cabozantinib and Neuroblastoma

Relapsed high-risk neuroblastoma has few effective therapies currently available or in development. Cabozantinib is an Food and Drug Administration approved multitargeted tyrosine kinase inhibitor for select adult malignancies with preclinical data suggesting efficacy against neuroblastoma. A safe and tolerable dose has been identified for children, but its efficacy remains unknown. We describe four children with relapsed metastatic neuroblastoma treated with cabozantinib. All four patients had extended disease control (two complete responsesfor >12 months, 2 stable disease >6 months) with manageable predictable toxicities requiring dose reduction in two patients. We discuss the potential for the use of cabozantinib in neuroblastoma.

Topics: Anilides; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neuroblastoma; Prognosis; Protein Kinase Inhibitors; Pyridines; Retrospective Studies

The use of clinical MRI scanners to conduct pre-clinical research facilitates comparisons with clinical studies. Here the utility and sensitivity of anatomical and functional MRI data/biomarkers acquired from transgenic mouse models of neuroblastoma using a dedicated radiofrequency (RF) coil on a clinical 3T scanner was evaluated.. Multiparametric MRI of transgenic mice bearing abdominal neuroblastomas was performed at 3T, and data cross-referenced to that acquired from the same mice on a pre-clinical 7T MRI system. T. Excellent T. Simultaneous multiparametric MRI of multiple tumour-bearing animals using this coil arrangement at 3T can provide high efficiency/throughput for both phenotypic characterisation and evaluation of novel therapeutics, and facilitate the introduction of functional MRI biomarkers into aligned imaging-embedded clinical trials.

Topics: Anaplastic Lymphoma Kinase; Anilides; Animals; Antineoplastic Agents; Contrast Media; Cyclophosphamide; Disease Models, Animal; Female; Magnetic Resonance Imaging; Magnets; Male; Mice; Mice, Transgenic; Mutation; N-Myc Proto-Oncogene Protein; Neuroblastoma; Phantoms, Imaging; Phenotype; Pyridines; Receptor Protein-Tyrosine Kinases; Signal-To-Noise Ratio; Stomach Neoplasms; Tumor Burden

MET is expressed on neuroblastoma cells and may trigger tumor growth, neoangiogenesis and metastasis. MET upregulation further represents an escape mechanism to various anticancer treatments including VEGF signaling inhibitors. We developed in vitro a resistance model to pan-VEGFR inhibition and explored the simultaneous inhibition of VEGFR and MET in neuroblastoma models in vitro and in vivo using cabozantinib, an inhibitor of the tyrosine kinases including VEGFR2, MET, AXL and RET. Resistance in IGR-N91-Luc neuroblastoma cells under continuous in vitro exposure pressure to VEGFR1-3 inhibition using axitinib was associated with HGF and p-ERK overexpression. Cabozantinib exhibited anti-proliferative effects in neuroblastoma cells and reduced cell migration in vitro as measured by phase-contrast with IncuCyte system. In vivo, an enhanced number of animals with IGR-N91-Luc metastases was noted following axitinib treatment as compared to control animals. Orally administered cabozantinib per gavage at 30 and 60 mg/kg/day significantly inhibited tumor growth of orthotopic adrenal IGR-N91-Luc and metastatic IMR-32-Luc xenografts. Antitumor activity was associated with decreased vascularization, inhibition of p-SRC and induction of apoptotic cell death. Activation of the HGF-mediated MET pathway is involved in escape to selective VEGFR inhibition in neuroblastoma suggesting combined inhibition of MET and VEGFR signaling to reduce secondary resistance and enhanced invasiveness.

Topics: Anilides; Animals; Apoptosis; Axitinib; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Hepatocyte Growth Factor; Humans; Imidazoles; Indazoles; Mice; Neoplasm Invasiveness; Neuroblastoma; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Xenograft Model Antitumor Assays

Children with high-risk neuroblastoma have poor survival rates, and novel therapies are needed. We hypothesized that cabozantinib would be effective against neuroblastoma tumor cells and tumors in preclinical models via inhibition of receptor tyrosine kinase signaling pathways.. We determined neuroblastoma cell viability after treatment with cabozantinib alone and in combination with 13-cis-retinoic acid, topotecan, and temozolomide using MTT assays. Inhibition of RET and intracellular signaling was measured by Western blot analysis of treated and untreated cells. To investigate the efficacy of cabozantinib against neuroblastoma tumors in vivo, neuroblastoma cells were injected orthotopically into immunocompromised mice, and mice were treated with oral cabozantinib. Tumors were evaluated for growth by determination of in vivo luminescence and final tumor weights.. All neuroblastoma cell lines were sensitive to cabozantinib, and IC50 values ranged from 1.6 to 16.2 μM. Cabozantinib treatment was synergistic with 13-cis-retinoic acid and chemotherapy agents topotecan and temozolomide. Cabozantinib treatment inhibited RET phosphorylation in all cell lines and ERK phosphorylation in more sensitive neuroblastoma cell lines. In mice with neuroblastoma xenograft tumors, cabozantinib treatment significantly reduced tumor growth.. Treatment of neuroblastoma tumor cells with cabozantinib inhibits RET and ERK phosphorylation and is effective against neuroblastoma tumor cell lines alone and in combination with 13-cis-retinoic acid, topotecan, and temozolomide. Cabozantinib treatment is also effective in reducing tumor growth in vivo. Cabozantinib therefore represents a novel therapeutic agent for neuroblastoma, and further preclinical and clinical studies are warranted.

Topics: Administration, Oral; Adrenal Gland Neoplasms; Anilides; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Survival; Dacarbazine; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Humans; Immunocompromised Host; Inhibitory Concentration 50; Isotretinoin; MAP Kinase Signaling System; Mice; Neoplasm Proteins; Neuroblastoma; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Pyridines; Temozolomide; Topotecan; Xenograft Model Antitumor Assays