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Mathematical modeling of BCG-based bladder cancer treatment using socio-demographics.

ABSTRACT: Cancer is one of the most widespread diseases around the world with millions of new patients each year. Bladder cancer is one of the most prevalent types of cancer affecting all individuals alike with no obvious "prototypical patient". The current standard treatment for BC follows a routine weekly Bacillus Calmette-Guérin (BCG) immunotherapy-based therapy protocol which is applied to all patients alike. The clinical outcomes associated with BCG treatment vary significantly among patients due to the biological and clinical complexity of the interaction between the immune system, treatments, and cancer cells. In this study, we take advantage of the patient's socio-demographics to offer a personalized mathematical model that describes the clinical dynamics associated with BCG-based treatment. To this end, we adopt a well-established BCG treatment model and integrate a machine learning component to temporally adjust and reconfigure key parameters within the model thus promoting its personalization. Using real clinical data, we show that our personalized model favorably compares with the original one in predicting the number of cancer cells at the end of the treatment, with [Formula: see text] improvement, on average.

SUBMITTER: Savchenko E

PROVIDER: S-EPMC10618543 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Mathematical modeling of BCG-based bladder cancer treatment using socio-demographics.

Savchenko Elizaveta E Rosenfeld Ariel A Bunimovich-Mendrazitsky Svetlana S

Scientific reports 20231031 1

Cancer is one of the most widespread diseases around the world with millions of new patients each year. Bladder cancer is one of the most prevalent types of cancer affecting all individuals alike with no obvious "prototypical patient". The current standard treatment for BC follows a routine weekly Bacillus Calmette-Guérin (BCG) immunotherapy-based therapy protocol which is applied to all patients alike. The clinical outcomes associated with BCG treatment vary significantly among patients due to ...[more]

PMID: 37907551

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Project description:BackgroundBacillus Calmette-Guérin (BCG) is the primary method of postoperative perfusion treatment for bladder cancer. The myeloid cell leukemia gene-1 (Mcl-1) is closely associated with the development of malignant tumors. Previous research by our group has demonstrated that downregulating Mcl-1 using shRNA can enhance the efficacy of BCG treatment in bladder cancer. This study aims to investigate the impact of Mcl-1 downregulation in combination with BCG treatment on bladder cancer, macrophage polarization, and the underlying mechanism of action, with the goal of reducing recurrence and metastasis in bladder cancer.MethodsThe GSE190529 dataset was analyzed to identify differential genes for enrichment analysis. The WGCNA algorithm was then employed to pinpoint gene modules closely associated with the Mcl-1 gene. The overlapping genes between these modules and the differentially expressed genes were subjected to enrichment analysis in GO and KEGG pathways to unveil crucial signaling pathways. In vitro experiments involved the co-culture of Raw264.7 macrophages and MB49 to establish a tumor microenvironment model, while in vivo experiments utilized an MNU-induced rat bladder cancer model. Various methods including Enzyme-Linked Immunosorbent Assay (ELISA), Western blot, immunofluorescence, HE staining, etc. were utilized to assess macrophage polarization and the expression of proteins linked to the ASK1/MKK7/JNK/cJUN signaling pathway.ResultsBioinformatics analysis indicates that the therapeutic mechanism of Mcl-1 in BCG treatment for bladder cancer may be linked to the Mitogen-Activated Protein Kinase (MAPK) signaling pathway. Both in vivo and in vitro experiments have demonstrated that the combination of BCG treatment and Mcl-1shRNA intervention results in elevated expression of M1 markers (TNF-α, CD86, INOS) and reduced expression of M2 markers (IL-10, CD206, Arg-1). Moreover, there was a notable increase in protein levels of P-ASK1, P-MKK7, P-JNK, P-cJUN, and CX43, leading to a significant rise in the apoptosis rate of bladder cancer cells and diminished proliferation, migration, and invasion capabilities. The expression of these markers can be reversed by employing the JNK signaling pathway inhibitor SP600125.ConclusionDown-regulation of Mcl-1 promotes the polarization of macrophages towards the M1 type through activation of the ASK1/MKK7/JNK signaling pathway. This enhances intercellular communication and improves the efficacy of BCG in bladder cancer treatment.

Dataset Information

Mathematical modeling of BCG-based bladder cancer treatment using socio-demographics.

Publications

Mathematical modeling of BCG-based bladder cancer treatment using socio-demographics.

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