Pre-clinical testing the effects of MALT1 inhibitor on endocrine resistant breast cancer

项目摘要/摘要 乳腺癌是美国女性癌症死亡的第二大原因，超过 70%的乳腺癌是雌激素受体阳性(ER+)。内分泌治疗有了显著的改善 ER+患者的存活率。然而，这些患者中约有40%复发并死于 难治或抵抗内分泌治疗。提出的调节这种抗性的因素包括ER和ER共同作用。 调节因子、细胞周期信号分子和生长因子受体通路。通过临床试验靶向 这些因素显示了一些成功，但总体结果并不令人满意。因此，发现新的目标 内分泌抵抗是开发新的乳腺癌治疗策略的关键障碍。我们的预赛 有数据表明这种靶标为黏膜相关淋巴组织淋巴瘤易位蛋白-1(MALT1)。 最初在B细胞淋巴瘤中发现的MALT1促进弥漫性大B细胞亚群的发展 淋巴瘤和MALT淋巴瘤。针对这些淋巴瘤的MALT1靶向疗法已经开发出来， 看起来是可以容忍的。我们的初步研究首次显示MALT1对他莫昔芬的耐药性增加 乳腺肿瘤细胞。阻断MALT1活性优先抑制三苯氧胺耐药乳腺肿瘤的生长 细胞。此外，阻断MALT1使耐他莫昔芬的细胞对他莫昔芬产生反应。更重要的是， MALT1水平高与他莫昔芬耐药和患者生存不良密切相关。我们假设 MALT1介导内分泌抵抗并促进耐药乳腺肿瘤细胞的生长，而MALT1是 治疗内分泌抵抗型乳腺癌的新靶点。在这个应用中，我们将使用临床化合物 JNJ-67856633，第一个正在测试的MALT1抑制剂，目前处于第一阶段临床试验，以确定 MALT1抑制剂治疗不同亚型内分泌抵抗型PDX乳腺肿瘤的疗效观察 在内分泌抵抗的PDX模型中，MALT1抑制剂与不同的内分泌治疗相结合。这个 这项临床前研究的结果将建立阻断MALT1的一种新的辅助治疗方法，以恢复 内分泌抵抗乳腺癌对内分泌治疗的反应性，并帮助启动治疗的临床试验 患有危及生命的内分泌抵抗型乳腺癌的患者。

Project Summary/Abstract Breast cancer is the second leading cause of cancer death among women in the United States, and more than 70% of breast cancers are estrogen receptor-positive (ER+). Endocrine therapy has dramatically improved survival of ER+ patients. However, approximately 40% of these patients relapse and die from metastases that are refractory or resist endocrine therapy. Factors proposed to mediate this resistance include ER and ER co- regulators, cell cycle signaling molecules and growth factor receptor pathways. Though clinical trials targeting these factors show some success, the overall outcome is unsatisfactory. Therefore, discovering new targets of endocrine resistance is a critical barrier to developing new breast cancer treatment strategies. Our preliminary data indicate such a target Mucosa-Associated Lymphoid Tissue Lymphoma Translocation Protein-1 (MALT1). MALT1, originally identified in B-cell lymphomas, promotes development of a subset of diffuse large B cell lymphomas and MALT lymphoma. Therapies targeting MALT1 for these lymphomas have been developed and seem well-tolerated. Our preliminary studies show for the first time that MALT1 is increased in tamoxifen-resistant breast tumor cells. Blocking MALT1 activity preferentially inhibits the growth of tamoxifen-resistant breast tumor cells. In addition, blocking MALT1 renders tamoxifen-resistant cells responsive to tamoxifen. More importantly, high MALT1 levels were strongly associated with tamoxifen resistance and poor patient survival. We hypothesize that MALT1 mediates endocrine resistance and promotes growth of resistant breast tumor cells, and MALT1 is a new target for treatment of endocrine-resistant breast cancer. In this application, we will use clinical compound JNJ-67856633, the first MALT1 inhibitor being tested currently in phase 1 clinical trial, to define the effects of MALT1 inhibitors on different subtypes of endocrine-resistant PDX breast tumors and to test the effectiveness of MALT1 inhibitors in combination with different endocrine therapies on endocrine-resistant PDX models. The results of this preclinical study will establish blocking MALT1 a new adjuvant therapy to restore the responsiveness of endocrine-resistant breast cancers to endocrine therapy, and help initiate clinical trials to treat patients suffering with the life-threating endocrine-resistant breast cancer.