A Study of OMP-305B83 in Subjects With Metastatic Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2235323 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:This a model from the article:
A mathematical model for IL-6-mediated, stem cell driven tumor growth and targeted treatment
Fereshteh Nazari, Alexander T. Pearson, Jacques Eduardo Nor, Trachette L. Jackson. PloS Computational Biology, 2018 Jan.
Abstract:
Targeting key regulators of the cancer stem cell phenotype to overcome their critical influence on tumor growth is a promising new strategy for cancer treatment. Here we present a modeling framework that operates at both the cellular and molecular levels, for investigating IL-6 mediated, cancer stem cell driven tumor growth and targeted treatment with anti-IL6 antibodies. Our immediate goal is to quantify the influence of IL-6 on cancer stem cell self-renewal and survival, and to characterize the subsequent impact on tumor growth dynamics. By including the molecular details of IL-6 binding, we are able to quantify the temporal changes in fractional occupancies of bound receptors and their influence on tumor volume. There is a strong correlation between the model output and experimental data for primary tumor xenografts. We also used the model to predict tumor response to administration of the humanized IL-6R monoclonal antibody, tocilizumab (TCZ), and we found that as little as 1mg/kg of TCZ administered weekly for 7 weeks is sufficient to result in tumor reduction and a sustained deceleration of tumor growth.
Author Summary:
A small population of cancer stem cells that share many of the biological characteristics of normal adult stem cells are believed to initiate and sustain tumor growth for a wide variety of malignancies. Growth and survival of these cancer stem cells is highly influenced by tumor micro-environmental factors and molecular signaling initiated by cytokines and growth factors. This work focuses on quantifying the influence of IL-6, a pleiotropic cytokine secreted by a variety of cell types, on cancer stem cell self-renewal and survival. We present a mathematical model for IL-6 mediated, cancer stem cell driven tumor growth that operates at the following levels: (1) the molecular level—capturing cell surface dynamics of receptor-ligand binding and receptor activation that lead to intra-cellular signal transduction cascades; and (2) the cellular level—describing tumor growth, cellular composition, and response to treatments targeted against IL-6.
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2019-10-02 | BIOMD0000000819 | BioModels
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Project description:Heterogeneity of endothelial cells that form the innermost layer of all vessels is critical for vascular sprouting and angiogenesis. After new vessels form, endothelial cell heterogeneity is believed to be gradually lost as vessels respond to flow-mediated signals, mature, remodel and become homeostatic. However, whether and at what level endothelial cell lost heterogeneity is poorly understood. Here we investigated heterogeneity change of endothelial cells under homeostatic laminar shear tress in comparison to static cultures.
2021-05-25 | GSE151867 | GEO
Project description:Co-stimulatory receptors such as GITR play key roles in regulating the effector functions of T cells. Agonistic anti-GITR antibodies have been investigated as a cancer immunotherapy with demonstrated efficacy in pre-clinical models. In human clinical trials, however, GITR agonist antibodies have shown limited therapeutic effect which may be due to a suboptimal receptor clustering-mediated signaling. To overcome this potential limitation, a rational protein engineering approach is needed to optimize GITR agonist-based immunotherapies. Here we show a novel bispecific molecule consisting of an anti-PD-1 antibody fused with a multimeric GITR ligand (anti-PD-1-GITR-L) that induces a PD-1-dependent and FcγR-independent GITR clustering, resulting in an enhanced activation, proliferation, and memory differentiation of primed antigen-specific GITR+PD-1+ T cells. The anti-PD-1-GITR-L bispecific is a PD-1 directed GITR-L construct that has a different mechanism of action (MoA) than the co-administration of anti-PD-1 plus GITR-L and demonstrated a dose-dependent immunologically driven tumor growth inhibition in syngeneic, genetically engineered and xenograft humanized mouse tumor models. Combination of anti-PD-1-GITR-L with TGFβ inhibition or chemotherapy (gemcitabine), respectively, resulted in tumor remission in immunogenically cold and checkpoint blockade resistant mouse models. Dose-dependent correlations between target saturation and Ki67 and TIGIT up-regulation on memory T cells have been observed following a single dose of anti-PD-1-GITR-L bispecific in mice and non-human primates. Anti-PD-1-GITR-L thus represents a novel bispecific approach for directing GITR agonism for cancer immunotherapy.
