Project 2: Reversing resistance caused by lineage plasticity through epigenetic therapy

前列腺癌的特征是依赖雄激素生长和靶向雄激素的药物 受体一直是治疗的支柱。在治疗的选择压力下，前列腺癌 耐药机制尽管治疗增长。在一部分患者中， 特异性导致对所有针对雄激素受体的治疗的抗性，并且很少有治疗性的雄激素受体特异性导致对所有针对雄激素受体的治疗的抗性。 选项.我们最近发现了两种谱系可塑性前列腺癌的机制，它们是可逆的， 表观遗传疗法总的目标是开发联合疗法来逆转或阻止谱系可塑性 并延长反应。首先，我们观察到TP 53和RB 1联合缺失的肿瘤进展为 需要EZH 2活性的雄激素受体非依赖性疾病。这表明EZH 2是一种 前列腺癌的治疗靶点。第二，我们发现前列腺癌的一个子集， 异常表达HNF 4G和HNF 1A，胃肠道谱系的主要调节因子，并绕过 前列腺谱系对雄激素信号传导的需求。BET抑制剂的抑制作用抑制了这一途径， 使前列腺癌对雄激素受体导向疗法敏感。在目标1中，我们将测试以下化合物的体内活性： AR阴性前列腺癌中的EZH 2抑制与抗雄激素Enzalutamide联合。在目标2中， 我们将测试BET抑制在HNF 4G/HNF 1A阳性前列腺癌中的体内活性， 恩杂鲁胺。在目标3中，我们将进行BET、EZH 2和P300/CBP的表观遗传抑制剂的临床前研究 在一组反映人类前列腺癌临床异质性的前列腺癌患者模型中， 前列腺癌对于我们的研究，我们将使用临床相关的药物，无论是在临床试验或首次 有临床潜力的学生拟议的研究是创新的，因为它测试了一种新的范式， 前列腺谱系的前列腺增生是可逆的和可药用的，并且由于其快速发展的潜力而具有重要意义。 为选择不多的患者提供新的治疗。

Prostate cancer is characterized by dependence on androgens for growth and drugs that target the androgen receptor has been the mainstay of therapy. Under selection pressure of treatment, prostate cancer evolves resistance mechanisms to grow despite therapy. In a subset of patients, the loss of prostate lineage specification results in resistance to all therapy directed at the androgen receptor and there are few therapeutic options. We have recently identified two mechanism of lineage plasticity prostate cancer that are reversible by epigenetic therapy. The overall goal is to develop combination therapy to reverse or prevent lineage plasticity and prolong response. First, we have observed that tumors with combined TP53 and RB1 loss progress to androgen receptor independent disease that required activity of EZH2. This suggests that EZH2 is a therapeutic target for this subset of prostate cancer. Second, we discovered that a subset of prostate cancer aberrantly express HNF4G and HNF1A, master regulators of the gastrointestinal lineage, and bypass the prostate lineage requirement for androgen signaling. Inhibition with BET inhibitors inhibit this pathway and re- sensitize prostate cancer to androgen receptor directed therapy. In Aim 1, we will test the in vivo activity of EZH2 inhibition in AR-negative prostate cancer in combination with the antiandrogen enzalutamide. In Aim 2, we will test the in vivo activity of BET inhibition in HNF4G/HNF1A positive prostate cancer in combination with enzalutamide. In Aim 3, we will perform preclinical studies of epigenetic inhibitor of BET, EZH2, and P300/CBP in a large panel of patient-derived models of prostate cancer that reflect the clinical heterogeneity of human prostate cancer. For our studies, we will use clinically relevant drugs that are either in clinical trials or are first in class with clinical potential. The proposed research is innovative because it tests a novel paradigm that loss of prostate lineage is reversible and druggable, and is significant because of the potential to rapidly develop novel treatment to patients with few options.