Dataset Information

Aurora Kinase A inhibition enhances DNA damage and tumor cell death with ¹³¹I-MIBG therapy in high-risk neuroblastoma.

ABSTRACT:

Background

Neuroblastoma is the most common extra-cranial pediatric solid tumor. ¹³¹I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical highly specific for neuroblastoma tumors, providing potent radiotherapy to widely metastatic disease. Aurora kinase A (AURKA) plays a role in mitosis and stabilization of the MYCN protein in neuroblastoma. Here we explore whether AURKA inhibition potentiates a response to MIBG therapy.

Results

Using an in vivo model of high-risk neuroblastoma, we demonstrated a marked combinatorial effect of ¹³¹I-MIBG and alisertib on tumor growth. In MYCN amplified cell lines, the combination of radiation and an AURKA A inhibitor increased DNA damage and apoptosis and decreased MYCN protein levels.

Conclusion

The combination of AURKA inhibition with ¹³¹I-MIBG treatment is active in resistant neuroblastoma models and is a promising clinical approach in high-risk neuroblastoma.

SUBMITTER: Kumar P

PROVIDER: S-EPMC10836112 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Publications

Aurora Kinase A inhibition enhances DNA damage and tumor cell death with <sup>131</sup>I-MIBG therapy in high-risk neuroblastoma.

Kumar Prerna P Koach Jessica J Nekritz Erin E Mukherjee Sucheta S Braun Benjamin S BS DuBois Steven G SG Nasholm Nicole N Haas-Kogan Daphne D Matthay Katherine K KK Weiss William A WA Gustafson Clay C Seo Youngho Y

Research square 20240118

<h4>Background</h4>Neuroblastoma is the most common extra-cranial pediatric solid tumor. <sup>131</sup>I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical highly specific for neuroblastoma tumors, providing potent radiotherapy to widely metastatic disease. Aurora kinase A (AURKA) plays a role in mitosis and stabilization of the MYCN protein in neuroblastoma. Here we explore whether AURKA inhibition potentiates a response to MIBG therapy.<h4>Results</h4>Using an <i>in vivo</i> mode ...[more]

PMID: 38313265

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Project description:BackgroundAlthough (131) I-metaiodobenzylguanidine ((131) I-MIBG) therapy is increasingly used for children with high-risk neuroblastoma, a paucity of lead-lined rooms limits its wider use. We implemented radiation safety procedures to comply with New York City Department of Health and Mental Hygiene regulations for therapeutic radioisotopes and administered (131) I-MIBG using rolling lead shields.ProcedurePatients received 0.67 GBq (18 mCi)/kg/dose (131) I-MIBG on an IRB-approved protocol (NCT00107289). Radiation safety procedures included private room with installation of rolling lead shields to maintain area dose rates ≤0.02 mSv/hr outside the room, patient isolation until dose rate <0.07 mSv/hr at 1 m, and retention of a urinary catheter with collection of urine in lead boxes. Parents were permitted in the patient's room behind lead shields, trained in radiation safety principles, and given real-time radiation monitors.ResultsRecords on 16 (131) I-MIBG infusions among 10 patients (age 2-11 years) were reviewed. Mean ± standard deviation (131) I-MIBG administered was 17.67 ± 11.14 (range: 6.11-40.59) GBq. Mean maximum dose rates outside treatment rooms were 0.013 ± 0.008 mSv/hr. Median time-to-discharge was 3 days post-(131) I-MIBG. Exposure of medical staff and parents was below regulatory limits. Cumulative whole-body dose received by the physician, nurse, and radiation safety officer during treatment was 0.098 ± 0.058, 0.056 ± 0.045, 0.055 ± 0.050 mSv, respectively. Cumulative exposure to parents was 0.978 ± 0.579 mSv. Estimated annual radiation exposure for inpatient nurses was 0.096 ± 0.034 mSv/nurse. Thyroid bioassay scans on all medical personnel showed less than detectable activity. Contamination surveys were <200 dpm/100 cm(2) .ConclusionsThe use of rolling lead shields and implementation of specific radiation safety procedures allows administration of high-dose (131) I-MIBG and may broaden its use without dedicated lead-lined rooms.

Project description:Calculating internal dose from therapeutic radionuclides currently relies on estimates made from multiple radiation exposure measurements, converted to absorbed dose in specific organs using the Medical Internal Radiation Dose (MIRD) schema. As an alternative biodosimetric approach, we utilized gene expression analysis of whole blood from patients receiving targeted radiotherapy. Collected blood from patients with relapsed or refractory neuroblastoma who received (131)I-labeled metaiodobenzylguanidine ((131)I-mIBG) at the University of California San Francisco (UCSF) was used to compare calculated internal dose with the modulation of chosen gene expression. A total of 40 patients, median age 9 years, had blood drawn at baseline, 72 and 96 h after (131)I-mIBG infusion. Whole-body absorbed dose was calculated for each patient based on the cumulated activity determined from injected mIBG activity and patient-specific time-activity curves combined with (131)I whole-body S factors. We then assessed transcripts that were the most significant for describing the mixed therapeutic treatments over time using real-time polymerase chain reaction (RT-PCR). Modulation was evaluated statistically using multiple regression analysis for data at 0, 72 and 96 h. A total of 10 genes were analyzed across 40 patients: CDKN1A; FDXR; GADD45A; BCLXL; STAT5B; BAX; BCL2; DDB2; XPC; and MDM2. Six genes were significantly modulated upon exposure to (131)I-mIBG at 72 h, as well as at 96 h. Four genes varied significantly with absorbed dose when controlling for time. A gene expression biodosimetry model was developed to predict absorbed dose based on modulation of gene transcripts within whole blood. Three transcripts explained over 98% of the variance in the modulation of gene expression over the 96 h (CDKN1A, BAX and DDB2). To our knowledge, this is a novel study, which uses whole blood collected from patients treated with a radiopharmaceutical, to characterize biomarkers that may be useful for biodosimetry. Our data indicate that transcripts, which have been previously identified as biomarkers of external exposures in ex vivo whole blood and in vivo radiotherapy patients, are also good early indicators of internal exposure. However, for internal sources of radiation, the biokinetics and physical decay of the radionuclide strongly influence the gene expression.

Dataset Information

Aurora Kinase A inhibition enhances DNA damage and tumor cell death with ¹³¹I-MIBG therapy in high-risk neuroblastoma.

Background

Results

Conclusion

Publications

Aurora Kinase A inhibition enhances DNA damage and tumor cell death with <sup>131</sup>I-MIBG therapy in high-risk neuroblastoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Aurora Kinase A inhibition enhances DNA damage and tumor cell death with 131I-MIBG therapy in high-risk neuroblastoma.

Background

Results

Conclusion

Publications

Aurora Kinase A inhibition enhances DNA damage and tumor cell death with <sup>131</sup>I-MIBG therapy in high-risk neuroblastoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Aurora Kinase A inhibition enhances DNA damage and tumor cell death with ¹³¹I-MIBG therapy in high-risk neuroblastoma.