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

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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.