Characterizing the theranostic potential of DLL3-targeting agents in high-grade neuroendocrine carcinomas of the lung and prostate - PROJECT ABSTRACT Small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC) are aggressive, high-grade neuroendocrine neoplasms (HG-NENs) that often metastasize and do not respond well to treatment. Lung cancer is the leading cause of cancer mortality worldwide and SCLC represents ~15% of lung cancers. Prostate cancer is the most common solid tumor and the second-leading cause of cancer-related death among men in the US. More than 20% of males with advanced prostate cancer eventually develop the highly aggressive NEPC form. Both SCLC and NEPC are characterized by similar genetic (RB1 and TP53 loss) and phenotypic features, as well as substantial intra-tumoral heterogeneity, which is implicated in therapeutic resistance. Identifying and developing novel treatment targets and strategies for SCLC and NEPC is a critical unmet need. Delta-like ligand 3 (DLL3) is an antigen expressed on the cell surface of HG-NENs, whereas in normal tissues expression is restricted to intracellular compartments, predominantly confined to the Golgi apparatus. DLL3 expression correlates with neuroendocrine marker expression, RB1 loss, and aggressive clinical features. Based on the over-expression of DLL3 in HG-NENs, we propose to utilize a DLL3-targeted radiolabeled monoclonal antibody (mAb) for non-invasive diagnosis using PET imaging (89Zr-DFO-SC16.56 Ab) as well as for image-based therapy (177Lu-DTPA-SC16.56). Our central hypothesis is that the overexpression of DLL3 on HG-NEN lesions can be exploited for diagnostic and therapeutic purposes. To examine this hypothesis, our phase I study will evaluate patients affected by HG-NENs with 89Zr-DFO-SC16.56 mAb PET/CT. Those who exhibit sufficient target expression in at least 80% of the growing lesions will be treated with 177Lu-DTPA- SC16.56. A key issue in such aggressive malignancies is the need to objectively determine treatment efficacy by quantifying the radiation dose delivered to the target and assessing tumor radiosensitivity, which engenders susceptibility to treatment. We will use molecular genomic tools to identify DLL3 transcripts and compare these with known molecular signatures in blood and tissue that can define neuroendocrine and prostate cancer tumors and correlate with response. The proposed study will investigate the safety and mechanistic basis of the efficacy of radiotheranostics specifically targeting DLL3, a novel target for lethal malignancies for which currently limited therapeutic tools exist. Our extensive experience in the development of DLL3-targeting PET agents and validation in SCLC and NEPC models, along with our preliminary clinical PET data in SCLC and NEPC patients, as well as our expertise in the ancillary use of molecular genomic tumor markers position us to successfully complete the aims of this study.
