Translating Stress Response Targeted Therapy for B-Cell Lymphomas

将应激反应靶向治疗转化为 B 细胞淋巴瘤

• 批准号: 8997374
• 负责人: GABRIELA CHIOSIS
• 金额: $ 31.79万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-30 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8997374
• 关键词: Affect; Apoptosis; Apoptotic; B-Cell Lymphomas; B-Lymphocytes; BCL2 gene; BCL2L11 gene; BCL6 gene; Biological; Biological Markers; Cell Line; Cells; Client; Clinical; Clinical Trials; Companions; Complement; Complex; Correlative Study; Data; Dependency; Development; Dose; Drug Combinations; Enrollment; Equilibrium; Feedback; Gene Expression Profile; Genetic; Goals; Heat shock proteins; Heat-Shock Proteins 90; Housekeeping; Human; Image; Immunotherapy; In Vitro; Individual; Joints; Label; Laboratories; Lead; Link; Lymphoma; MCL1 gene; Malignant Neoplasms; Measures; Membrane; Methods; Mitochondria; Molecular; Molecular Profiling; Oncogenes; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase I Clinical Trials; Phase II Clinical Trials; Play; Positron-Emission Tomography; Protein Isoforms; Proteins; Reagent; Receptor Signaling; Receptors, Antigen, B-Cell; Recycling; Refractory; Regimen; Relapse; Research; Resistance; Risk; Role; Safety; Second Primary Cancers; Signal Pathway; Specimen; Stress; Testing; Therapeutic; Therapeutic Agents; Translating; Translations; Work; base; biological adaptation to stress; cell type; chemotherapy; combinatorial; design; drug development; effective therapy; imaging biomarker; improved; in vivo; inhibitor/antagonist; killings; large cell Diffuse non-Hodgkin' s lymphoma; medical schools; mimetics; novel; novel therapeutics; overexpression; preclinical study; predicting response; predictive marker; release of sequestered calcium ion into cytoplasm; response; small molecule; targeted agent; targeted treatment; therapeutic target; tumor; uptake

Project-3: (Weill Cornell Medical College and MSK) Translating Stress Response Targeted Therapy for B-Cell Lymphomas John Leonard/Clinical and Ari Melnick/Translational/Basic PROJECT SUMMARY Diffuse large B-cell lymphomas (DLBCLs) are a heterogeneous group of malignancies, the complexity of which still remains to be fully resolved. At least 30-40% of patients are not cured with current chemo-immunotherapy regimens. Improved treatments are urgently needed for these patients. Chemotherapy resistance and relapse are particularly high in patients with certain molecular features, such as those with an “Activated B-cell (ABC)” like gene expression signature, or those with translocations or overexpression of the MYC and BCL2 oncogenes (so-called “double-hit” DLBCLs). Even when cured our current best therapies are highly toxic and carry a significant risk of inducing secondary cancers. Our research seeks to identify fundamental biological mechanisms that drive the survival of DLBCLs including its resistant subtypes. Along these lines we find that DLBCLs are generally addicted to particular stress response proteins. A tumor-enriched form of Hsp90 (TE- Hsp90) plays an essential role in DLBCLs by supporting the actions of the BCL6, MYC and BCL2 oncoproteins, as well as maintaining B-cell receptor (BCR) signaling. Our team developed a small molecule that selectively inhibits TE-Hsp90 without affecting general Hsp90 housekeeping functions. This molecule, called PUH71 has an accordingly wide therapeutic window and potent activity against DLBCL cells. PUH71 is well tolerated in our phase I clinical trial. We developed a method to accurately measure tumor exposure through PET imaging of I124-labeled PUH71, which may serve as a companion biomarker to guide individualized dosing and interpret clinical responses. We hypothesize that PUH71 can serve as an effective therapeutic agent for DLBCL, including those with ABC- and double-hit molecular signatures. We predict that response can be predicted through PUH71 imaging and biologic biomarkers. We predict that PUH71 will serve as a platform drug for development of effective and well-tolerated combinatorial therapy regimens. Finally, we also developed YK198, a potent and specific inhibitor of specific allosteric states of Hsp70, with activity against DLBCL cells at least in part due to disruption of anti-apoptotic signaling pathways. We hypothesize that Hsp70 inhibitors will be useful therapeutic agents for DLBCL and may overcome possible PUH71 induced Hsp70 feedback resistance. Therefore we propose to perform a PUH71 phase II clinical trial in patients with DLBCL with concordant imaging and biomarker studies, to compare and contrast biological dependency of Hsp90 and Hsp70 inhibitors in DLBCL patient specimens, and to design and test rational combinatorial regimens with PUH71 and YK198.

项目 3：（威尔康奈尔医学院和 MSK） 将应激反应靶向治疗转化为 B 细胞淋巴瘤 约翰·伦纳德/临床和阿里·梅尔尼克/翻译/基础 项目概要 弥漫性大 B 细胞淋巴瘤 (DLBCL) 是一组异质性恶性肿瘤，其复杂性 仍有待彻底解决。至少 30-40% 的患者无法通过当前的化学免疫疗法治愈 治疗方案。这些患者迫切需要改进的治疗方法。化疗耐药和复发 在具有某些分子特征的患者中尤其高，例如具有“激活的 B 细胞 (ABC)”的患者 例如基因表达特征，或者 MYC 和 BCL2 易位或过度表达的特征 癌基因（所谓的“双重打击”DLBCL）。即使治愈了，我们目前最好的疗法也具有剧毒，并且 具有诱发继发性癌症的重大风险。我们的研究旨在确定基本的生物学 驱动DLBCL（包括其耐药亚型）生存的机制。沿着这些思路我们发现 DLBCL 通常对特定的应激反应蛋白上瘾。肿瘤富集形式的 Hsp90 (TE- Hsp90) 通过支持 BCL6、MYC 和 BCL2 的作用，在 DLBCL 中发挥重要作用 癌蛋白，以及维持 B 细胞受体 (BCR) 信号传导。我们的团队开发了一种小分子 选择性抑制 TE-Hsp90，而不影响一般 Hsp90 的管家功能。这个分子， PUH71 具有相应的宽治疗窗和针对 DLBCL 细胞的有效活性。 PUH71 是 在我们的 I 期临床试验中耐受​​性良好。我们开发了一种准确测量肿瘤暴露的方法 通过 I124 标记的 PUH71 的 PET 成像，它可以作为伴随生物标志物来指导 个体化剂量并解释临床反应。我们假设 PUH71 可以作为一种有效的 DLBCL 的治疗剂，包括具有 ABC 和双重打击分子特征的治疗剂。我们预测 可以通过 PUH71 成像和生物标志物来预测反应。我们预测PUH71将服役 作为开发有效且耐受性良好的组合治疗方案的平台药物。最后，我们 还开发了 YK198，一种 Hsp70 特定变构状态的有效且特异性抑制剂，具有对抗 DLBCL 细胞至少部分归因于抗凋亡信号通路的破坏。我们假设 Hsp70 抑制剂将成为 DLBCL 的有用治疗剂，并可能克服 PUH71 可能诱导的 Hsp70 反馈电阻。因此我们建议对DLBCL患者进行PUH71 II期临床试验 通过一致的成像和生物标志物研究，比较和对比 Hsp90 和 DLBCL 患者标本中的 Hsp70 抑制剂，并设计和测试合理的组合方案 PUH71 和 YK198。