Investigating Resistance Mechanisms to Non-covalent Bruton's Tyrosine Kinase Inhibitors and Therapeutic Approaches to Overcome Resistance for Patients with B-Cell Malignancies

研究非共价布鲁顿酪氨酸激酶抑制剂的耐药机制以及克服 B 细胞恶性肿瘤患者耐药性的治疗方法

• 批准号: 10537252
• 负责人: Olivia Skye Montoya
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2025-09-08
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537252
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Adult; Affinity; Aftercare; Agammaglobulinaemia tyrosine kinase; Alternative Therapies; B lymphoid malignancy; B-Cell Antigen Receptor; B-Cell Lymphomas; B-Cell Neoplasm; BCL2 gene; Binding; Binding Sites; Biochemical; Biological Assay; Cell Line; Cell Therapy; Cells; Chronic Lymphocytic Leukemia; Clinical Trials; Combined Modality Therapy; Consensus; Data; Development; Disease; Disease remission; Drug Targeting; Drug resistance; Engineering; Enzymes; Follicular Lymphoma; Generations; Genes; Genetic; Genomics; Goals; Hematologic Neoplasms; Immunocompromised Host; Immunotherapy; In Vitro; Incidence; Knowledge; Lead; Lymphoma; Malignant Neoplasms; Mantle Cell Lymphoma; Mature B-Lymphocyte; Mutate; Mutation; Mutation Analysis; Non-Hodgkin' s Lymphoma; Outcome; PLCG2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Prevalence; Protac; Receptor Signaling; Recurrence; Relapse; Reporting; Research; Resistance; Resistance development; Role; Safety; Sampling; Scientist; Signal Pathway; Signal Transduction; Testing; Therapeutic; Time; Toxic effect; Tyrosine; Tyrosine Kinase Inhibitor; Variant; Waldenstrom Macroglobulinemia; Xenograft procedure; alternative treatment; base; chemotherapy; chronic lymphocytic leukemia cell; design; in vivo; inhibitor; inhibitor therapy; mouse model; next generation; novel; novel strategies; novel therapeutic intervention; patient population; personalized cancer therapy; phase 1 study; relapse patients; resistance mechanism; resistance mutation; response; small molecule inhibitor; targeted agent; targeted cancer therapy; targeted treatment

PROJECT SUMMARY B-cell malignancies such as chronic lymphocytic leukemia (CLL) and other forms of Non-Hodgkin lymphomas (NHL) are common hematologic malignancies typically occurring in adults. These malignancies arise from dysfunctional, mature B-cells. Irregular signaling of the B-Cell receptor (BCR) pathway can lead to proliferation and survival of B-cell malignancies making Bruton’s tyrosine (BTK), a kinase early in the BCR pathway, an attractive target for cancer therapy. While available treatments can lead to disease remission, nearly all patients relapse, leading to the consensus that CLL remains to be considered an incurable disease. Covalent (irreversible) small molecule inhibitors of BTK, such as ibrutinib, have transformed the management of CLL, mantle cell lymphoma (MCL), and Waldenström’s Macroglobulinemia (WM). Covalent BTK inhibitors are efficacious in multiple B-cell malignancies, however due to resistance and intolerance, many patients discontinue these agents. To overcome these problems, highly selective and reversible non-covalent BTK inhibitors have been developed. They are currently being tested in clinical trials showing safety and promising efficacy in multiple B-cell neoplasms, including heavily pre-treated CLL, MCL, WM, and follicular lymphoma, demonstrating that non-covalent BTK inhibitors might address a growing unmet need for alternative therapies for these patients. Despite the beneficial features of pirtobrutinib and a high overall response rate seen in the Phase 1 studies, some patients with previously treated CLL and B-cell malignancies did not respond to treatment or relapsed after initial response to monotherapy. Based on next-generation mutational analysis of BTK, PLCG2, and additional genes recurrently mutated in CLL prior to non-covalent BTK inhibitor therapy and at the time of on treatment progression, we have now identified novel BTK and PLCG2 variants that were only detectable post-treatment. Given these preliminary findings, I hypothesize that on-target mutations within BTK or the B-cell receptor signaling pathway (such as PLCG2 mutations) result in resistance to non-covalent BTK inhibition and that combining BTK inhibitors with other CLL targeting drugs will circumvent said resistance. Currently, there are no reports of resistance mechanisms to non-covalent BTK inhibitors in patients. This proposal will identify the mechanisms by which cells develop resistance to non-covalent BTK inhibition and challenge that resistance with additional targeted therapies in the following aims: Aim 1: Identify the mechanism underlying novel BTK mutations observed in acquired resistance to non-covalent BTK inhibition. Aim 2: Test combination therapies to overcome resistance to BTK inhibitors in B-cell lymphoma. There is an exponential need for therapeutic alternatives due to an increased incidence of patients with acquired resistance. The results of this study will have a major impact for patients with a variety of B-cell malignancies. Additionally, these findings will inform the development of rational combination therapies with non-covalent BTK inhibitors.

