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Role of LSD1 in Triple Negative Breast Cancer Development and Therapeutic Response

LSD1 在三阴性乳腺癌发展和治疗反应中的作用

基本信息

批准号：
10898981
负责人：
Yi Huang
金额：
$ 34.86万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10898981
关键词：
Ablation American Animal Model Antineoplastic Agents Automobile Driving Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast Cancer therapy CD8-Positive T-Lymphocytes Cancer Biology Cancer Etiology Cessation of life Chemoresistance Chemotherapy-Oncologic Procedure Clinical Combination Drug Therapy Complex DNA Data Development Drug usage Epigenetic Process Foundations Genetic Transcription Genetically Engineered Mouse HDAC5 gene Histones Hypermethylation Immunotherapy In Vitro KDM1A gene Knock-out Malignant Neoplasms Mediating Molecular Neoplasm Metastasis Oncogenic Oncoproteins Patient-derived xenograft models of breast cancer Patients Post-Translational Protein Processing Prognosis Protein Overexpression Proteins Recurrence Refractory Regimen Relapse Repression Repressor Proteins Resistance Resistance development Role T cell infiltration Therapeutic Effect Transcription Repressor Treatment Efficacy Tumor Immunity Tumor Suppression Tumor Suppressor Genes Woman anti-PD-1 anti-PD1 antibodies anti-PD1 therapy anti-tumor immune response breast cancer progression cancer clinical trial cancer stem cell cancer subtypes cancer therapy cancer type cell killing chemokine chemotherapeutic agent chemotherapy clinical efficacy clinically relevant demethylation effector T cell epigenetic silencing genetic corepressor histone demethylase histone modification immunogenic improved in vivo inhibitor insight malignant breast neoplasm mammary mouse model novel novel therapeutic intervention overexpression pre-clinical programmed cell death ligand 1 response restraint stem-like cell targeted agent targeted treatment therapeutic target therapy resistant tissue-factor-pathway inhibitor 2 trait treatment response triple-negative invasive breast carcinoma tumor tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Breast cancer (BC) is the most common cancer and the second leading cause of cancer death in American women. About 10-20% of breast cancers are triple-negative breast cancer (TNBC), which has a propensity to metastasize, recur, and develop resistance to chemotherapy. TNBC is the only subtype of BC for which there is no targeted therapy. Chemotherapies remain the mainstay of treatment for TNBC, but their clinical efficacy is often limited by resistance. Immunotherapy is emerging as an exciting new treatment option for TNBC patients. While TNBC is more likely to respond to immunotherapy, overall response rate is still low. Developing novel and more effective TNBC therapies is an unmet biomedical need as most of advanced TNBCs do not respond well to current therapies. Epigenetic alterations such as DNA hypermethylation and histone dysregulation have been associated with all stages of TNBC formation and progression. Lysine-specific demethylase 1 (LSD1) is the first identified histone demethylase which specifically demethylates H3K4me1/2. LSD1 is a key component of multiple transcription repressor complexes. Tumors in TNBC patients frequently express higher level of LSD1 compared to other BC groups. Clinically, LSD1 protein overexpression is significantly associated with worse prognosis in TNBC patients, making it an attractive therapeutic target. Our recent study has revealed a new mechanism driving LSD1 protein overexpression in TNBC through HDAC5-mediated posttranslational modification. Treatment with LSD1 inhibitors effectively suppresses tumor progression and sensitizes TNBC cells to chemotherapeutic agents. Furthermore, LSD1 ablation stimulates antitumor immunity and potentiates the efficacy of anti-PD-1 antibody in poorly immunogenic TNBC. LSD1 inhibition leads to reexpression of a key epigenetically silenced tumor suppressor gene, Tissue Factor Pathway Inhibitor 2 (TFPI2), which is required for tumor suppression and responsiveness to immunotherapy. Based on these findings, we hypothesize that LSD1 overexpression facilitates TNBC development and inhibition of LSD1 improves TNBC therapies by inducing TFPI2-mediated cell killing and antitumor immunity. Aim1. Determine the functional roles of LSD1 overexpression in TNBC development; Aim2. Evaluate the in vitro and in vivo therapeutic efficacy of LSD1 inhibition against TNBC; Aim3. Elucidate the immunogenic effects of LSD1 inhibition in TNBC. The results from the proposed studies are expected to provide new mechanistic insights and key preclinical evidence for using LSD1 inhibitors in TNBC. In the long run, these studies may lead to new and improved therapies for patients with relapsed and refractory TNBC.

项目总结/文摘