The impact of the spatial heterogeneity of resistant cells and fibroblasts on treatment response

Abstract

A long-standing practice in the treatment of cancer is that of hitting hard with the maximum tolerated dose to eradicate tumors. This continuous therapy, however, selects for resistant cells, leading to the failure of the treatment. A different type of treatment strategy, adaptive therapy, has recently been shown to have a degree of success in both preclinical xenograft experiments and clinical trials. Adaptive therapy is used to maintain a tumor’s volume by exploiting the competition between drug-sensitive and drug-resistant cells with minimum effective drug doses or timed drug holidays. To further understand the role of competition in the outcomes of adaptive therapy, we developed a 2D on-lattice agent-based model. Our simulations show that the superiority of the adaptive strategy over continuous therapy depends on the local competition shaped by the spatial distribution of resistant cells. Intratumor competition can also be affected by fibroblasts, which produce microenvironmental factors that promote cancer cell growth. To this end, we simulated the impact of different fibroblast distributions on treatment outcomes. As a proof of principle, we focused on five types of distribution of fibroblasts characterized by different locations, shapes, and orientations of the fibroblast region with respect to the resistant cells. Our simulation shows that the spatial architecture of fibroblasts modulates tumor progression in both continuous and adaptive therapy. Finally, as a proof of concept, we simulated the outcomes of adaptive therapy of a virtual patient with four metastatic sites composed of different spatial distributions of fibroblasts and drug-resistant cell populations. Our simulation highlights the importance of undetected metastatic lesions on adaptive therapy outcomes.

Effective dose window for containing tumor burden under tolerable level

“…It is worth noting that the effect of microenvironmental factors on the EDW discussed here applies to a tumor where microenvironmental factors are rather uniformly distributed. In a real tumor, however, tumor microenvironmental factors are heterogeneously distributed 49 – 53 , which drive diverse treatment outcomes observed 50 , 53 , 54 .…”

A survey of open questions in adaptive therapy: Bridging mathematics and clinical translation

“…Such models could more faithfully incorporate the tumor microenvironment and the role of normal cells. Such models could then evaluate how best to manage or exploit EMDR when designing adaptive therapy protocols ( M A et al, 2022 ). Even more might be gained by developing models that also recapitulate tissue homeostasis prior to carcinogenesis.…”

Agent-Based Modelling Reveals the Role of the Tumor Microenvironment on the Short-Term Success of Combination Temozolomide/Immune Checkpoint Blockade to Treat Glioblastoma

“…Many solid tumours exhibit significant inter/intratumor heterogeneity (Galon et al, 2006;Heindl et al, 2015), particularly in spatial distribution of cell types. The heterogeneous tumour microenvironment plays a significant role in determining cancer phenotypes by exerting selective pressure through a myriad of mechanisms (Yuan, 2016;Masud et al, 2022). With the advent of highly-multiplexed imaging technologies, including imaging mass cytometry (IMC), generating detailed information on the spatial configuration of the tumour became a reality (Chang et al, 2017;Elaldi et al, 2021).…”