Manipulating normal estrogen physiology as a therapeutic approach in cancer

操纵正常雌激素生理学作为癌症的治疗方法

• 批准号: 10561945
• 负责人: Donald P McDonnell
• 金额: $ 55.86万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-07 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561945
• 关键词: Activities of Daily Living; Alcohol consumption; Animal Model; Brain; Breast Cancer Treatment; Breast Cancer therapy; Cancer Model; Cell physiology; Cells; Complex; Data; Development; Diet; Disease; Effectiveness; Environment; Estradiol; Estrogen Receptor Modulators; Estrogen Receptor alpha; Estrogen Receptors; Estrogen Therapy; Estrogen receptor positive; Estrogens; Exhibits; Exposure to; Feedback; Glioblastoma; Gonadal Steroid Hormones; Hypothalamic structure; Immune; Immune Targeting; Immune system; Immunosuppression; Immunotherapy; Incidence; Interferon Type I; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant Reproductive System Neoplasm; Malignant neoplasm of lung; Malignant neoplasm of thyroid; Myeloid Cells; Nature; Neurons; Occupational; Outcome; Pathway interactions; Patient-Focused Outcomes; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiology; Population; Process; Proliferating; Receptor Signaling; Reproductive system; Secondary to; Signal Transduction; Smoking; Sun Exposure; T-Cell Activation; Therapeutic; Tissues; Treatment Efficacy; Tumor Biology; Tumor Immunity; Tumor Pathology; Tumor Promotion; Tumor-associated macrophages; antagonist; attenuation; cancer cell; cytokine; cytotoxicity; effector T cell; gender difference; hormone therapy; malignant breast neoplasm; melanoma; migration; neoplastic cell; next generation; novel drug combination; receptor expression; reproductive; reproductive hormone; response; sexual dimorphism; targeted agent; therapy development; tumor; tumor growth; tumor microenvironment; Activities of Daily Living; Alcohol consumption; Animal Model; Brain; Breast Cancer Treatment; Breast Cancer therapy; Cancer Model; Cell physiology; Cells; Complex; Data; Development; Diet; Disease; Effectiveness; Environment; Estradiol; Estrogen Receptor Modulators; Estrogen Receptor alpha; Estrogen Receptors; Estrogen Therapy; Estrogen receptor positive; Estrogens; Exhibits; Exposure to; Feedback; Glioblastoma; Gonadal Steroid Hormones; Hypothalamic structure; Immune; Immune Targeting; Immune system; Immunosuppression; Immunotherapy; Incidence; Interferon Type I; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant Reproductive System Neoplasm; Malignant neoplasm of lung; Malignant neoplasm of thyroid; Myeloid Cells; Nature; Neurons; Occupational; Outcome; Pathway interactions; Patient-Focused Outcomes; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiology; Population; Process; Proliferating; Receptor Signaling; Reproductive system; Secondary to; Signal Transduction; Smoking; Sun Exposure; T-Cell Activation; Therapeutic; Tissues; Treatment Efficacy; Tumor Biology; Tumor Immunity; Tumor Pathology; Tumor Promotion; Tumor-associated macrophages; antagonist; attenuation; cancer cell; cytokine; cytotoxicity; effector T cell; gender difference; hormone therapy; malignant breast neoplasm; melanoma; migration; neoplastic cell; next generation; novel drug combination; receptor expression; reproductive; reproductive hormone; response; sexual dimorphism; targeted agent; therapy development; tumor; tumor growth; tumor microenvironment

