M. Maurer2, N. J. Skill1,2, Y. Bren-Mattison2, M. A. Maluccio2 1Louisiana State University Health Sciences Center, Interdisciplinary Oncology, New Orleans, LA, USA 2Louisiana State University Health Sciences Center, Surgery, New Orleans, LA, USA
Introduction: Neuroendocrine Tumors (NET) are a group of rare cancers originating from neuroendocrine cells within multiple organs. The evidence that supports medical decision making must consider the heterogeneity of these tumors, differences in biologic behavior between primary sites, and the moderate to high risk of developing metastatic disease over a patient’s lifetime. Based on preliminary omic studies and current clinical trials in other cancers, the enzyme 5′-nucleotidase (CD73) has been identified as a potential biomarker for patient stratification as well as likely treatment target for NET patients. CD73 is a cell membrane bound enzyme and has been linked to cancer development through the biosynthesis of adenosine from AMP. Increased expression of CD73 in tumors is associated with worse outcomes in stomach, pancreas, and lung cancers. Recently, small-molecule drugs that target CD73 directly or downstream of adenosine signaling pathway have been developed and are currently in clinical trials for other cancers.
Methods: Our laboratory operates one of the largest independent biorepositories for NET tissues and liquid biopsies. NET tumors and liquid biopsies from patients with NET were quantified for CD73, adenosine, and AMP. Tumor CD73 levels were quantified by Western blotting and ELISA (n=8). Plasma adenosine and AMP levels were quantified by HPLC/MS in plasma samples prior to surgery (N=12). Circulating CD73 levels were quantified by flow cytometry in peripheral blood mononuclear cells (PBMC) collected from patients with progressive NET post resection (N=25). Control PBMC and plasma samples were collected from living renal donors (LRD).
Results: AMP (the substrate for CD73) levels were markedly increased (>LRD+2SD) in plasma of NET patients compared to controls suggesting that this mechanism is a component of the metabolic alterations in NET. CD73 expression was increased in 20% of NET tumors congruent with elevated levels of adenosine (>LRD + 2SD) observed in plasma in 24% of patients from a separate cohort. Circulating CD73 levels are measurable and were increased (>LRD+2SD) within a subset of NET patients (8%) that are most relevant to our current prospective studies.
Conclusion: In a subset of NET patients, identified via increased tumor expression of CD73, increased circulating levels of CD73, and/or increased circulating levels of adenosine, targeting CD73 activity with emerging CD73 inhibitors may be reasonable to consider in certain patients. In this initial evaluation, up to 24% of patients would be potential candidates for CD73 targeted treatment. However, a caveat of this study is that the tumor and liquid biopsy analysis was not performed in matched samples from the same patient nor did we have enough events to link CD73 to cancer specific outcomes. Our prospective studies use the CD73 tumor expression to identify patients most relevant to further analysis and to better link the results to outcomes.