Neuroblastoma is the most common extracranial malignant solid tumor in children. Although the conventional treatment options are often curative at early stages, advanced disease remains fatal for a large percentage of patients, particularly for those who become resistant to conventional therapy. MIBG is taken up by sympathetic neurons via a specific norepinephrine transporter (NET) and 90% of all neuroblastoma tumors are MIBG-avid. Thus, when MIBG is labeled with 131I, a radionuclide that emits therapeutic beta particles with a relatively long physical half-life (8.02 days), 131I-MIBG becomes an agent for targeted radionuclide therapy of neuroblastoma. For the treatment with131I-MIBG, individualized radiation dosimetry can be achieved by pretherapy imaging using the same tracer with a different radioiodine such as I-123. I-123 is a favored imaging agent using gamma camera and SPECT;but it has a relatively shorter half-life than that of I-131 (13.2 hours versus 8.02 days) so that following the full time course of 123I-MIBG behavior in patients over a few days is not straightforward, and technically challenging. Instead, another radioiodine, I-124 has a closer half-life (4.2 days) to that of I-131, and can be imaged by PET that is considered quantitatively more accurate than SPECT. Our goals are to use 124I-MIBG PET/CT as an individualized 131I-MIBG radiotherapy prescription tool to achieve optimal treatment of tumors and minimal radiation dose to radiosensitive organs. Since 124I-MIBG has not been used in children for this indication (although 124I-MIBG was used in a limited number of adults), carefully designed preclinical studies with end points of radiation dose estimations should proceed before its human use.
Our specific aims are:
Aim 1 : To determine the distribution of 124I-MIBG in tumors and normal organs in vivo using animal models of neuroblastoma. Small animal PET/CT with 124I-MIBG will be performed at multiple time points over four days, and the imaging data will be analyzed to study pharmacokinetics in tumors and other organs.
Aim 2 : To calculate the pediatric human-equivalent effective radiation dose in the range of patient sizes from preclinical 124I-MIBG imaging data. For this aim, our goal is to estimate the normal organ doses with 124I-MIBG to ensure safety, not specifically intended for 131I-MIBG treatment prescription. We will apply for the IND, and will prepare for human imaging as a part of this aim.
Aim 3 : To assess the feasibility of tumor and organ dosimetry with pediatric 124I-MIBG PET/CT in selected neuroblastoma patients who are scheduled for 131I-MIBG treatment. We will develop a patient-specific dosimetry calculation tool that will be available for the dose prescription of 131I-MIBG. Estimations of radiation dose will be focused on the determination of optimal activity needed to effectively deliver therapeutic dose to tumor cells while keeping radiation dose to normal organs at an acceptable level. The outcomes of the individualized prescription of the 131I-MIBG treatment will be descriptively compared to the therapy outcomes, particularly the primary tumor size reduction.
The goal of this project is to develop individualized radiation dosimetry tool using 124I-m-iodobenzylguanidine (mIBG) PET/CT imaging for 131I-MIBG radionuclide therapy of high-risk advanced neuroblastoma in children. We will perform preclinical investigations to calculate radiation dose estimates in imaging of 124I-MIBG in humans, and develop software tools for human use in calculating individualized tumor and organ radiation dose for 131I-MIBG prescription to maximize the radiation delivery to tumors while keeping normal organs at an acceptable radiation exposure level.
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