项目摘要 B细胞恶性肿瘤，例如慢性淋巴细胞性白血病（CLL）和其他形式的非霍奇金 淋巴瘤（NHL）是通常发生在成年人中的常见血液学恶性肿瘤。这些恶性肿瘤 来自功能失调的成熟B细胞。 B细胞受体（BCR）途径的不规则信号传导可能导致 B细胞恶性肿瘤的扩散和生存使Bruton的酪氨酸（BTK），BCR早期的激酶 途径，是癌症治疗的有吸引力的靶标。虽然可用的治疗可以导致疾病的缓解，但 几乎所有患者中继，都达成共识，即CLL仍然被认为是一种无法治愈的疾病。 BTK的共价（不可逆）小分子抑制剂，例如ibrutinib，已经改变了管理 CLL，地幔细胞淋巴瘤（MCL）和Waldenström的大球蛋白血症（WM）。共价BTK抑制剂 在多个B细胞恶性肿瘤中有效，但是由于耐药性和肠道耐药性，许多患者 停止这些代理。为了克服这些问题，高度选择性和可逆的非共价BTK 已经开发了抑制剂。他们目前正在临床试验中进行测试，显示安全性和承诺 多种B细胞肿瘤的效率，包括经过严重预处理的CLL，MCL，WM和卵泡淋巴瘤， 证明非共价BTK抑制剂可能会满足对替代疗法的不满意的需求 对于这些患者。尽管pirobrutinib具有有益的特征，并且在 第1阶段研究，一些先前治疗过的CLL和B细胞Malignancys的患者没有反应 对单一疗法的初步反应后处理或中继。 基于对BTK，PLCG2和其他基因的下一代突变分析，重复突变 在非共价BTK抑制剂治疗之前和治疗进展时，在CLL中，我们现在已经有了 发现仅可检测到后处理的新型BTK和PLCG2变体。考虑到这些初步 调查结果，我假设BTK或B细胞接收器信号通路内的目标突变（这样） 作为PLCG2突变）导致对非共价BTK抑制的抗性，并将BTK结合起来 具有其他CLL靶向药物的抑制剂将避免上述耐药性。目前，没有报告 对患者非共价BTK抑制剂的抗性机制。该建议将确定机制 细胞会产生对非共价BTK抑制和挑战的抵抗力 靶向疗法以下目的：目标1：确定新型BTK突变的机制 在获得对非共价BTK抑制的获得性中观察到。目标2：克服测试组合疗法 B细胞淋巴瘤中BTK抑制剂的抗性。由于 获得性耐药性患者的事件增加。这项研究的结果将产生重大影响 适用于各种B细胞恶性肿瘤的患者。此外，这些发现将为发展 非共价BTK抑制剂的有理组合疗法。