastoma (2, 3), and preclinical studies have shown that administration of TEM followed by IRN results in schedule-dependent synergy against mouse models of this disease (4). Based on encouraging preliminary reports of this combination in children with relapsed solid tumors (5 -7), the Children's Oncology Group is now conducting a national phase II trial of this drug pair to define its activity for neuroblastoma in first relapse. It is unlikely, however, that this two-drug combination will be curative for the majority of patients with high-risk disease at relapse due to drug resistance.One recognized mechanism of TEM resistance is a high level of expression of methylguanine-DNA m...

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“…Phase II studies showed efficacy of topotecan in combination with cyclophosphamide (5) or with vincristine and doxorubicin (6), and of temozolomide as monotherapy (7). Topotecan alone or in combination with cyclophosphamide showed response rates up to 76% in previously untreated patients (8) and 64% in patients with refractory or relapsed neuroblastoma, in combination with vincristine and doxorubicin (TVD; ref.…”

mentioning

confidence: 99%

Inhibition of Poly(ADP-Ribose) Polymerase-1 Enhances Temozolomide and Topotecan Activity against Childhood Neuroblastoma

Daniel

Rozanska

Thomas

et al. 2009

Clinical Cancer Research

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Purpose: High-risk neuroblastoma is characterized by poor survival rates, and the development of improved therapeutic approaches is a priority. Temozolomide and topotecan show promising clinical activity against neuroblastoma. Poly(ADP-ribose) polymerase-1 (PARP-1) promotes DNA repair and cell survival following genotoxic insult; we postulated that its inhibition may enhance the efficacy of these DNA-damaging drugs in pediatric cancers. Experimental Design: We evaluated the chemosensitizing properties of the PARP inhibitor AG014699 (Pfizer, Inc.) in combination with temozolomide and topotecan, against human neuroblastoma cells and xenografts, alongside associated pharmacologic and toxicologic indices. Results: Addition of PARP-inhibitory concentrations of AG014699 significantly potentiated growth inhibition by both topotecan (1.5-to 2.3-fold) and temozolomide (3-to 10-fold) in vitro, with equivalent effects confirmed in clonogenic assays. In two independent in vivo models (NB1691 and SHSY5Y xenografts), temozolomide caused a xenograft growth delay, which was enhanced by co-administration of AG014699, and resulted in complete and sustained tumor regression in the majority (6 of 10; 60%) of cases. Evidence of enhanced growth delay by topotecan/AG014699 co-administration was observed in NB1691 xenografts. AG014699 metabolites distributed rapidly into the plasma (C max , 1.2-1.9 nmol/L at 30 min) and accumulated in xenograft tissues (C max ,1-2 Amol/L at 120 min), associated with a sustained suppression of PARP-1enzyme activity. Doses of AG014699 required for potentiation were not toxic per se. Conclusions: These data show enhancement of temozolomide and topotecan efficacy by PARP inhibition in neuroblastoma. Coupled with the acceptable pharmacokinetic, pharmacodynamic, and toxicity profiles of AG014699, our findings provide strong rationale for investigation of PARP inhibitors in pediatric early clinical studies.

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Phase II Study of Temozolomide in Relapsed or Refractory High-Risk Neuroblastoma: A Joint Société Française des Cancers de l’Enfant and United Kingdom Children Cancer Study Group–New Agents Group Study

Abstract: Temozolomide shows activity in heavily pretreated patients with NB, and deserves further evaluation in combination with another drug.

Cited by 58 publications

References 31 publications

Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms

Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms

Targeting Methylguanine-DNA Methyltransferase in the Treatment of Neuroblastoma

Inhibition of Poly(ADP-Ribose) Polymerase-1 Enhances Temozolomide and Topotecan Activity against Childhood Neuroblastoma

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