Evaluation of deoxynucleosides as a novel resistance mechanism for radiotherapy

摘要 镥-177 dotatate显著改善无进展生存期、缓解率、总生存期和质量 对于胃肠道神经内分泌肿瘤患者， 发病率仍然很低（18%），可能是由于DNA的内源性修复。修复被镥-177破坏的DNA 随着时间的推移，癌细胞需要脱氧核糖核苷三磷酸，这可以通过从头产生 或补救DNA修复途径。氚阻断从头途径，并且镥和 在ETCTN试验#10388中对Trilidine进行了评价。然而，当从头途径被抑制时， 补救途径被上调并导致对放射治疗的抗性。我们建议测量 挽救途径产生的脱氧核苷作为入组患者放射敏感性的生物标志物 在ETCTN #10388中。此外，我们将评估ATR抑制剂抑制补救途径的能力， 探索放射疗法、三氟甲磺酸和ATR抑制的组合的临床前活性。拟议 目的是高度创新的，并将：1）阐明癌细胞对细胞毒性药物的抗性机制， 放射性药物和氚的影响; 2）更好地解决所用单个脱氧核糖核苷的来源 3）支持开发一种新的三联疗法， ATR抑制剂可抑制DNA修复的从头和补救途径，并增强治疗效果。 镥的活性。

Abstract Lutetium-177 dotatate significantly improves progression free survival, response rate, overall survival and quality of life over standard therapy for patients with gastrointestinal neuroendocrine tumors, however, overall response rates remain low (18%), likely due to endogenous repair of DNA. To repair DNA damaged by lutetium-177 dotatate, cancer cells require deoxyribonucleotide triphosphates, which can be generated by either the de novo or salvage DNA repair pathway. Triapine blocks the de novo pathway, and the combination of lutetium and triapine is being evaluated in the ETCTN trial #10388. However when the de novo pathway is inhibited, the salvage pathway is upregulated and causes resistance to radiation therapy. We propose to measure deoxynucleosides, generated by the salvage pathway, as a biomarker of radiation sensitivity in patients enrolled in ETCTN #10388. In addition, we will evaluate the ability of ATR inhibitors to inhibit the salvage pathway and explore the preclinical activity of the combination of radiation therapy, triapine and ATR inhibition. The proposed aims are highly innovative and would; 1) elucidate a mechanism of resistance for cancer cells to the cytotoxic effects of radiopharmaceuticals and triapine; 2) better resolve the source for single deoxyribonucleosides used in the salvage DNA repair pathway; 3) support the development of a novel combination strategy of triapine and ATR inhibitors to inhibit both the de novo and salvage pathways for DNA repair and enhance the therapeutic activity of lutetium.