PO.EN01.01 · 内分泌肿瘤

新设计的选择性雌激素受体下调剂及其在乳腺恶性肿瘤微环境和造血中的作用

Newly-designed selective estrogen receptor downregulators and their role in the tumor microenvironment and hematopoiesis in breast malignancies

编号 2289 展板 11 时间 4/20 09:00–12:00 区域 Section 34 主讲 Diana Marquez Garban, MD

分会场 Hormone Receptor Signaling and Therapeutic Targeting

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作者与单位 Authors & Affiliations

Mario Morales Martinez¹, Javier Mansilla², Eduardo Mauricio Gonzalez¹, Begoña Comin-Anduix¹, Marisol Chavez¹, Brian Aguirre³, Julia Aguade Gorgorio⁴, Gang Deng², Nalo M. Hamilton⁵, Hannah Mikkola⁴, Madhuri Wadehra³, Michael E. Jung², Richard J. Pietras¹, Diana C. Marquez Garban¹

¹Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA,²Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA,³Pathology and Laboratory Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA,⁴Molecular, Cell and Developmental Biology, UCLA, Los Angeles, CA,⁵UCLA School of Nursing, Los Angeles, CA

摘要 Abstract

中文摘要

表达雌激素受体α（ERalpha）的乳腺癌（BC）占美国新诊断患者的70%。以抗雌激素药物或芳香化酶抑制剂进行的内分泌治疗，无论单独使用还是与CDK 4/6抑制剂联合使用，都是表达ERalpha的BC的重要干预手段，并且仍是最有效的靶向治疗策略之一。然而，许多局限性BC患者以及几乎所有晚期BC患者最终都会对现有内分泌治疗方案产生耐药。相比之下，免疫治疗正在改变许多癌症的治疗格局。然而，除少数三阴性乳腺癌（TNBC）外，大多数乳腺癌对这一有前景的免疫治疗方法耐药。目前已描述了多种免疫耐药机制。值得注意的是，据报道BC驱动骨髓中造血干细胞和祖细胞的扩增与分化，使造血偏向免疫抑制性髓系谱系。乳腺恶性肿瘤中髓系生成的这种失调导致免疫抑制性和促肿瘤髓系亚群（如髓源性抑制细胞，MDSC）的异常扩增。与FDA批准的SERD氟维司群（Fulvestrant）和依拉司群（Elacestrant）相比，我们新设计的选择性雌激素受体下调剂JD128（SERD），无论单独使用还是与CDK 4/6抑制剂联合使用，都显著降低了多种ERalpha+ BC细胞系的体外增殖（P< 0.01）。这伴随着ERalpha蛋白及mRNA水平的显著下降，证实了ERalpha蛋白的降解。此外，雌激素刺激来自正常女性供者的CD34+骨髓干细胞、多能祖细胞和MDSC的增殖，这一效应被SERD JD128和氟维司群抑制，表明造血干细胞和祖细胞表达雌激素受体并对雌激素作出反应。此外，SERD JD128抑制BC细胞乳腺球的增殖，并降低癌症干细胞标志物的表达。重要的是，占据肿瘤微环境（TME）的MDSC的积累和活性似乎在ER阳性和ER阴性肿瘤中均会发生。此外，TME中雌激素反应性的MDSC可通过SERD治疗被靶向以阻断雌激素信号传导。这些雌激素介导的对造血细胞扩增/激活的效应，对SERD在ER阳性或ER阴性BC中的潜在临床应用具有意义。[资助方：CIRM DISC2-14166、UCLA JCCC乳腺癌奖、Tower癌症研究基金会、Hickey基金会、NIH/NCI U54 CA143930 CDU-UCLA JCCC合作项目、CBCRP B27IB3869、DOD BCRP Level 2-BC181420]

查看英文原文 English abstract

Breast cancers (BC) with estrogen receptor-alpha (ERalpha) expression represent 70% of newly-diagnosed patients in the US. Endocrine therapies with antiestrogens or aromatase inhibitors, either alone or combined with CDK 4/6 inhibitors, are an important intervention for BCs that express ERalpha, and these remain among the most effective targeted treatment strategies. However, a number of patients with localized BC, and essentially all patients with advanced BC, eventually become resistant to current endocrine therapy regimens. In contrast, immunotherapy is transforming the landscape of treatment for many cancers. However, most breast cancers, apart from a minority of triple-negative breast cancers (TNBC), are resistant to this promising immunotherapeutic approach. Several mechanisms of immune resistance have been described. Of note, BCs are reported to drive expansion and differentiation of hematopoietic stem and progenitor cells in the bone marrow to skew hematopoiesis toward an immunosuppressive myeloid lineage. This dysregulation of myelopoiesis in breast malignancy leads to aberrant expansion of immunosuppressive and tumor-promoting myeloid subpopulations such as myeloid-derived suppressor cells (MDSCs). Our newly-designed selective estrogen receptor down-regulator JD128 (SERDs) markedly reduces in vitro proliferation of several ERalpha+ BC cell lines, alone and combined with CDK 4/6 inhibitors, when compared with FDA-approved SERDs Fulvestrant and Elacestrant (P< 0.01). This was accompanied by a significant decrease of ERalpha protein as well as mRNA levels, confirming ERalpha protein degradation. Further, estrogen stimulated proliferation of CD34+ bone marrow stem cells, multipotent progenitors and MDSCs derived from normal female donors, an effect that was inhibited by SERD JD128 and Fulvestrant indicating that hematopoietic stem and progenitor cells express estrogen receptors and respond to estrogen. In addition, SERD JD128 inhibited proliferation of BC cell mammospheres and reduced expression of cancer stem cell markers. Importantly, accumulation and activity of MDSCs that occupy the tumor microenvironment (TME) appear to occur in both ER-positive and ER-negative tumors. Moreover, estrogen-responsive MDSCs in the TME can be targeted by SERD therapy to block estrogen signaling. These estrogen-mediated effects on hematopoietic cell expansion/activation have implications for potential clinical use of SERDs in ER-positive or ER-negative BCs. [Funded by: CIRM DISC2-14166, UCLA JCCC Breast Cancer Award, Tower Cancer Research Foundation, Hickey Foundation, NIH/NCI U54 CA143930 CDU-UCLA JCCC Partnership, CBCRP B27IB3869, DOD BCRP Level 2-BC181420]

利益披露 Disclosure

M. Morales Martinez, None.. J. Mansilla, None.. E. Mauricio Gonzalez, None.. B. Comin-Anduix, None.. M. Chavez, None.. B. Aguirre, None.. J. Aguade Gorgorio, None.. G. Deng, None.. H. Mikkola, None.. M. Wadehra, None.. M. E. Jung, None.. R. J. Pietras, None.. D. C. Marquez Garban, None.

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