scholarly journals Mathematical Modeling Shows That the Response of a Solid Tumor to Antiangiogenic Therapy Depends on the Type of Growth

Mathematics ◽  
2020 ◽  
Vol 8 (5) ◽  
pp. 760 ◽  
Author(s):  
Maxim Kuznetsov
Keyword(s):  
Mathematical Modeling ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Antiangiogenic Therapy ◽  
Convective Motion ◽  
Growth Speed ◽  
Necrotic Tissue ◽  
Intrinsic Resistance ◽  
Growth Type ◽  
Additive Character

It has been hypothesized that solid tumors with invasive type of growth should possess intrinsic resistance to antiangiogenic therapy, which is aimed at cessation of the formation of new blood vessels and subsequent shortage of nutrient inflow to the tumor. In order to investigate this effect, a continuous mathematical model of tumor growth is developed, which considers variables of tumor cells, necrotic tissue, capillaries, and glucose as the crucial nutrient. The model accounts for the intrinsic motility of tumor cells and for the convective motion, arising due to their proliferation, thus allowing considering two types of tumor growth—invasive and compact—as well as their combination. Analytical estimations of tumor growth speed are obtained for compact and invasive tumors. They suggest that antiangiogenic therapy may provide a several times decrease of compact tumor growth speed, but the decrease of growth speed for invasive tumors should be only modest. These estimations are confirmed by numerical simulations, which further allow evaluating the effect of antiangiogenic therapy on tumors with mixed growth type and highlight the non-additive character of the two types of growth.

scholarly journals Simulations on the efficacy of radiotherapy with different time schemes of antiangiogenic therapy

2021 ◽  
Author(s):  
Mert Tuzer ◽  
Defne Yilmaz ◽  
Mehmet Burcin Unlu
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Antiangiogenic Therapy ◽  
Growth Control ◽  
Antiangiogenic Agents ◽  
Mathematical Framework ◽  
Antiangiogenic Treatment ◽  
Linear Partial Differential Equations ◽  
Radiotherapy Alone ◽  
Antiangiogenic Drug

The combination of radiotherapy and antiangiogenic agents has been suggested to be potent in tumor growth control compared to the application of antiangiogenic therapy or radiotherapy alone. Since radiotherapy is highly dependent on the oxygen level of the tumor area, antiangiogenic agents are utilized for the reoxygenation of tumor vasculature. We present a mathematical framework to investigate the efficacy of radiotherapy combined with antiangiogenic treatment. The framework consists of tumor cells, vasculature, and oxygenation levels evolving with time to mimic a tumor microenvironment. Non-linear partial differential equations (PDEs) are employed to simulate each component of the framework. Different treatment schemes are investigated to see the changes in tumor growth and oxygenation. To test combination schedules, radiation monotherapy, neoadjuvant, adjuvant, and concurrent cases are simulated. The efficiency of each therapy scheme on tumor growth control, the changes in tumor cell density, and oxygen levels shared by tumor cells are represented. The simulation results indicate that the application of radiotherapy after antiangiogenic treatment is more efficient in tumor growth control compared to other therapy schemes. The present study gives an insight into the possible interaction and timing of the combination of radiotherapy and antiangiogenic drug treatment.

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

ANTITUMOR EFFECT OF COLLOIDAL SILVER BISILICATE IN EXPERIMENTAL IN VITRO AND IN VIVO STUDIES

2019 ◽  
Vol 65 (5) ◽  
pp. 760-765
Author(s):  
Margarita Tyndyk ◽  
Irina Popovich ◽  
A. Malek ◽  
R. Samsonov ◽  
N. Germanov ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Human Tumor ◽  
Significant Inhibition ◽  
In Vivo Studies ◽  
Ehrlich Carcinoma ◽  
In Vivo Experiments

The paper presents the results of the research on the antitumor activity of a new drug - atomic clusters of silver (ACS), the colloidal solution of nanostructured silver bisilicate Ag6Si2O7 with particles size of 1-2 nm in deionized water. In vitro studies to evaluate the effect of various ACS concentrations in human tumor cells cultures (breast cancer, colon carcinoma and prostate cancer) were conducted. The highest antitumor activity of ACS was observed in dilutions from 2.7 mg/l to 5.1 mg/l, resulting in the death of tumor cells in all studied cell cultures. In vivo experiments on transplanted Ehrlich carcinoma model in mice consuming 0.75 mg/kg ACS with drinking water revealed significant inhibition of tumor growth since the 14th day of experiment (maximally by 52% on the 28th day, p < 0.05) in comparison with control. Subcutaneous injections of 2.5 mg/kg ACS inhibited Ehrlich's tumor growth on the 7th and 10th days of the experiment (p < 0.05) as compared to control.

scholarly journals Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1102
Author(s):  
Alexander E. Kabakov ◽  
Anna O. Yakimova
Keyword(s):  
Heat Shock ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Liver Tumors ◽  
Oxygen Deficiency ◽  
Transarterial Embolization ◽  
Antiangiogenic Therapy ◽  
Adaptation To Hypoxia ◽  
Mesenchymal Transition

Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. Both the lack of oxygen by itself and the hypoxia-responsive phenotypic modulations render tumor cells more radioresistant, so that hypoxic tumors are a serious challenge for radiotherapy. An understanding of causes of the radioresistance of hypoxic tumors would help to develop novel ways for overcoming this challenge. Molecular targets for and various approaches to radiosensitizing hypoxic tumors are considered in the present review. It is here analyzed how the hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, heat shock proteins, glucose-regulated proteins, epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial–mesenchymal transition and exosome generation contribute to the radioresistance of hypoxic tumors or may be inhibited for attenuating this radioresistance. The pretreatments with a multitarget inhibition of the cancer cell adaptation to hypoxia seem to be a promising approach to sensitizing hypoxic carcinomas, gliomas, lymphomas, sarcomas to radiotherapy and, also, liver tumors to radioembolization.

