Evaluation of Norepinephrine Transporter Expression and Metaiodobenzylguanidine Avidity in Neuroblastoma: A Report from the Children's Oncology Group

DuBois, Steven G.; Geier, Ethan G.; Batra, Vandana; Yee, Sook Wah; Neuhaus, John; Segal, Mark R.; Martı́nez, Daniel; Pawel, Bruce; Yanik, Greg; Naranjo, Arlene; London, Wendy B.; Kreissman, Susan G.; Baker, David L.; Attiyeh, Edward F.; Hogarty, Michael D.; Maris, John M.; Giacomini, Kathleen M.; Matthay, Katherine K.

doi:10.1155/2012/250834

Cited by 49 publications

(64 citation statements)

References 27 publications

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“…Clinically, our group and others have shown that there is a significant correlation between tumor NET expression and MIBG accumulation [9-11]. Our group has also identified tumors that are MIBG-avid but have little or no NET expression, and other tumors that express high levels of NET but do not accumulate MIBG [10]. These findings suggest that there are alternative mechanisms by which MIBG is specifically taken up and/or retained by neuroblastoma.…”

Section: Introductionmentioning

confidence: 53%

Vesicular monoamine transporter protein expression correlates with clinical features, tumor biology, and MIBG avidity in neuroblastoma: a report from the Children’s Oncology Group

Temple

Mendelsohn

Kim

et al. 2015

Eur J Nucl Med Mol Imaging

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Purpose Vesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2) are thought to mediate MIBG uptake in adult neuroendocrine tumors. In neuroblastoma, the norepinephrine transporter (NET) has been investigated as the principal MIBG uptake protein, though some tumors without NET expression concentrate MIBG. We investigated VMAT expression in neuroblastoma and correlated expression with MIBG uptake and clinical features. Methods We evaluated VMAT1 and VMAT2 expression by immunohistochemistry (IHC) in neuroblastoma tumors from 76 patients with high-risk metastatic disease treated on a uniform cooperative group trial (COG A3973). All patients had baseline MIBG diagnostic scans centrally reviewed. IHC results were scored as the product of intensity grading (0-3+) and percent of tumor cells expressing the protein of interest. Association of VMAT1 and VMAT2 scores with clinical and biological features was tested using Wilcoxon rank-sum tests. Results Patient characteristics were typical of high-risk neuroblastoma, though the cohort was intentionally enriched for patients with MIBG non-avid tumors (n=20). VMAT1 and VMAT2 were expressed in 62% and 75% of neuroblastoma tumors, respectively. VMAT1 and VMAT2 scores were both significantly lower in MYCN amplified tumors and in tumors with high mitotic karyorrhectic index. MIBG avid tumors had significantly higher VMAT2 scores compared to MIBG non-avid tumors (median 216 vs. 45; p = 0.04). VMAT1 expression did not correlate with MIBG avidity. Conclusions VMAT1 and VMAT2 are expressed in the majority of neuroblastomas. Expression correlates with other biological features. Expression level of VMAT2 but not VMAT1 correlates with avidity for MIBG.

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Section: Introductionmentioning

confidence: 53%

Vesicular monoamine transporter protein expression correlates with clinical features, tumor biology, and MIBG avidity in neuroblastoma: a report from the Children’s Oncology Group

Temple

Mendelsohn

Kim

et al. 2015

Eur J Nucl Med Mol Imaging

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“…131 I-MIBG will be studied in Europe in combination with Busulfan/Melphalan ASCR in patients with suboptimal responses to initial therapy, and will be evaluated in COG as part of induction. While tumor norepinephrine transporter (NET) expression appears to correlate with MIBG avidity, 40 the relationship between NET expression and response to therapy is unknown. Analysis of NET expression and other potential markers of sensitivity to 131 I-MIBG will be important as trials proceed.…”

