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

基本信息

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
项目类别：
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&apos 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&apos 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

项目摘要

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.

项目概要/摘要乳腺癌是美国女性癌症死亡的第二大原因，超过 70% 的乳腺癌为雌激素受体阳性 (ER+)。内分泌治疗显着改善 ER+患者的生存率。然而，大约 40% 的患者复发并死于转移难治性或抵抗内分泌治疗。介导这种耐药性的因素包括 ER 和 ER co- 调节因子、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，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这样的目标是粘膜相关淋巴组织淋巴瘤易位蛋白-1 (MALT1)。 MALT1 最初在 B 细胞淋巴瘤中发现，可促进弥漫性大 B 细胞亚群的发育淋巴瘤和 MALT 淋巴瘤。针对这些淋巴瘤的 MALT1 疗法已经开发出来并且看起来耐受性很好。我们的初步研究首次表明 MALT1 在他莫昔芬耐药中增加乳腺肿瘤细胞。阻断MALT1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 MALT1 会使他莫昔芬耐药细胞对他莫昔芬产生反应。更重要的是，高 MALT1 水平与他莫昔芬耐药和患者生存率低密切相关。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，并且MALT1是治疗内分泌抵抗性乳腺癌的新靶点。在此应用中，我们将使用临床化合物 JNJ-67856633，第一个 MALT1 抑制剂，目前正在 1 期临床试验中进行测试，以确定其效果 MALT1抑制剂对不同亚型的内分泌耐药PDX乳腺肿瘤的疗效并测试 MALT1 抑制剂与不同内分泌疗法联合治疗内分泌耐药 PDX 模型。这这项临床前研究的结果将建立一种新的阻断 MALT1 的辅助疗法来恢复内分泌抵抗性乳腺癌对内分泌治疗的反应，并帮助启动治疗的临床试验患有危及生命的内分泌抵抗性乳腺癌的患者。