Evaluation of Deoxynucleosides as a Novel Resistance Mechanism for Radiotherapy

The ongoing ETCTN trial NCI #10388 seeks to overcome DNA repair as a mechanism of non-response to radiation therapy, by adding tripaine, a ribonucleotide reductase inhibitor capable of blocking the de novo pathway of DNA repair, to lutetium.4, 5 Unfortunately, in a trial like NCI #10388, where triapine pharmacologically blocks the de novo ribonucleotide reductase pathway, the salvage pathway becomes overactive, and can contribute to non-response.6 Therefore, there is a critical need to evaluate the salvage pathway as a biomarker of response. In addition, the source of salvaged single deoxyribonucleosides for DNA repair must be discovered. At least two sources for single deoxyribonucleosides exists—from surrounding cells in a paracrine-like fashion, or, from distant cells, like skeletal muscle, in an endocrine-like manner. Thus, this proposed supplement tests the hypothesis that distant cells like skeletal muscle shed single deoxyribonucleosides into blood and raise their concentration in blood after triapine-lutetium dotatate exposure versus baseline. The overall goal for this supplement to UM1CA186712 is to develop and validate an LC/MSMS assay for the evaluation deoxynucleosides in blood and to perform this as an exploratory objective in NCI #10388 (A phase I trial of triapine and lutetium dotatate in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors) in the 14 patient expansion cohort and to assess preclinical activity of our proposed novel combination study.