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Impact of local and systemic cellular senescence toward Triple Negative Breast Cancer growth and drug therapy

局部和全身细胞衰老对三阴性乳腺癌生长和药物治疗的影响

基本信息

批准号：
10651820
负责人：
Irfan Khan
金额：
$ 5.27万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10651820
关键词：
AP20187 Affect Aging Apoptosis Bone Marrow Cells Bone Marrow Transplantation Breast Cancer Cell Breast Cancer Treatment CASP8 gene CDKN2A gene Cause of Death Cell Aging Cell Cycle Cell Cycle Arrest Cells Chronic Clinical Trials DNA cassette Dasatinib Data Defense Mechanisms Embryonic Development Engineering Environment Exposure to Extracellular Matrix Proteins Goals Grant Growth Growth Factor Homeostasis Immune Immune checkpoint inhibitor Immune system Implant Injections Invaded Knowledge Length Malignant Neoplasms Messenger RNA Modeling Monitor Mus Names Neoplasm Metastasis Organ Organism Outcome Pathway interactions Peptide Hydrolases Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Play Population Process Proliferating Protein Analysis Proteins Quercetin Recurrence Risk Role Set protein Specimen Spleen Stress System Tail Testing Therapeutic Tissues Tumor Suppression Tumor Tissue Veins anti-PD-1 breast cancer progression cancer therapy cell injury cell type checkpoint inhibition cytokine effective therapy efficacious treatment efficacy evaluation experimental study fitness immunosenescence in vivo in vivo Model insight intraperitoneal malignant breast neoplasm mouse model novel strategies pharmacologic prevent prognostic recruit senescence suicide gene transcriptome sequencing treatment strategy triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumor progression tumorigenesis wound healing

项目摘要

ABSTRACT Triple negative breast cancer is considered one of the most aggressive forms of breast cancer and efficacious treatment options are lacking. A potential therapeutic avenue is related to senescent cells. Cellular senescence engages in important roles for many aspects of tissue homeostasis. As the natural process of aging occurs along with stresses and insults from the environment, cells in various organs and tissues of the body can undergo senescence, a phase of arrested growth and exit from the cell cycle that is established in order to prevent further propagation of damaged cells. A defining feature of senescent cells is their senescence- associated secretory phenotype (SASP), a group of cytokines, proteases, and growth factors, which are thought to recruit cells of the immune system to clear out damaged cells. Length of exposure to the SASP impacts what happens to the microenvironment. During embryonic development, wound healing, suppression of tumor growth, and recruitment of immune cells, short-lived, reversible senescence of defined cell populations and the resultant SASP promote optimal fitness for the organism. On the other hand, when senescent cells are present chronically, the SASP can have more negative effects, which include promoting an environment for tumorigenesis and metastasis. In terms of TNBC, no known studies have been carried out that assess how senescence and the SASP impact TNBC progression. In my preliminary studies, I have utilized the ATTAC mouse model (=Apoptosis through Activated Caspase 8). In this model, senescent cells express a drug-inducible suicide gene cassette under the control of p16Ink4a regulatory sequences. When given an inducing drug, AP20187, senescent cells expressing p16ink4a are eliminated by apoptosis. Thus, the first aim of my grant is to assess the effect of local and systemic senescent cells on growth and metastasis of the syngeneic TNBC cells in the ATTAC mice as hosts. The preliminary data suggest that continuous clearance of host senescent cells results in reduced tumor growth. Based on this, under a second aim I wish to analyze the impact that senolytics (drugs that eliminate senescent cells) have on the efficacy of cancer therapeutics (i.e. immune checkpoint inhibitors) towards TNBC. No known studies have yet been done that look at the relationship between immune checkpoint inhibitors and senescence towards TNBC. Thus, completion of these aims will provide not only insight on how TNBC growth is affected by both the microenvironment and the system as a whole, but also the possibility of discovering unique pharmacological targets for more effective TNBC treatments.

摘要