Experimentally-driven mathematical modeling to improve combination targeted and cytotoxic therapy for HER2+ breast cancer

Abstract

The goal of this study is to experimentally and computationally investigate combination trastuzumab-paclitaxel therapies and identify potential synergistic effects due to sequencing of the therapies with in vitro imaging and mathematical modeling. Longitudinal alterations in cell confluence are reported for an in vitro model of BT474 HER2+ breast cancer cells following various dosages and timings of paclitaxel and trastuzumab combination regimens. Results of combination drug regimens are evaluated for drug interaction relationships based on order, timing, and quantity of dose of the drugs. Altering the order of treatments, with the same total therapeutic dose, provided significant changes in overall cell confluence (p < 0.001). Two mathematical models are introduced that are constrained by the in vitro data to simulate the tumor cell response to the individual therapies. A collective model merging the two individual drug response models was designed to investigate the potential mechanisms of synergy for paclitaxel-trastuzumab combinations. This collective model shows increased synergy for regimens where trastuzumab is administered prior to paclitaxel and suggests trastuzumab accelerates the cytotoxic effects of paclitaxel. The synergy derived from the model is found to be in agreement with the combination index, where both indicate a spectrum of additive and synergistic interactions between the two drugs dependent on their dose order. The combined in vitro results and development of a mathematical model of drug synergy has potential to evaluate and improve standard-of-care combination therapies in cancer.

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

“…Specifically, HER2 overexpression is linked to shorter G 1 -phase and consequently early S-phase entry during cell cycle. Similarly, other types of biological information such as the number and type of antibody binding sites on HER2 receptors, target specificity of antibodies, and efficacy in releasing single or multiple drug conjugates to the site are important while quantifying the ADCC of an antibody-drug conjugate (ADC) [54,55]. These drug/receptor-specific details are used while devising related mathematical models as shown later in Section 4 of this paper.…”

“…A similar theoretical analysis can be done for the use of anti-HER2 drugs for HER2 + BC. Even though there are mathematical models related to the use of trastuzumab and T-DM1 for HER2 + BC [55,[68][69][70][71], similar models related to lapatinib, pertuzumab, and neratinib are yet to be reported.…”

“…In another study, heterogeneous cell lines (MDA-MB-468, SUM149PT, MDA-MB-231, and MDA-MB-453) were used to quantify the cellular uptake and treatment response to doxorubicin related to TNBC [26]. In vitro experiments used to develop mathematical models of BC are reported in [1,26,55]. Compared to in vitro models which are based on certain BC cell lines, experimental mice models (in vivo) are used more frequently to estimate parameter values of mathematical models [71,155].…”

“…Another interesting study used a histological data-based mathematical model from a clinical trial (48 patients) to predict the response of BC patients to neoadjuvant chemotherapy [37]. In this study, the authors showed that it is possible to evaluate the treatment outcome of patients using the analysis of the parameters First of all, both in vivo and in vitro models were used to derive mathematical models of breast cancer (Figure 1) [1,26,50,55,155]. For instance, in [1], experimental evidence on the growth of the MCF-7 cell line, intercellular interaction between tumor cells, and interaction with the immune cells (natural killer (NK) cells, cytotoxic T-lymphocytes (CTLs), white blood cells (WBCs)) and estradiol (estrogen) was used to develop a mathematical model.…”

“…In the case of combination therapies, apart from predicting effective drug combinations, mathematical models can be used to determine effective order of drug administration. In [55,178], the authors investigated the influence of the order of drug administration on treatment outcomes when multiple drugs are used to treat BC. Some mathematical models specifically portray mechanisms related to the HER2 + BC subtype [55,70,71].…”