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

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：生殖系统癌症，就其本质而言，以性别二型的方式发生 并受到生殖激素和性类固醇反应失调的影响。的 雌激素对大多数乳腺癌病理生物学的贡献以及内分泌治疗的积极影响 对这种疾病的治疗效果已经很好了。然而， 患有各种非生殖性癌症的患者也表现出两性异形（例如肺癌， 黑色素瘤、胶质母细胞瘤和甲状腺癌）。而这些差异背后的机制是 复杂和多因素的，确定的促成因素是吸烟，阳光照射， 饮酒、饮食和职业环境。性的贡献被低估了 激素本身与非生殖性癌症的病理生物学有关。我们已经确定癌细胞 雌激素/雌激素受体-α（ER α）在免疫系统和大脑中的外在作用 几种不同癌症的动物模型中的肿瘤病理学。雌激素促进 免疫抑制性肿瘤微环境通过直接作用于髓样细胞导致衰减 T细胞活化/功能。然而，抑制脑中特定部位的ER作用具有矛盾的效果， 增加不同组织来源的肿瘤的生长。了解癌细胞的外在 ER的药理学将告知如何最好地使用现有的内分泌疗法，并对治疗方法具有指导意义 开发下一代调节剂，并能够开发新的药物组合， 治疗乳腺癌和妇科癌症以及其他生殖系统以外的癌症。 假设：ER调节剂对不同癌症的最大治疗功效将通过以下方式实现： 开发实现雌激素对癌细胞内在作用的强力抑制的干预， 对肿瘤中免疫细胞库/功能的有利作用，并且不干扰稳态反馈 调节影响肿瘤生物学过程表达的脑机制。 目的：（1）明确肿瘤相关髓系细胞中ER对肿瘤病理生物学的影响机制。 (2)定义脑中ER表达调节影响生长的过程的机制 肿瘤。(3)评价选择性靶向ER的肿瘤细胞外源性活性的治疗方法。 影响：乳腺癌和其他雌激素调节的癌症的内分泌疗法的有效性 由于集中于开发靶向ER/雌激素的癌细胞内在作用的药剂而受到限制。通过 定义ER调节免疫细胞功能的机制，以及它如何调节下丘脑 这些活动影响肿瘤生物学的外围，将有可能开发下一代ER调节剂 针对有利的癌细胞内在和外在作用进行优化。这样的治疗剂应该具有用于患者的效用。 ER阳性和阴性（生殖和非生殖）癌症的治疗。