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

项目总结/摘要 乳腺癌是美国女性癌症死亡的第二大原因， 70%的乳腺癌是雌激素受体阳性（ER+）。内分泌治疗已经大大改善了 ER+患者的生存率。然而，大约40%的这些患者复发并死于转移， 难治性或抵抗内分泌治疗。提出的介导这种抗性的因素包括ER和ER共表达。 调节因子、细胞周期信号分子和生长因子受体途径。虽然临床试验针对 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。我们的初步 数据表明了这样的靶粘膜相关类淋巴组织淋巴瘤易位蛋白-1（MALT 1）。 MALT 1最初在B细胞淋巴瘤中发现，促进弥漫性大B细胞亚群的发育 淋巴瘤和MALT淋巴瘤。已经开发了针对这些淋巴瘤的靶向MALT 1的疗法， 似乎很宽容。我们的初步研究首次表明，MALT 1在他莫昔芬耐药的人中增加， 乳腺肿瘤细胞阻断MALT 1活性优先抑制他莫昔芬耐药乳腺肿瘤的生长 细胞此外，阻断MALT 1使他莫昔芬耐药细胞对他莫昔芬产生反应。更重要的是， 高MALT 1水平与他莫昔芬耐药性和患者存活率低密切相关。我们假设 MALT 1介导内分泌抗性并促进抗性乳腺肿瘤细胞的生长， 治疗内分泌抵抗性乳腺癌的新靶点。在本申请中，我们将使用临床化合物 JNJ-67856633是目前在I期临床试验中检测的首个MALT 1抑制剂，用于定义以下药物的作用 MALT 1抑制剂对不同亚型的内分泌耐药PDX乳腺肿瘤的作用并测试其有效性 MALT 1抑制剂与不同内分泌疗法联合在内分泌耐药PDX模型上的应用。的 这项临床前研究的结果将建立阻断MALT 1的新的辅助治疗，以恢复 内分泌抵抗性乳腺癌对内分泌治疗的反应，并帮助启动临床试验， 患有危及生命的内分泌抵抗性乳腺癌的患者。

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.