MALT1 Targeted Therapy for B-Cell Lymphoma

描述(申请人提供)：最近的研究已经确定了MALT1副天冬氨酸酶活性的小分子抑制剂，MALT1是一种参与B细胞受体(BCR)信号通路的蛋白酶和支架蛋白，在激活的B细胞样弥漫性大B细胞淋巴瘤(ABC-DLBCL)的异种移植模型中，它们在体外和体内都能有效地杀死淋巴瘤。DLBCL是最常见的淋巴瘤，ABC-DLBCL是最耐药的亚型。此外，bcr途径参与了几种淋巴瘤亚型的细胞增殖和生存，包括滤泡性淋巴瘤、套细胞淋巴瘤和慢性淋巴细胞性白血病/淋巴瘤。然而，并不是所有的ABC-DLBCL细胞株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，即那些在MALT1下游持有突变的人更有可能具有耐药性。同样，就像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或其下游靶点的突变或通过激活替代的生存途径来阻止对MALT1抑制剂的反应。此外，联合用药治疗淋巴瘤是该疾病的黄金标准，已被证明是最有效的，因此我们假设，抑制MALT1与其他化疗或靶向治疗药物联合使用将是最有价值的。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抑制反应的遗传背景；2)确定肿瘤用于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(基于疾病的实际知识、AIMS 1和2中发现的耐药机制以及无偏见的高通量筛选)。

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).