2021-12-20 | GSE189359 | GEO
Project description:Role of vascular normalization in benefit from metronomic chemotherapy.
Mpekris F1, Baish JW2, Stylianopoulos T3, Jain RK4.
Author information
Abstract
Metronomic dosing of chemotherapy-defined as frequent administration at lower doses-has been shown to be more efficacious than maximum tolerated dose treatment in preclinical studies, and is currently being tested in the clinic. Although multiple mechanisms of benefit from metronomic chemotherapy have been proposed, how these mechanisms are related to one another and which one is dominant for a given tumor-drug combination is not known. To this end, we have developed a mathematical model that incorporates various proposed mechanisms, and report here that improved function of tumor vessels is a key determinant of benefit from metronomic chemotherapy. In our analysis, we used multiple dosage schedules and incorporated interactions among cancer cells, stem-like cancer cells, immune cells, and the tumor vasculature. We found that metronomic chemotherapy induces functional normalization of tumor blood vessels, resulting in improved tumor perfusion. Improved perfusion alleviates hypoxia, which reprograms the immunosuppressive tumor microenvironment toward immunostimulation and improves drug delivery and therapeutic outcomes. Indeed, in our model, improved vessel function enhanced the delivery of oxygen and drugs, increased the number of effector immune cells, and decreased the number of regulatory T cells, which in turn killed a larger number of cancer cells, including cancer stem-like cells. Vessel function was further improved owing to decompression of intratumoral vessels as a result of increased killing of cancer cells, setting up a positive feedback loop. Our model enables evaluation of the relative importance of these mechanisms, and suggests guidelines for the optimal use of metronomic therapy.
KEYWORDS:
drug delivery; immune response; oxygenation; thrompospondin-1; tumor perfusion
2020-01-20 | MODEL2001200002 | BioModels
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2023-08-15 | GSE240489 | GEO
Project description:This study is intended to provide access to Romidepsin for participants who received Romidepsin in other trials sponsored by Gloucester Pharmaceuticals or Celgene Corporation and for participants whom the investigator feels may benefit from continuing treatment with Romidepsin.
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Project description:Recent progress in dissecting molecular mechanisms essential for the survival and propagation of cancer cells triggered rapid development of targeted therapies. Although many of these therapies produce impressive initial responses in tumor suppression, the onset of resistance is practically unavoidable. One of the main approaches for preventing this refractory condition relies on the development of effective combination therapies. Unfortunately, selection of optimal targets for combinatorial treatments is often confounded by limitations in our understanding of tumor biology. Here, we describe an unbiased comprehensive strategy that combines ex-vivo shRNA-based genome wide screening, proteomic profiling using BioID and patient tumor sequencing data analyses to overcome current challenges in identifying the best fit co-targeting agents. Integrating these strategies, we selected EGFR and EPHA2 receptors as molecules of choice for co-targeting in cancer cells, and generated a bispecific fully humanized anti-EGFR/EPHA2 antibody with druggable bioanalytical properties that very effectively suppresses tumor growth compared to its prototype therapeutic anti-EGFR antibody, cetuximab. Despite the overactivation of EGFR signaling in multiple malignancies, the therapeutic applicability of cetuximab is limited due to frequent resistance and could benefit from being used in a combination with another targeted compound. Our analysis indicates that EGFR and EPHA2 expression positively correlate in various cancer types and thus, are available for co-targeting in most tumors. Therefore, our work not only presents an efficient unbiased strategy for selecting optimal targets for combination therapies, but also describes a novel bispecific antibody, which has a high potential for being developed into a new clinically-relevant biologics effective in a broad variety of malignancies.
2023-01-27 | PXD023034 | Pride
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Project description:Comparison of liver developmental gene expression of human hepatic stem cells (HpSCs), human primary fetal liver cells (FLCs), human adult hepatocyte (AH) and HpSCs or FLC-derived humanized liver. 8 Samples were analyzed
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