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

• 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
• 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

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.

项目概要/摘要 乳腺癌 (BC) 是美国人最常见的癌症，也是癌症死亡的第二大原因 女性。大约 10-20% 的乳腺癌是三阴性乳腺癌 (TNBC)，这种乳腺癌有发生转移的倾向。 转移、复发并对化疗产生耐药性。 TNBC 是 BC 中唯一存在的亚型 没有针对性治疗。化疗仍然是 TNBC 的主要治疗方法，但其临床疗效 常常受到阻力的限制。免疫疗法正在成为 TNBC 患者令人兴奋的新治疗选择。 虽然 TNBC 更有可能对免疫治疗产生反应，但总体反应率仍然较低。开发新颖且 更有效的 TNBC 疗法是一个未满足的生物医学需求，因为大多数晚期 TNBC 反应不佳 到目前的治疗方法。 DNA 高甲基化和组蛋白失调等表观遗传改变已被 与 TNBC 形成和进展的所有阶段相关。赖氨酸特异性脱甲基酶 1 (LSD1) 是第一个 鉴定出特异性去甲基化 H3K4me1/2 的组蛋白去甲基化酶。 LSD1是多种药物的关键组成部分 转录抑制复合物。 TNBC 患者的肿瘤经常表达较高水平的 LSD1 到其他 BC 团体。临床上，LSD1蛋白过度表达与预后较差显着相关。 TNBC 患者，使其成为有吸引力的治疗目标。我们最近的研究揭示了一种新机制 通过 HDAC5 介导的翻译后修饰驱动 LSD1 蛋白在 TNBC 中过度表达。 LSD1 抑制剂治疗可有效抑制肿瘤进展并使 TNBC 细胞对 化疗剂。此外，LSD1 消除可刺激抗肿瘤免疫并增强 抗 PD-1 抗体在免疫原性差的 TNBC 中的疗效。 LSD1 抑制导致关键的重新表达 表观遗传沉默的肿瘤抑制基因，组织因子途径抑制剂 2 (TFPI2)，这是 肿瘤抑制和对免疫治疗的反应。基于这些发现，我们假设 LSD1 过表达促进 TNBC 发展，LSD1 的抑制通过诱导 TNBC 改善 TNBC 治疗 TFPI2 介导的细胞杀伤和抗肿瘤免疫。目标1。确定 LSD1 的功能作用 TNBC 发展中的过度表达；目标2。评估LSD1的体外和体内治疗效果 对TNBC的抑制作用；目标3。阐明 LSD1 抑制对 TNBC 的免疫原性作用。结果来自 拟议的研究预计将为使用提供新的机制见解和关键的临床前证据 TNBC 中的 LSD1 抑制剂。从长远来看，这些研究可能会为患者带来新的和改进的疗法 患有复发性和难治性 TNBC。