Abstract 7625: The liquid biomarker thymidine kinase activity reflecting proliferation rate can provide guidance in drug development and address Project Optimus
Authors: Mattias Bergqvist, Hanna Ritzén, Amy Williams
Journal: Cancer Research (2024)

Abstract Thymidine Kinase (TK) plays a basic role in DNA synthesis and cell proliferation. The enzyme is highly cell cycle dependent and correlates with cell growth state. Numerous studies have consistently shown elevated TK activity (TKa) in the blood of patients with solid tumors and active disease. DiviTum® TKa, a clinically and analytically validated FDA cleared assay, measures and quantifies TKa in serum or plasma in humans and animals. TKa as a biomarker offers valuable information at all stages of drug development, from drug efficacy and dose response studies in cell culture and xenograft models, to patient selection and treatment monitoring in clinical trials. The launch of FDA Project Optimus highlights the need for new biomarkers to assist in drug development to identify optimal dose. Using TKa to measure the impact on cell proliferation as a drug evaluation endpoint can confirm mechanism of action efficacy and a minimally effective dose of a new compound rather than a maximally tolerated dose. TKa can be used as a pharmacodynamic tool to improve study endpoints. TKa data in cultured cells and mouse xenografts demonstrates that a complete shutdown of tumor cell proliferation can be observed well before and at much lower drug-doses than when cell death or toxicity is used as the dose determination endpoint. Increased dosing of CDK4/6 inhibitors demonstrates immediate impact on TKa levels in cell lines and provides signals of drug effect at doses where cell viability is unaffected. After initiation of samuraciclib treatment, a CDK7 inhibitor, a significant reduction in TKa levels in blood from metastatic breast cancer (MBC) patients was observed, indicating inhibition of cell cycle progression. For patients on samuraciclib therapy and with stable disease before progression, TKa levels were significantly lower than pre-treatment (p=0.0038). Post-progression TKa levels increased to significantly higher levels than during therapy including the last sample measured before progression (p=0.014). Baseline blood TKa levels are predictive for progression free survival (PFS) allowing for the early stratification of patients with long vs short PFS. In patients with MBC, TKa levels during the first treatment cycle are strongly predictive for PFS. Suppressed TKa levels after 2 and 4 weeks of CDK4/6 inhibitor therapy predict longer PFS than high TKa levels at the same time points (HR 5.65; p&amp;lt; 0.0001). MBC patients monitored &amp;gt;3 months and showing low TKa levels have very low likelihood of progression within 30- to 60 days, &amp;lt;2% and &amp;lt;6%, respectively. TKa is a translational liquid biomarker that bridges results between preclinical and clinical studies, providing fundamental information for drug development decision making. Citation Format: Mattias Bergqvist, Hanna Ritzén, Amy Williams. The liquid biomarker thymidine kinase activity reflecting proliferation rate can provide guidance in drug development and address Project Optimus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7625.