Paracrine signaling through MYCN enhances tumor-vascular interactions in neuroblastoma.

Neuroblastoma, a tumor of peripheral neural crest origin, numbers among the most common childhood cancers. Both amplification of the proto-oncogene MYCN and increased neoangiogenesis mark high-risk disease. Because angiogenesis is regulated by phosphatidylinositol 3-kinase (PI3K), we tested a clinical PI3K inhibitor, NVP-BEZ235, in MYCN-dependent neuroblastoma. NVP-BEZ235 decreased angiogenesis and improved survival in both primary human (highly pretreated recurrent MYCN-amplified orthotopic xenograft) and transgenic mouse models for MYCN-driven neuroblastoma. Using both gain- and loss-of-function approaches, we demonstrated that the antiangiogenic efficacy of NVP-BEZ235 depended critically on MYCN in vitro and in vivo. Thus, clinical PI3K/mammalian target of rapamycin inhibitors drove degradation of MYCN in tumor cells, with secondary paracrine blockade of angiogenesis. Our data demonstrated significantly improved survival in treated animals and suggest that NVP-BEZ235 should be tested in children with high-risk, MYCN-amplified neuroblastoma.

Vorinostat increases expression of functional norepinephrine transporter in neuroblastoma in vitro and in vivo model systems.

PURPOSE: Histone deacetylase (HDAC) inhibition causes transcriptional activation or repression of several genes that in turn can influence the biodistribution of other chemotherapeutic agents. Here, we hypothesize that the combination of vorinostat, a HDAC inhibitor, with (131)I-meta-iodobenzylguanidine (MIBG) would lead to preferential accumulation of the latter in neuroblastoma (NB) tumors via increased expression of the human norepinephrine transporter (NET). EXPERIMENTAL DESIGN: In vitro and in vivo experiments examined the effect of vorinostat on the expression of NET, an uptake transporter for (131)I-MIBG. Human NB cell lines (Kelly and SH-SY-5Y) and NB1691-luc mouse xenografts were employed. The upregulated NET protein was characterized for its effect on (123)I-MIBG biodistribution. RESULTS: Preincubation of NB cell lines, Kelly, and SH-SY-5Y, with vorinostat caused dose-dependent increases in NET mRNA and protein levels. Accompanying this was a corresponding dose-dependent increase in MIBG uptake in NB cell lines. Four- and 2.5-fold increases were observed in Kelly and SH-SY-5Y cells, respectively, pretreated with vorinostat in comparison to untreated cells. Similarly, NB xenografts, created by intravenous tail vein injection of NB1691-luc, and harvested from nude mice livers treated with vorinostat (150 mg/kg i.p.) showed substantial increases in NET protein expression. Maximal effect of vorinostat pretreatment in NB xenografts on (123)I-MIBG biodistribution was observed in tumors that exhibited enhanced uptake in vorinostat-treated [0.062 ± 0.011 µCi/(mg tissue-dose injected)] vs. -untreated mice [0.022 ± 0.003 µCi/(mg tissue-dose injected); P < 0.05]. CONCLUSIONS: The results of our study provide preclinical evidence that vorinostat treatment can enhance NB therapy with (131)I-MIBG.

Non-stem cell origin for oligodendroglioma.

Malignant astrocytic brain tumors are among the most lethal cancers. Quiescent and therapy-resistant neural stem cell (NSC)-like cells in astrocytomas are likely to contribute to poor outcome. Malignant oligodendroglial brain tumors, in contrast, are therapy sensitive. Using magnetic resonance imaging (MRI) and detailed developmental analyses, we demonstrated that murine oligodendroglioma cells show characteristics of oligodendrocyte progenitor cells (OPCs) and are therapy sensitive, and that OPC rather than NSC markers enriched for tumor formation. MRI of human oligodendroglioma also suggested a white matter (WM) origin, with markers for OPCs rather than NSCs similarly enriching for tumor formation. Our results suggest that oligodendroglioma cells show hallmarks of OPCs, and that a progenitor rather than a NSC origin underlies improved prognosis in patients with this tumor.

Radiation dose estimation using preclinical imaging with 124I-metaiodobenzylguanidine (MIBG) PET.

PURPOSE: A pretherapy 124I-metaiodobenzylguanidine (MIBG) positron emission tomography (PET)/computed tomography (CT) provides a potential method to estimate radiation dose to normal organs, as well as tumors prior to 131I-MIBG treatment of neuroblastoma or pheochromocytoma. The aim of this work was to estimate human-equivalent internal radiation dose of 124I-MIBG using PET/CT data in a murine xenograft model. METHODS: Athymic mice subcutaneously implanted with NB1691 cells that express high levels of human norepinephrine transporter (n = 4) were imaged using small animal microPET/CT over 96 h (approximate imaging time points: 0.5, 2, 24, 52, and 96 h) after intravenous administration of 3.07-4.84 MBq of 124I-MIBG via tail vein. The tumors did not accumulate 124I-MIBG to a detectable level. All four animals were considered as control and organ radiation dosimetry was performed. Volumes of interest were drawn on the coregistered CT images for thyroid, heart, lung, liver, kidney, and bladder, and transferred to PET images to obtain pharmacokinetic data. Based on tabulated organ mass distributions for both mice and adult male human, preclinical pharmacokinetic data were extrapolated to their human-equivalent values. Radiation dose estimations for different age groups were performed using the OLINDA/EXM software with modified tissue weighting factors in the recent International Commission on Radiological Protection (ICRP) Publication 103. RESULTS: The mean effective dose from 124I-MIBG using weighting factors from ICRP 103 to the adult male was estimated at 0.25 mSv/MBq. In different age groups, effective doses using values from ICRP 103 were estimated as follows: Adult female: 0.34, 15-yr-old: 0.39 mSv/MBq, 10-yr-old: 0.58 mSv/MBq, 5-yr-old: 1.03 mSv/MBq, 1-yr-old: 1.92 mSv/MBq, and newborn: 3.75 mSv/ MBq. For comparison, the reported effective dose equivalent of 124I-NaI for adult male (25% thyroid uptake, MIRD Dose Estimate Report No. 5) was 6.5 mSv/MBq. CONCLUSIONS: The authors estimated human-equivalent internal radiation dose of 124I-MIBG using preclinical imaging data. As a reference, the effective dose estimation showed that 124I-MIBG would deliver less radiation dose than 124I-NaI, a radiotracer already being used in patients with thyroid cancer.