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

项目总结/摘要 乳腺癌是美国最常见的恶性肿瘤，也是癌症死亡的第二大原因 妇女大约10-20%的乳腺癌是三阴性乳腺癌（TNBC），其具有在乳腺癌中转移的倾向。 转移、复发并对化疗产生耐药性。TNBC是BC的唯一亚型， 没有针对性治疗。化疗仍然是TNBC治疗的主要手段，但其临床疗效有待进一步研究。 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更有可能对免疫疗法产生反应，但总体反应率仍然很低。开发新的和 更有效的TNBC疗法是一种未满足的生物医学需求，因为大多数晚期TNBC反应不佳 目前的治疗方法。表观遗传学改变，如DNA超甲基化和组蛋白失调， 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（LSD 1）是第一个 鉴定了特异性地使H3 K4 me 1/2去甲基化的组蛋白去甲基化酶。LSD 1是多个 转录抑制因子复合物。TNBC患者的肿瘤通常表达更高水平的LSD 1， 其他BC组。临床上，LSD 1蛋白过表达与恶性肿瘤的预后不良显著相关。 TNBC患者，使其成为一个有吸引力的治疗目标。我们最近的研究揭示了一种新的机制 通过HDAC 5介导的翻译后修饰驱动TNBC中的LSD 1蛋白过表达。 用LSD 1抑制剂治疗有效地抑制肿瘤进展并使TNBC细胞对以下物质敏感： 化疗剂。此外，LSD 1消融刺激抗肿瘤免疫并增强免疫原性。 抗PD-1抗体在免疫原性较差的TNBC中的功效。LSD 1抑制导致一个关键的重新表达 表观遗传学沉默的肿瘤抑制基因，组织因子途径抑制剂2（TFPI 2），这是必需的， 肿瘤抑制和对免疫疗法的反应性。基于这些发现，我们假设LSD 1 过表达促进TNBC发展，并且LSD 1的抑制通过诱导TNBC的生长而改善TNBC疗法。 TFPI 2介导的细胞杀伤和抗肿瘤免疫。目标1.确定LSD 1的功能角色 TNBC发展中的过表达; Aim 2.评价LSD 1的体外和体内治疗功效 对TNBC的抑制; Aim 3.阐明LSD 1抑制在TNBC中的免疫原性作用。的结果 这些研究有望为使用这些药物提供新的机制见解和关键的临床前证据。 TNBC中的LSD 1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治疗方法。 复发性和难治性三阴乳腺癌

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.