High-risk Neuroblastoma is responsible for 15% of childhood cancer mortality. Despite intensification of cytotoxic therapy and the use of multimodality treatments, survival rates have not changed appreciably in the past 15 years. Furthermore, there is a markedly increased treatment related morbidity and mortality.
High-risk neuroblastoma is a radiosensitive tumor and local control can be achieved with doses of 21 Gy. Currently, external beam radiation therapy is considered an essential component of high-risk neuroblastoma therapy, and the current Phase 3 trial is exploring doses of 36 Gy for patients with gross residual disease following attempts at surgical resection (COG ANBL0532).
However, our current therapeutic approach for achieving remission does not include any targeted therapeutic approaches, and there is a clear need for developing agents with a broader therapeutic index. Targeted therapies for cancer rely on exploiting molecular aberrations unique to the tumor cell compared to host tissues. This is especially critical in the developing child.
The norepinephrine transporter (NET) complex is differentially overexpressed on the cell surface of most human neuroblastomas and provides a highly specific mechanism for directing uptake of norepinephrine analogues into the tumor. Metaiodobenzylguanidine(MIBG), radiolabeled with the β-emitter Iodine-131 (131I), is one such compound, and we have extensive experience with this agent as a targeted radiotherapeutic. Response rates of 40-50% have been shown in Phase 2 clinical trials, far surpassing anti-tumor activity of any other investigational agent being studied in children with relapsed high-risk neuroblastoma. However, not all MIBG-avid tumors respond, uptake is highly variable, and hematopoietic toxicity from circulating radionuclide requires that autologous stem cell support is available at higher dosing.
Additonally, 131I damages DNA through beta particle emission but the path length of beta energy is such that it does not impact the cell in which MIBG is concentrated but rather the tumor cells which reside at a distance. This radiobiologic fact explains why it is difficult to obtain bone marrow response presumably due to the inability to kill isolated tumor cells.
Astatine-211 (211At) is a short-lived (7.2 hour) α- emitting halogen with considerably high energy that potentially addresses many of these shortcomings including limiting hematopoietic toxicity and enhancing tumor cell kill. We hypothesize that targeted radiotherapy with the α-particle emitting norepinephrine analogue meta-[211At]astatobenzylguanidine (211At-MABG) will be safe and effective against human neuroblastoma.
With the support of the Hyundai scholars grant ,I will continue to develop my research efforts in determining the antitumor activity of 211At-MABG in preclinical models of human neuroblastoma.I will also utilise the award for determining the biodistribution and radiotoxicology of 211At-MABG in animal models. Also, the award will also be used to provide research and funding support to perform the portfolio of preclinical studies required to support an Investigational New Drug (IND) application, following the standard operating procedures already in place for high specific activity 131I-MIBG. The grant will also be used for initiation of studies to determine the maximum tolerated dose and potential anti-neuroblastoma activity of 211At-MABG in a Phase 1/2a clinical trial. This would help provide data and validation for a Phase 1 dose escalation trial of 211At-MABG in patients with refractory neuroblastoma.
