Biology subjects

Kavousanakis, M.

Publications and source records attributed to Kavousanakis, M..

4 recordsLinked to original sources

bioRxiv2025

A Digital Twin to Optimize Treatment Efficacy of Targeted Alpha-particle Therapies by Antibody-Radioconjugate Cocktails Against Solid Tumors

Advanced solid tumors are incurable. Antibody-delivered targeted alpha-particle (-particle) radionuclide therapies (TAT) comprise a tumor-agnostic treatment type, due to the unparalleled killing efficacy of, and irradiation precision (4-5 cell lengths) by, -particles, as well as the selectivity in tumor cell targeting by antibody technologies. However, cells not being directly hit by -particles will likely not be killed. METHODSTo address the limited solid tumor penetration by highly specific and strongly binding antibody-radioconjugates, an experimentally informed digital twin, based on transport (diffusion/advection) first principles, was developed to describe an approach where a fraction of the administered (radio)activity is delivered by a separate type of a model -particle antibody-radioconjugate of low(er)/no affinity for the same marker. The latter was chosen because it can irradiate cells residing in the deep regions of solid tumors away from vasculature. RESULTSThe digital twin that was trained and validated on spheroids that were employed as surrogates of the avascular tumor regions, demonstrated that the investigated cocktails of antibody-radioconjugates with controlled affinities exhibited better inhibition of spheroid growth compared to the extent of growth inhibition by the high-affinity antibody-radioconjugate alone, for the same total (incubated) activity concentrations; this prediction was independent of spheroid size and/or level of expression of the targeted markers. CONCLUSIONThe findings of this study suggest that antibody-delivered TAT (that is already in the clinic) can be augmented by delivering a fraction of the same total activity by low(er) affinity antibody-radioconjugates. This combination of separate antibody-radioconjugates with variable affinities (for the same targeted marker) is a promising approach to possibly even more delay recurrence and further prolong survival of patients with advanced solid tumors.

bioengineering↗

bioRxiv2025

Spatio-temporal dynamics of M1 and M2 macrophages in a multiphase model of tumor growth

This study investigates the complex dynamics of vascular tumors and their interplay with macrophages, key agents of the innate immune response. We model the tumor microenvironment as a multiphase fluid, with each cellular population treated as a distinct, non-mixing phase. The framework also incorporates diffusible species that are critical for processes such as nutrient transport, angio-genesis, chemotaxis, and macrophage activation. Numerical simulations of our model show how phenotypic and spatial heterogeneity in the macrophage population arises and how such heterogeneity impacts a tumors growth dynamics. Finally, we propose an immunotherapeutic strategy based on the experimental agent vactosertib which promotes an anti-tumor macrophage phenotype. Our simulations demonstrate an increased density of anti-tumor macrophages over the period of a few months, followed by a relapse period where the tumor regains its original dynamics.

bioengineering↗

bioRxiv2024

Modeling of chemo-radiotherapy targeting growing vascular tumors: a continuum-level approach

The aim of this study is to demonstrate the enhanced efficiency of combined therapeutic strategies for the treatment of growing tumors, based on computational experiments of a continuous-level modeling framework. In particular, the tumor growth is simulated within a contaminated tissue and treated as a multiphase fluid of high viscosity, with each cellular species considered as a distinct fluid phase. Our model integrates the impact of chemical species on tumor dynamics, and we model -through reaction-diffusion equations- the spatio-temporal evolution of oxygen, vascular endothelial growth factor (VEGF) and chemotherapeutic agents. Simulations of a growing tumor exposed to external radiation showcase the rapid impact of radiotherapy on tumor suppression, however this effect diminishes over time. To enhance the therapeutic efficiency of radiotherapy, we investigate the combination of external radiation with the anti-VEGF drug bevacizumab and the cytotoxic drug docetaxel. Our simulations demonstrate that this synergistic approach integrates the immediate effectiveness of radiation therapy with the enduring tumor-suppressive capabilities of chemotherapy.

bioengineering↗

bioRxiv2024

Transport Cocktails for Cancer Therapeutics

Beyond biological cell heterogeneity, evidenced by different resistances to therapeutics, "delivery heterogeneity" crucially limits treatment efficacy for advanced solid tumors: variations in therapeutic drug delivery to different tumor areas (perivascular, perinecrotic) leading to nonuniform drug concentrations/doses and to unsuccessful treatment (cancer cell kill). Short-range (40-80 {micro}m), high energy (1-5 MeV) alpha-particles successfully address the biological heterogeneity: the double-strand DNA breaks they cause make them impervious to cell resistance mechanisms. Multiresponsive nanocarriers and/or engineered antibody-drug-conjugates are elegant approaches to delivering such alpha-particle emitters. Delivery heterogeneity, however, remains a challenge in established (i.e. large, vascularized) tumors. Remarkably, delivery properties enabling efficacy at the cell scale (targeting selectivity, affinity, cell drug uptake) may act against spatial delivery uniformity at the tumor scale (binding-site barrier effect1). We have previously demonstrated, in different mouse models, that spatial delivery uniformity, key to the effective killing of solid tumors, can be achieved utilizing combinations of different, distinct delivery carriers of the same emitter, but with different, complementary delivery properties, "leaving no cancer cell behind". We build first principles reaction-transport models (quantitatively informed by experiments) that explain the "geographically complementary" behaviors of such carrier cocktails, and help optimally design these cocktails and their delivery protocols.

cancer biology↗