Post-Doc Johns Hopkins Baltimore, Maryland, United States
Disclosure(s):
Nouran Zaid: No financial relationships to disclose
Objectives: Fibroblast activation protein (FAP) is highly expressed on cancer-associated fibroblasts (CAFs) in the tumor stroma, which can account for >90% of the volume in desmoplastic tumors. Accordingly, FAP is a compelling “pan-tumor” target in radiopharmaceutical therapy (RPT). Although FAP-targeted agents show preclinical promise, clinical outcomes are largely limited to stable disease or partial responses in patients with high stromal content or FAP expression. To better understand this, we developed a mathematical model capturing the interaction between FAP targeting, radiation-induced CAF senescence, and FAP expression, to evaluate tumor response to FAP-targeted RPT.
Methods: A mathematical model integrating radiobiology, pharmacokinetics, cell signaling in Tumor microenvironment (TME) and tumor growth, was developed to predict tumor mass nadir during [177Lu]Lu-DOTAGA.(SA.FAPi)2 therapy in breast cancer (BC). The model was solved using the modeling software SimBiology/MATLAB (version R2024a; MathWorks, Inc.). The total tumor mass (MT-total) described by the model consists of tumor cells surrounded by CAFs, which are assumed to contribute 25% to the initial MT-total for BC. The growth rates of the tumor cells and CAFs decrease according to the Gompertz model. The distributed [177Lu]Lu-DOTAGA.(SA.FAPi)2 in TME undergo bivalent binding to CAF-expressed FAP. The energies of emitted beta particles from bound and internalized [177Lu]Lu-DOTAGA.(SA.FAPi)2 were assumed uniformly distributed across the tumor volume. The linear quadratic model was used to describe radiation-induced cell kill to tumor cells due to cross irradiation and CAF senescence [1]. A 6-cycle dosing regimen (7.4 GBq/cycle, 6-week intervals) was simulated in accordance with the standard protocol for [¹⁷⁷Lu]Lu-PSMA-617 therapy. Median patients’ pharmacokinetics derived from the literature for [177Lu]Lu-DOTAGA.(SA.FAPi)2 were used to obtain the dose rate over time. We assessed tumor mass reduction and the radiation absorbed dose (AD) to kidneys as the main excreting organ. Model parameters were adapted to simulate non-small cell lung cancer (NSCLC) and pancreatic cancer by incorporating cancer-specific CAF fractions, growth rates and radiosensitivities.
Results: The developed mathematical model described the radiation-induced double strand breaks that lead to CAF senescence, with subsequent increase in cytokine secretion promoting tumor vascular growth. Due to slow senescence kinetics, the model predicted that senescent CAFs remain resident within the tumor microenvironment throughout the treatment period. Senescent CAFs showed a 1.75-fold increase in FAP expression vs proliferating CAFs. In BC, an initial 11-g tumor mass (50th percentile a patient population) decreased by 14% by the end of the 6th cycle. NSCLC and pancreatic tumors of 11 g decreased by 32% and 7.1%, respectively. Kidney AD reached 10.3 Gy.
Conclusions: This mathematical model offers mechanistic insight into CAF response during FAP-targeted RPT and the implications for tumor control. Such modeling may guide clinical trial design by reducing empiricism and identifying treatment strategies with potential efficacy.
Citations: [1] Zaid et al., Journal of Nuclear Medicine, 2025; DOI: 10.2967/jnumed.124.268457
