Project 1: EZH2 Inhibition to Prevent/Overcome Chemoresistance

摘要-项目1 克服化疗耐药性发展并最大限度地保持敏感性的能力 有效的卵巢癌化疗是改善卵巢癌预后的关键。这个 卵巢癌肿瘤微环境(TME)是一种重要的治疗介体，但研究较少。 抵抗。具体地说，这种TME的基质成分极大地影响癌症对 化疗，但目前还没有针对间质TME的癌症支持特性的策略。 肿瘤相关间充质干细胞/基质细胞(CA-MSCs)是一种基质祖细胞， 间质TME的组成和功能。CA-MSCs有力地促进了肿瘤的发展 BMP2、BMP4等生长因子的分泌和细胞周期的改变导致化疗耐药 细胞外基质(ECM)。CA-MSCs起源于癌症介导的正常人表观遗传重编程 通过改变组蛋白甲基转移酶EZH2的基因组定位。转录因子WT1 在CA-MSCs中高度上调，似乎驱动了CA-MSCs所必需的EZH2的这种改变的基因组定位。 MSC队形。重要的是，CA-MSC的表型似乎是可逆的，CA-MSC的逆转或 “正常化”与提高对铂类药物的敏感性和患者的存活率相关。我们的初步数据 提示药物抑制EZH2可阻断MSC向CA-MSC的重编程，增加CA-MSC的表达。 MSC正常化以防止化疗耐药。因此我们假设，抑制EZH2将扰乱 卵巢癌的间质支持可改善治疗反应，减少转移，以及 延缓疾病复发，维持对铂的敏感性。我们建议： 目的1：进行第二代EZH2抑制剂CPI-0209的第一阶段剂量递增研究 联合卡铂治疗铂敏感的复发性卵巢癌。 目的：研究EZH2抑制对卵巢间质TME的影响。 目的3：确定WT1在介导EZH2驱动的CA-MSC重新编程和 化疗耐药。 这项工作完成后，我们将确定CPI-0209与 复发性卵巢癌铂类化疗预防间质介导的化疗耐药。我们 还将确定CPI-0209诱导患者CA-MSC正常化的能力。此外，我们将拥有 CA-MSC重编程过程中WT1介导的EZH2基因定位机制的研究 使未来能够更有针对性地瞄准CA-MSC表型。总而言之，这部作品代表了一部小说 通过靶向肿瘤间质TME提高卵巢癌化疗敏感性的方法。

ABSTRACT – PROJECT 1 The ability to overcome the development of chemotherapy resistance and maintain sensitivity to the most effective chemotherapy in ovarian cancer, platinum, is critical to improving outcomes in ovarian cancer. The ovarian cancer tumor microenvironment (TME) is an important, though understudied, mediator of treatment resistance. Specifically, the stromal composition of this TME dramatically influences how cancer responds to chemotherapy, yet no strategies exist to target the cancer-supportive properties of the stromal TME. Carcinoma-associated mesenchymal stem/stromal cells (CA-MSCs) are stromal progenitor cells that dictate the composition and function of the stromal TME. CA-MSCs strongly promote the development of chemotherapy resistance through the secretion of growth factors such as BMP2 and BMP4 and alteration of the extracellular matrix (ECM). CA-MSCs arise from cancer mediated epigenetic reprogramming of normal MSCs through altered genomic localization of the histone methyltransferase EZH2. WT1, a transcription factor highly upregulated in CA-MSCs, appears to drive this altered genomic localization of EZH2 necessary for CA- MSC formation. Importantly, the CA-MSC phenotype appears to be reversible and CA-MSC reversion or ‘normalization’ correlates with improved sensitivity to platinum and patient survival. Our preliminary data indicate pharmacologic inhibition of EZH2 blocks the reprograming of MSC into CA-MSC and increases CA- MSC normalization to prevent chemotherapy resistance. We thus hypothesize that inhibiting EZH2 will disrupt stromal support of ovarian cancer leading to improved treatment response, reduction in metastasis, and delayed disease recurrence with maintenance of platinum sensitivity. We propose to: Aim 1: Conduct a phase 1 dose-escalation study of the second generation EZH2 inhibitor, CPI-0209, in combination with Carboplatin in platinum sensitive, recurrent ovarian cancer. Aim 2: Determine the impact of EZH2 inhibition on the ovarian stromal TME. Aim 3: Determine the role of WT1 in mediating EZH2-driven CA-MSC reprogramming and chemotherapy resistance. Upon completion of this work, we will have determined the potential for using CPI-0209 in combination with platinum chemotherapy in recurrent ovarian cancer to prevent stromal-mediated chemotherapy resistance. We will also define the ability of CPI-0209 to induce CA-MSC normalization in patients. Further, we will have identified the mechanism of WT1 mediated EZH2 genomic localization during CA-MSC reprogramming enabling future, more focused targeting of the CA-MSC phenotype. Collectively, this work represents a novel approach to enhancing ovarian cancer chemotherapy sensitivity by targeting the cancer stromal TME.