Section: Relapsed Diseasementioning

confidence: 99%

Genetic discoveries and treatment advances in neuroblastoma

Bagatell

Cohn

2016

Current Opinion in Pediatrics

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Purpose of review Major advances in our understanding of the genetic basis of neuroblastoma and the role somatic alterations play in driving tumor growth have led to improvements in risk-stratified therapy and have provided the rationale for targeted therapies. In this review, we highlight current risk-based treatment approaches and discuss the opportunities and challenges of translating recent genomic discoveries into the clinic. Recent Findings Significant progress in the treatment of neuroblastoma has been realized using risk-based treatment strategies. Outcome has improved for all patients, including those classified as high-risk, although survival remains poor for this cohort. Integration of whole-genome DNA copy number and comprehensive molecular profiles into neuroblastoma classification systems will allow more precise prognostication and refined treatment assignment. Promising treatments that include targeted systemic radiotherapy, pathway-targeted small molecules, and therapy targeted at cell surface molecules are being evaluated in clinical trials, and recent genomic discoveries in relapsed tumor samples have led to the identification of new actionable mutations. Summary The integration of refined treatment stratification based on whole-genome profiles with therapeutics that target the molecular drivers of malignant behavior in neuroblastoma has the potential to dramatically improve survival with decreased toxicity.

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“…This systemic radiopharmaceutical is distributed to metastatic sites throughout the body (4). Approximately 90% of neuroblastoma tumors accumulate MIBG via the norepinephrine transporter (NET), making MIBG a targeted option for the majority of patients (5–6). MIBG at its usual maximum feasible dose of 18 mCi/kg has been shown to be among the most active agents for children with relapsed or refractory neuroblastoma (7–9).…”

Section: Introductionmentioning

confidence: 99%

Phase I Study of Vorinostat as a Radiation Sensitizer with 131I-Metaiodobenzylguanidine (131I-MIBG) for Patients with Relapsed or Refractory Neuroblastoma

DuBois

Groshen

Park

et al. 2015

Clinical Cancer Research

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Purpose 131I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase 1 study was to determine the maximum tolerated doses of vorinostat and MIBG in combination. Experimental Design Patients ≤ 30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible. Patients received oral vorinostat (dose levels 180 and 230 mg/m2) daily Days 1–14. MIBG (dose levels 8, 12, 15, and 18 mCi/kg) was given on Day 3 and peripheral blood stem cells on Day 17. Alternating dose escalation of vorinostat and MIBG was performed using a 3+3 design. Results 27 patients enrolled to 6 dose levels, with 23 evaluable for dose escalation. No dose-limiting toxicities (DLT) were seen in the first three dose levels. At dose level 4 (15 mCi/kg MIBG/230 mg/m2 vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG/230 mg/m2 vorinostat), two patients had dose-limiting bleeding (one grade 3 and one grade 5). At dose level 5a (18 mCi/kg MIBG/180 mg/m2 vorinostat), 0 of 6 patients had DLT. The most common toxicities were neutropenia and thrombocytopenia. The response rate was 12% across all dose levels and 17% at dose level 5a. Histone acetylation increased from baseline in peripheral blood mononuclear cells collected on Days 3 and 12–14. Conclusions Vorinostat at 180 mg/m2/dose is tolerable with 18 mCi/kg MIBG. A phase 2 trial comparing this regimen to single-agent MIBG is ongoing.

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Evaluation of Norepinephrine Transporter Expression and Metaiodobenzylguanidine Avidity in Neuroblastoma: A Report from the Children's Oncology Group

Cited by 49 publications

References 27 publications

Vesicular monoamine transporter protein expression correlates with clinical features, tumor biology, and MIBG avidity in neuroblastoma: a report from the Children’s Oncology Group

Vesicular monoamine transporter protein expression correlates with clinical features, tumor biology, and MIBG avidity in neuroblastoma: a report from the Children’s Oncology Group

Genetic discoveries and treatment advances in neuroblastoma

Phase I Study of Vorinostat as a Radiation Sensitizer with 131I-Metaiodobenzylguanidine (131I-MIBG) for Patients with Relapsed or Refractory Neuroblastoma

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