Efficacy of DAN-222, a novel investigational polymeric nanoparticle with topoisomerase I inhibitor, as monotherapy in breast cancer models and when combined with PARP inhibitor.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1081-1081
Author(s):  
Ashley P Wright ◽  
Jodi D Bradley ◽  
Timothy Hagerty ◽  
Emily A Wyatt
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Topoisomerase I ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Topoisomerase I Inhibitor ◽  
Polymeric Nanoparticle ◽  
Cancer Tumor

1081 Background: Patients with BRCA-positive HER2-negative breast cancer benefit from PARP inhibitor therapy, but additional benefit is still desired. PARP inhibition alone does not prevent all mechanisms for repairing damage to DNA such as homologous recombination repair. An attractive combination for treating such patients would be combining a topoisomerase I inhibitor with a PARP inhibitor given the dual mechanism this would provide for DNA damage and inhibited repair, leading to tumor cell death. This combination has been tried in multiple phase 1 studies, but myelotoxicity prevented the combination from being evaluated further. DAN-222 is a novel investigational polymeric nanoparticle conjugated with camptothecin, a topoisomerase I inhibitor, that provides significant accumulation of drug in tumor tissues via the enhanced permeability and retention (EPR) effect and significantly reduced bone marrow exposure compared to native chemotherapy. These observations underscore the potential advantages of DAN-222 alone as well as in combination with other agents such as PARP inhibitors in solid tumors. Here, we report the effects of DAN-222 monotherapy and in combination with a PARP inhibitor on the growth inhibition in an HRD+ TNBC breast cancer (MDA-MB-436) and an HRD- ovarian (OVCAR3) xenograft mouse model. Methods: HRD+ breast cancer tumor cells (MDA-MB-436) were implanted into female NCr nu/nu mice and HRD- ovarian cancer tumor cells (OVCAR3) were implanted into female CB.17 SCID mice. Mice were randomized to vehicle or treatment arms until tumors reached 2000 mm3 or day 45 (MDA-MB-436) or 1000mm3 or day 45 (OVCAR3). The groups evaluated include multiple dose levels of DAN-222 as monotherapy and those also combined with niraparib. Results: Results were consistent in both the HRD+ and HRD- tumor models with profound dose-response of DAN-222 monotherapy inhibiting tumor growth. Additionally, synergy was demonstrated when DAN-222 was combined with niraparib, clearly evident with low doses of both products when used in combination. The table below highlights the synergy of the combination of DAN-222 at 0.3 mg/kg and niraparib at 25 mg/kg above each agent alone on the tumor growth inhibition in the MDA-MB-436 xenograft. Conclusions: Combining a PARP inhibitor with a topoisomerase I inhibitor delivered via this polymeric nanoparticle delivery system (DAN-222) has synergistic efficacy in both HRD+ and HRD- xenograft tumor models. These data support continued development of DAN-222 to treat solid tumors and its combination use with PARP inhibitors.[Table: see text]

TIGIT Induces (CD3+) T Cell Dysfunction by Inhibiting Glucose Metabolism and its Reversal by TIGIT and/or PD-1 Blockade in Colorectal Cancer

2021 ◽  
Author(s):  
qi shao ◽  
Lei Wang ◽  
maoling yuan ◽  
Xiaohong Jin ◽  
changping wu
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Peripheral Blood ◽  
Cancer Tissue ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Abstract Background: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immunosuppressive receptor expressed on the surface of immune cells, suppressing immune responses by activating the intracellular negative regulatory signals. TIGIT plays an important role in the pathogenesis of various tumors, but its immune escape in colorectal cancer remains unclear.Methods: In this study, TIGIT expression in the peripheral blood and tissue microarrays was detected flow cytometry and immunofluorescence and its relationship with prognosis was evaluated. The proliferation and cytokines of TIGIT+ T cells were measured. Glucose metabolism and key enzymes were detected by qPCR or western blot. After establishing the co-cultured system and xenotransplant models, TIGIT antibody alone or combined with PD-1 antibody was blocked to observe the tumor growth.Results: We found that the proportion of CD3+TIGIT+ T cells was increased in peripheral blood and cancer tissue in colorectal cancer patients when compared with the healthy donors. These cells exhibited functional defects, low proliferative activity, impaired cytokine production and reduced glucose metabolism. A strong association was also observed between the elevated TIGIT expression and poor prognosis. In the in vitro co-culture assays of T cells and tumor cells, the suppressed glucose metabolic activity of T cells was reversed by TIGIT blockade. In addition, this blockade induced the apoptosis and reduced G2/M transit in tumor cells. The antitumor efficacy of TIGIT Ab therapy was further demonstrated in a human colorectal xenograft mice model while co-blockers of TIGIT and PD-1 exhibited synergistic suppressing effects on tumor growth.Conclusions: It is suggest that while TIGIT induces CD3+ T cell dysfunction in colorectal cancer, co-targeting TIGIT and PD-1 can lead to an effective antitumor response and may serve as a novel therapeutic strategy for colorectal patients.

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