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DePillis2003 - The dynamics of an optimally controlled tumor model: A case study

ABSTRACT: The dynamics of an optimally controlled tumor model: A case study L.GDe Pillisab ARadunskayaa https://doi.org/10.1016/S0895-7177(03)00133-X Abstract We present a phase-space analysis of a mathematical model of tumor growth with an immune response and chemotherapy. We prove that all orbits are bounded and must converge to one of several possible equilibrium points. Therefore, the long-term behavior of an orbit is classified according to the basin of attraction in which it starts. The addition of a drug term to the system can move the solution trajectory into a desirable basin of attraction. We show that the solutions of the model with a time-varying drug term approach the solutions of the system without the drug once traatment has stopped. We present numerical experiments in which optimal control therapy is able to drive the system into a desirable basin of attraction, whereas traditional pulsed chemotherapy is not.

SUBMITTER: Mohammad Umer Sharif Shohan

PROVIDER: BIOMD0000000909 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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			Action	DRS
	BIOMD0000000909?filename=curation_image.png	Other
	BIOMD0000000909?filename=curation_notes.txt	Txt
	BIOMD0000000909?filename=dePillis2003-biopax2.owl	Owl
	BIOMD0000000909?filename=dePillis2003-biopax3.owl	Owl
	BIOMD0000000909?filename=dePillis2003-matlab.m	Other

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Project description:An alternative or follow-up adjunct to conventional maximum tolerated dose (MTD) chemotherapy now in advanced phase III clinical trial assessment is metronomic chemotherapy?the close regular administration of low doses of drug with no prolonged breaks. A number of preclinical studies have shown metronomic chemotherapy can cause long term survival of mice with advanced cancer, including metastatic disease, in the absence of overt toxicity, especially when combined with targeted antiangiogenic drugs. However, similar to MTD chemotherapy acquired resistance eventually develops, the basis of which is unknown. Using a preclinical model of advanced human ovarian (SKOV-3-13) cancer in SCID mice, we show that acquired resistance can develop after terminating prolonged (over 3 months) successful therapy utilizing daily oral metronomic topotecan plus pazopanib, an oral antiangiogenic tyrosine kinase inhibitor (TKI). Two resistant sublines were isolated from a single mouse, one from a solid tumor (called KH092-7SD, referred to as 7SD) and another from ascites tumor cells (called KH092-7AS, referred to as 7AS). Using these sublines we show acquired resistance to the combination treatment is due to tumor cell alterations that confer relative refractoriness to topotecan. The resistant phenotype is heritable, associated with reduced cellular uptake of topotecan and could not be reversed by switching to MTD topotecan or to another topoisomerase-1 inhibitor, CPT-11, given either in a metronomic or MTD manner nor switching to another antiangiogenic drug, e.g. the anti-VEGFR-2 antibody, DC101, or another TKI, sunitinib. Thus, in this case cross resistance seems to exist between MTD and metronomic topotecan, the basis of which is unknown. However, gene expression profiling revealed several potential genes that are stably upregulated in the resistant lines, that previously have been implicated in resistance to various chemotherapy drugs, and which, therefore, may contribute to the drug resistant phenotype. Two-condition experiment, ovarian cell line (SKOV-3-13) sensitive to daily oral metronomic topotecan plus pazopaniband treatemnt compared to two in- vivo selected resistant sublines from a solid tumor (called KH092-7SD) and another from ascites tumor cells (called KH092-7AS). Biological replicates: 4 independently grown and harvested cell line passages. Two technical replicate per condition (including dye swap).

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DePillis2003 - The dynamics of an optimally controlled tumor model: A case study

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