MALT1 Targeted Therapy for B-Cell Lymphoma

描述（由申请人提供）：最近的研究已经发现了MALT1（一种参与b细胞受体（BCR）信号通路的蛋白酶和支架蛋白）的副半胱氨酸酶活性的小分子抑制剂，在体外和体内的活化b细胞样弥漫性大b细胞淋巴瘤（ABC-DLBCL）异种移植模型中有效地杀死淋巴瘤。DLBCL是最常见的淋巴瘤，而ABC-DLBCL是最具化疗耐药的亚型。此外，BCR通路参与多种淋巴瘤亚型的细胞增殖和存活，包括滤泡性淋巴瘤、套细胞淋巴瘤和慢性淋巴细胞白血病/淋巴瘤。然而，并非所有的ABC-DLBCL细胞系和原发患者样本在体外对MALT1抑制剂同样敏感。因此，我们假设对MALT1抑制剂的反应将取决于abc - dlbcl的遗传背景，即MALT1下游突变的细胞更有可能产生耐药性。同样，正如已经报道的其他靶向治疗一样，获得性耐药机制可能会通过MALT1或其下游靶点突变或激活替代生存途径来阻止对MALT1抑制剂的反应。此外，淋巴瘤联合药物治疗是该疾病的金标准，并且已被证明是最有效的，因此我们假设MALT1抑制将在与其他化疗或靶向治疗药物联合治疗时最有价值。因此，为了有效地将MALT1抑制剂转化为临床实践，我们的具体目标是：1)确定对MALT1抑制有反应的遗传背景；2)定义肿瘤逃避治疗的可能耐药机制，3)使用整体方法设计和测试联合疗法（基于对疾病的实际了解，目标1和2中发现的耐药机制以及无偏倚的高通量筛选的合理组合）。

DESCRIPTION (provided by applicant): Recent studies have identified small molecule inhibitors of the paracaspase activity of MALT1, a protease and scaffolding protein involved in the B-cell receptor (BCR) signaling pathway, that are effective killing lymphomas in vitro and in vivo in xenograft models of Activated B-cell like Diffuse Large B-cell Lymphoma (ABC-DLBCL). DLBCL is the most common lymphoma and ABC-DLBCL its most chemoresistant subtype. Moreover, the BCR pathway is involved in cell proliferation and survival of several lymphoma subtypes, including follicular lymphoma, mantle cell lymphoma and chronic lymphocytic leukemia/lymphoma. However, not all ABC-DLBCL cell lines and primary patient samples were equally sensitive to MALT1 inhibitors in vitro. Thus, we hypothesize that response to MALT1 inhibitors will be dependent on the genetic background of ABC-DLBCLs, being those holding mutations downstream of MALT1 more likely to be resistant. Likewise, as already reported for other targeted therapies, acquired resistance mechanisms could arise that prevent response to MALT1 inhibitors by either mutation in MALT1 or its downstream targets or by activation of alternative survival pathways. Moreover, lymphoma therapy with drug combinations is the gold standard for the disease and has been proven most effective, thus we hypothesize that MALT1 inhibition will be most valuable in combination with other chemotherapeutic or targeted therapy agents. Consequently, in order to effectively translate MALT1 inhibitors to the clinical practice, our specific aims are: 1) To determine the genetic background of responders to MALT1 inhibition; 2) To define possible resistance mechanisms that tumors will deploy to escape therapy and 3) To design and test combination therapies using a holistic approach (rational combination based on actual knowledge of the disease, resistance mechanisms found in Aims 1 and 2 and, unbiased high throughput screening).