COMBINATION HIGH-LET MOLECULAR RADIOTHERAPY OF RELAPSED REFRACTORY NEUROBLASTOMA

PROJECT SUMMARY There is a critical need for more effective treatments for metastatic and relapsed neuroblastoma (NB), the most commonly diagnosed extracranial solid cancer in children and the most common cancer in infancy. Following years of advancement of multimodal therapies, 60 % of high risk NB will recur after treatment, resulting in a 5% survival rate at 5 years. Conventional regimens now include targeted radiotherapy to the norepinephrine transporter (NET). This is a well-validated biomarker expressed in >90% of patients, and is targeted by 131I-MIBG – a beta particle emitting NET substrate. SSTR2 is another important neuroendocrine specific target, which is also highly expressed in >70% of NB. FDA-approved SSTR2 radiopeptides, 68Ga/177Lu-DOTA-TATE have showed some efficacy in investigational use in pediatrics. However, both 131I-MIBG and 177Lu- DOTA-TATE are low linear energy transfer, beta particle-emitting agents, which lack the capacity to ablate cancer cells or occult small lesions. 131I-MIBG treatment only achieves a long-term response in about 30% of NB patients, which is far lower than NET expression incidence. High linear energy transfer emissions have the capacity to eliminate microscopic occult disease sites, while sparing distant tissues from the long path lengths of conventional beta-emitting treatments. In this application we put forwards a combination treatment strategy with novel ligands to address multiple failure points of conventional targeted radiotherapy for this devastating disease. To NET, we target 77Br-MBBG (a highly chemically stable, auger emitting meta-bromobenzylguanidine) and to SSTR2 we have developed 227Th-L804-LM3 (a best-in-class Thorium-227 alpha emitter- conjugated antagonist for SSTR2). These high LET agents will selectively kill cancer cells with definitive anticancer effects; and the synergistic elimination of low expressors of either target will be compensated by the combination approach. We deploy and characterize these next generation agents to advance NB care in standard xenografts and advanced patient derived models of NB. We monitor treatment efficacy of 77Br-MBBG, 227Th-L804-LM3 and their combinations, and compare to conventional 131I-MIBG and 177Lu-DOTA-TATE treatment. We monitor tumor response; target expression using quantitative molecular imaging analogs; DNA damage and repair; and genomic profiles of NB in the de novo and post-treatment states. Through these studies, we anticipate to optimize novel treatment approach that can undergo near term translation at Washington University in St. Louis Children’s Hospital.