PET imaging to monitor NET-1 and GD2 expression in neuroblastoma

Abstract

Within neuroblastoma (NB), approximately 50% of patients are considered high-risk, presenting widespread distant metastasis and, frequently, MYCN amplification. NB is further characterised by the selective presence of the noradrenaline transporter (NET-1) and the GD2 disialoganglioside in a majority of cases. Targeted therapies against both NET-1 and GD2 have improved patient survival, however, many patients eventually relapse from disease. mIBG (meta-iodobenzylguanadine) is a noradrenaline analogue used for diagnosis and treatment of NB, yet despite 90% of patients presenting NET-1 expressing tumours and being characaterised as 'mIBG avid', less than 50% respond to targeted 131I-mIBG radiotherapy. This may be, in part, due to the limitations of spatial resolution and image quantification of single photo emission computed tomography (SPECT) acquisitions performed with 123I-mIBG. To address these deficiencies I have investigated the use of a fluorinated noradrenaline analogue, 18F-mFBG, for use with positron emission tomography (PET) imaging. Of note, a first-in-human study using 18F-mFBG has demonstrated clear benefits of using this tracer compared to 123I-mIBG, yet the tracer has not been fully translated to clinical practice due to a complicated radio-synthesis. The ability of pharmacological intervention to modulate NET-1 expression in NB has been highlighted with preclinical and clinical studies using the histone deacetylate (HDAC) inhibitor, vorinostat. I wanted to build on this work by investigating compounds that may increase NET-1 expression whilst simultaneously targeting other pathways critical in patients with high-risk disease, in particular the PI3k/Akt/mTOR pathway. I hypothesised that drugs targeting mTORC1/2 can increase NET-1 expression in NB models, to which I investigated the use of 18F-mFBG as a tool to quantify these changes in vitro and in vivo. GD2 expression is also thought to be ubiquitously expressed in NB and GD2-targeted immunotherapy (Dinutuximab/Dinutuximab-Beta) has provided promising improvements in the event free survival of patients compared to historical 'standard therapies'. However, NB tumours with positive, but low, GD2 expression are likely to relapse. Current methods to investigate tumour GD2 expression are invasive (tumour biopsies) and only provide a snapshot of the disease. In an attempt to better understand the efficacy and pitfalls of GD2 immunotherapy, I have developed an 89Zr-labelled GD2 antibody that could provide a means of measuring the tumour GD2 expression level in situ.