Background: Cancers of the reproductive system, by their very nature, occur in a sexually dimorphic manner and are influenced by exposure to reproductive hormones and dysregulated responses to sex steroids. The contributions of estrogens to the pathobiology of most breast cancers and the positive impact of endocrine therapies on outcome in this disease are well established. However, the incidence and long-term outcomes of patients with a variety of non-reproductive cancers also demonstrate sexual dimorphism (e.g. lung cancer, melanoma, glioblastoma and thyroid cancer). Whereas the mechanisms underlying these differences are complex and multifactorial, established contributing factors are gender differences in smoking, sun exposure, alcohol consumption, diet and occupational environments. Underappreciated are the contributions of sex hormones themselves to the pathobiology of non-reproductive cancers. We have determined that cancer cell extrinsic actions of estrogens/estrogen receptor-alpha (ERa) in the immune system and in the brain contribute to tumor pathology in animal models of several different cancers. Estrogens facilitate the development of an immune suppressive tumor microenvironment through direct actions on myeloid cells resulting in the attenuation of T cell activation/function. Inhibition of ER action in specific loci in the brain, however, has the paradoxical effect of increasing the growth of tumors from different tissues of origin. Understanding the cancer cell extrinsic pharmacology of ER will inform how best to use existing endocrine therapies, be instructive as to approaches to develop the next generation of modulators and enable the development of new drug combinations for the treatment of breast and gynecological cancers and other cancers originating outside of the reproductive system. Hypothesis: Maximal therapeutic efficacy of ER modulators for different cancers will be realized with the development of interventions that achieve robust inhibition of cancer cell intrinsic actions of estrogens, exhibit favorable effects on immune cell repertoire/function in tumors, and do not interfere with the homeostatic feedback mechanisms in the brain that modulate the expression of processes that impact tumor biology. Aims: (1) Define the mechanisms by which ER in tumor associated myeloid cells impacts tumor pathobiology. (2) Define the mechanism(s) by which ER expression in the brain regulates processes which impact the growth of tumors. (3) Evaluate therapeutic approaches to selectively target tumor cell extrinsic activities of ER. Impact: The effectiveness of endocrine therapies for breast cancer and other estrogen-modulated cancers has been limited by the focus on developing agents that target cancer cell intrinsic actions of ER/estrogens. By defining the mechanisms by which ER regulates immune cell function, and how it regulates hypothalamic activities that impact tumor biology in the periphery it will be possible to develop next generation ER modulators optimized for favorable cancer cell intrinsic and extrinsic actions. Such therapeutics should have utility for the treatment of ER-positive and -negative (reproductive and non-reproductive) cancers.

背景：生殖系统的癌症本质上以性二态性方式出现 并受到暴露于生殖激素和对性类固醇的反应失调的影响。这 雌激素对大多数乳腺癌病理生物学的贡献和内分泌的积极影响 对该疾病预后的疗法已经确定。但是， 各种非生殖癌的患者也表现出性二态性（例如，肺癌， 黑色素瘤，胶质母细胞瘤和甲状腺癌）。而这些差异的基础机制是 复杂而多因素，建立的促成因素是吸烟，阳光暴露的性别差异， 饮酒，饮食和职业环境。被低估的是性的贡献 激素本身是非生殖癌的病理生物学。我们已经确定癌细胞 免疫系统和大脑中雌激素/雌激素受体-Alpha（ERA）的外在作用 在几种不同癌症的动物模型中进行肿瘤病理学。雌激素有助于发展 免疫抑制性肿瘤微环境通过直接作用对髓样细胞的直接作用，导致衰减 T细胞激活/功能。但是，抑制大脑特定基因座的ER作用具有矛盾的效果 增加来自不同原始组织的肿瘤的生长。了解癌细胞外部 ER的药理学将告知如何最好地使用现有的内分泌疗法，对方法有启发性 开发下一代调节剂，并为开发新药组合 乳房和妇科癌症和其他起源于生殖系统之外的癌症的处理。 假设：ER调节剂对不同癌症的最大治疗功效将通过 发展雌激素癌细胞内在作用的干预措施的发展， 对肿瘤中免疫细胞库/功能的有利影响，并且不会干扰体内稳态反馈 大脑中调节影响肿瘤生物学的过程表达的机制。 目的：（1）定义与肿瘤相关的髓样细胞中ER影响肿瘤病理生物学的机制。 （2）定义了在大脑中ER表达调节过程的机制，从而影响生长 肿瘤。 （3）评估治疗方法，以选择性地靶向ER的肿瘤细胞外部活性。 影响：内分泌疗法对乳腺癌和其他雌激素调节癌的有效性具有 受到靶向ER/雌激素固有作用的开发剂的关注限制。经过 定义ER调节免疫细胞功能的机制，以及如何调节下丘脑 影响周围肿瘤生物学的活动，可以开发下一代ER调节剂 优化有利的癌细胞固有和外在作用。这种治疗剂应该具有实用性 ER阳性和阴性（生殖和非生殖）癌症的治疗。