Development of Novel Agents for Imaging and Therapy of Neuroendocrine Tumors
Currently, somatostatin receptor type 2 (SSTR2) directed peptide-receptor radiotherapy (PRRT) has improved outcomes for patients with Grades 1 and 2 neuroendocrine tumors (NETs), but has had little effect on Grade 3 NETs or neuroendocrine carcinomas (NECs). Chemokine receptor 4 (CXCR4) plays a crucial role in multiple malignancies by stimulating cell proliferation, angiogenesis, migration and metastasis of cancer cells. Studies have demonstrated a significant loss of SSTR2 expression with up-regulated CXCR4 expression in high grade NETs. Pentixafor is a CXCR4 antagonist currently under investigation in Europe but is not yet FDA-approved in the United States.
CXCR4 is crucial for metastases of high-grade NETs and NECs and therefore will be an excellent target for diagnosis, staging and therapy. Our goal is to evaluate the efficacy and safety of radiolabeled-pentixafor in a pre-clinical model of NETs and NECs. We believe this research will potentially provide data for CXCR4-guided diagnosis and radiotherapy for patients with high grade tumors. We will test these hypotheses through three specific aims.
Quantify the CXCR4 expression in specimens with high grade NETs and NECs.
Evaluate the acute and sub-chronic toxicity and determine the maximum tolerated dose (MTD) of 177Lu, 90Y and 212Pb-Pentixafor, particularly bone marrow toxicity.
Evaluate the therapeutic efficacy of CXCR4-targeted PRRT in a preclinical model of high-grade neuroendocrine tumors of bronchioles, pancreas, small bowel and cervix.
With the achievement of these aims, we expect to delineate the level of CXCR4 expression in a cohort of high-grade human NETs and NECs. We will further evaluate the toxicity of 177Lu, 90Y and 212Pb-Pentixafor in mice. Finally, 177Lu, 90Y and 212Pb-Pentixafor as novel therapeutic radiopharmaceuticals will be used to treat mice bearing human high-grade NET and NEC tumor xenografts. This pre-clinical safety, toxicity and efficacy evaluation will provide applicable information for a precise PRRT regimen using 177Lu, 90Y and 212Pb-Pentixafor targeting CXCR4 alone and in combination with 177Lu-DOTATATE or 90Y-DOTATOC targeting SSTR2. This research project is significant in illustrating the CXCR4 expression level and prevalence in high-grade NETs and NECs patient specimens. Importantly, this research will address renal and hematologic toxicities which are the limiting factors for precise personalized PRRT therapy. Finally, we will investigate the therapeutic effect with the new target of CXCR4 in comparison with therapy targeting SSTR2 in a pre-clinical model. We expect this series of step-by-step studies to provide valuable supplemental data for further clinical application, with the ultimate goal of developing a theranostics pair of 68Ga-Pentixafor (imaging) along with 177Lu, 90Y, or 212Pb-Pentixafor for treatment of highly aggressive NETs and NECs.