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

MALT1抑制剂对内分泌耐药乳腺癌的临床前测试

• 批准号: 10579334
• 负责人: Jianguo Liu
• 金额: $ 21.17万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-24 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579334
• 关键词: Adjuvant Therapy; Aromatase Inhibitors; B-Cell Lymphomas; BCL10 gene; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; CASP8 gene; CDK4 gene; Cancer Etiology; Cell Cycle; Cells; Cessation of life; Chronic Lymphocytic Leukemia; Clinical; Clinical Trials; Complex; Data; Development; Disease; Disease Progression; Dose; Endocrine; Estrogen receptor positive; Estrogens; FRAP1 gene; Fulvestrant; Growth; Growth Factor Receptors; In Vitro; Life; Lymphocyte Activation; Lymphoma; Mammary Neoplasms; Mediating; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Mutate; Neoplasm Metastasis; Non-Hodgkin' s Lymphoma; Outcome; PIK3CG gene; Pathway interactions; Patient-Focused Outcomes; Patient-derived xenograft models of breast cancer; Patients; Phase I Clinical Trials; Pre-Clinical Model; Preclinical Testing; Proliferating; Recurrent disease; Refractory; Regulatory T-Lymphocyte; Relapse; Resistance; Signal Pathway; Signal Transduction; Signaling Molecule; TRAF6 gene; Tamoxifen; Testing; Time; Toxic effect; Tumor Immunity; United States; Woman; antagonist; effective therapy; effectiveness testing; experience; hormone therapy; improved; in vivo; in vivo Model; inhibitor; large cell Diffuse non-Hodgkin' s lymphoma; malignant breast neoplasm; mucosa-associated lymphoid tissue lymphoma; patient derived xenograft model; pharmacologic; preclinical study; recruit; relapse patients; resistance mechanism; small molecule; standard of care; success; targeted treatment; treatment strategy; tumor; virtual

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.

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+）。内分泌疗法已大大改善 ER+患者的生存。但是，这些患者中约有40％复发，死于转移 是耐火或抵抗内分泌疗法。提出介导这种耐药性的因素包括ER和ER共同 调节剂，细胞周期信号分子和生长因子受体途径。尽管临床试验针对 这些因素显示出一些成功，总体结果并不令人满意。因此，发现了新的目标 内分泌耐药性是制定新的乳腺癌治疗策略的关键障碍。我们的初步 数据表明这种靶粘膜相关的淋巴组织淋巴瘤易位蛋白1（MALT1）。 MALT1最初在B细胞淋巴瘤中鉴定出来，促进了弥漫性大B细胞的子集的发展 淋巴瘤和麦芽淋巴瘤。已经开发了针对MALT1的靶向MALT1的疗法 看起来很耐受。我们的初步研究表明，抗他莫昔芬耐药的MALT1增加 乳腺肿瘤细胞。阻止MALT1活性优先抑制他莫昔芬耐药性乳腺肿瘤的生长 细胞。另外，阻断MALT1会导致他莫昔芬对他莫昔芬的反应。更重要的是， 高MALT1水平与他莫昔芬的耐药性和患者生存不良密切相关。我们假设 MALT1介导内分泌耐药性并促进抗性乳腺肿瘤细胞的生长，MALT1为 治疗内分泌乳腺癌的新靶标。在此应用中，我们将使用临床化合物 JNJ-67856633，这是目前在第一阶段临床试验中测试的第一个MALT1抑制剂，以定义 MALT1对内分泌耐药性PDX乳腺肿瘤不同亚型的抑制剂并测试有效性 MALT1抑制剂与内分泌耐药性PDX模型的不同内分泌疗法结合使用。这 这项临床前研究的结果将建立阻塞MALT1一种新的辅助治疗，以恢复 内分泌乳腺癌对内分泌疗法的反应性，并有助于启动临床试验以治疗 患有威胁生命的内分泌乳腺癌的患者。