胸苷激酶活性作为一种转化生物标志物，用于支持肿瘤药物开发中的剂量优化并作为患者监测工具

IntroductionThymidine Kinase (TK) is a cell-cycle regulated enzyme essential to DNA synthesis and a marker of cell proliferation and tumor aggressiveness. TK is released into the bloodstream and measurement of its activity (TKa) serves as a predictive and dynamic biomarker providing valuable insights in drug development. These studies aim to demonstrate the role of TKa-from evaluating drug effects in cells and preclinical studies to guiding dosing, patient stratification and monitoring in clinical trials. The FDA Project Optimus underscores the need for biomarkers that can support drug dosing optimization based on biological responses rather than maximum tolerated dose.MethodsTKa was investigated as a translational biomarker of pharmacodynamic (PD) response across preclinical and clinical settings, studying cell cycle inhibitor drugs effect on TKa levels. In HR+ breast cancer cell lines, the effects on both sensitive cells (CDKS) and cells with acquired resistance (CDKR) to CDK4/6 inhibition were studied. Clinically, the effects of CDK2 inhibition were evaluated in a phase 1/2 dose escalation study and CDK4/6 inhibition in the real-world setting, including dose adjustments, from TKa monitored breast cancer patients treated at US institutes. TKa was measured with the FDA cleared DiviTum ® TKa assay (Biovica, Sweden). ResultsTKa was significantly reduced in CDKS cells treated with increasing doses of palbociclib for 3 days compared to drug vehicle (DMSO) with the highest dose of palbociclib suppressing TKa >95% vs DMSO (p <0.05). No significant impact on TKa were observed in CDKR cells at any palbociclib dose.CDK-2 inhibition impact on TKa and pRb was demonstrated, with significant correlation between increasing drug exposure and decreasing TKa levels (p <0.05). Combination of CDK2- and 4/6 inhibitors plus fulvestrant achieved the greatest TKa suppression (p <0,05). Real-world evidence from breast cancer patients demonstrates how TKa monitoring can support individualized dose adjustments of CDK4/6 inhibitors. A lack of drug-induced TKa suppression may indicate suboptimal efficacy, justifying either dose escalation or a different therapy combination, while a strong and sustained drug-induced TKa suppression signals therapy efficacy and disease control. Dose adjustments of CDK4/6 inhibitors show how different dosing impact TKa levels and PD suppression of tumor proliferation reflects cell-cycle control. Examples of dose adjustments and drug concentration on TKa levels will be presented. ConclusionsTKa acts as a translational biomarker and a surrogate for anti-tumor activity, offering an evidence-based approach to balance efficacy and tolerability. TKa patterns can provide early signals of drug efficacy, identify patients with sustained cell-cycle inhibition, refine dose-response understanding and improve patient monitoring.