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

基本信息

批准号：
10781906
负责人：
Olivia Skye Montoya
金额：
$ 4.77万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
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：
2022-09-09 至 2025-09-08
项目状态：
未结题

项目摘要

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.

项目概要 B 细胞恶性肿瘤，例如慢性淋巴细胞白血病 (CLL) 和其他形式的非霍奇金淋巴瘤淋巴瘤 (NHL) 是常见的血液系统恶性肿瘤，通常发生在成人中。由功能失调的成熟 B 细胞引起 B 细胞受体 (BCR) 通路的不规则信号传导可导致 B 细胞恶性肿瘤的增殖和存活使得布鲁顿氏酪氨酸 (BTK) 成为 BCR 早期的一种激酶途径，癌症治疗的一个有吸引力的目标虽然现有的治疗可以导致疾病缓解，几乎所有患者都会复发，这使得人们一致认为 CLL 仍然被认为是一种不治之症。 BTK 的共价（不可逆）小分子抑制剂，例如依鲁替尼，已经改变了治疗方法 CLL、套细胞淋巴瘤 (MCL) 和华氏巨球蛋白血症 (WM) 的共价 BTK 抑制剂。对多种 B 细胞恶性肿瘤有效，但由于耐药性和不耐受性，许多患者为了克服这些问题，需要使用高度选择性和可逆的非共价 BTK。抑制剂已经开发出来，目前正在临床试验中进行测试，显示出安全性和前景。对多种 B 细胞肿瘤（包括经过深度治疗的 CLL、MCL、WM 和滤泡性淋巴瘤）的疗效，证明非共价 BTK 抑制剂可能会解决替代疗法日益增长的未满足需求尽管 pirtobrutinib 具有有益的特点并且总体缓解率很高。第一阶段研究，一些先前接受过 CLL 和 B 细胞恶性肿瘤治疗的患者对治疗或对单一疗法初始反应后复发。基于 BTK、PLCG2 和其他经常突变的基因的下一代突变分析在非共价 BTK 抑制剂治疗之前和治疗进展时的 CLL 中，我们现在确定了新的 BTK 和 PLCG2 变体，这些变体只能在治疗后检测到。结果，我认为 BTK 或 B 细胞受体信号通路（例如如 PLCG2 突变）导致对非共价 BTK 抑制的抗性，并且结合 BTK 抑制剂与其他 CLL 靶向药物联合使用可规避上述耐药性，目前尚无报道。该提案将确定患者对非共价 BTK 抑制剂的耐药机制。通过这种方式，细胞对非共价 BTK 抑制产生抗性，并用额外的方法挑战该抗性靶向治疗旨在实现以下目标：目标 1：确定新型 BTK 突变的潜在机制观察到对非共价 BTK 抑制的获得性耐药。目标 2：测试联合疗法以克服。 B 细胞淋巴瘤对 BTK 抑制剂的耐药性由于以下原因，对治疗替代方案的需求呈指数级增长。获得性耐药的患者发生率增加，这项研究的结果将产生重大影响。此外，这些发现将为患有各种 B 细胞恶性肿瘤的患者提供信息。与非共价 BTK 抑制剂的合理联合治疗。