Translating Stress Response Targeted Therapy for B-Cell Lymphomas

项目3：(威尔·康奈尔医学院和MSK) 翻译应激反应靶向治疗B细胞淋巴瘤 John Leonard/临床和Ari Melnick/翻译/基础 项目总结 弥漫性大B细胞淋巴瘤(DLBCL)是一组异质性的恶性肿瘤，其复杂性 仍有待完全解决。至少30%-40%的患者无法用目前的化学免疫疗法治愈 养生法。迫切需要改善这些患者的治疗方法。化疗耐药与复发 在具有某些分子特征的患者中尤其高，例如那些具有“激活的B细胞(ABC)”的患者 如基因表达特征，或伴有MYC和BCL2易位或过度表达的患者 癌基因(即所谓的“双重打击”的DLBCL)。即使治愈了，我们目前最好的疗法也是剧毒的 具有诱发继发性癌症的巨大风险。我们的研究试图确定基本的生物学 驱动DLBCL生存的机制，包括其耐药亚型。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。一种肿瘤富集型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。我们的团队开发了一种小分子 这选择性地抑制TE-Hsp90，而不影响一般Hsp90的内务功能。这种分子， 因此，名为PUH71的药物具有广泛的治疗窗口和强大的抗DLBCL细胞活性。PUH71是 在我们的I期临床试验中耐受性良好。我们开发了一种精确测量肿瘤暴露的方法 通过对I124标记的PUH71的PET成像，可以作为指导 个体化给药，解读临床反应。我们假设PUH71可以作为一种有效的 治疗DLBCL的药物，包括那些具有ABC和双重分子签名的药物。我们预测 可以通过PUH71成像和生物标志物来预测疗效。我们预测PUH71将为 作为开发有效和耐受性良好的联合治疗方案的平台药物。最后，我们 还开发了YK198，一种有效和特定的Hsp70变构状态的抑制剂，具有抗Hsp70的活性 DLBCL细胞至少部分是由于抗凋亡信号通路中断所致。我们假设热休克蛋白70 抑制剂将成为治疗DLBCL的有效药物，并可能克服PUH71诱导的Hsp70 反馈阻力。因此，我们建议对DLBCL患者进行PUH71 II期临床试验 结合影像和生物标记物研究，比较和对比Hsp90和Hsp90的生物依赖性 HSP70抑制剂在DLBCL患者标本中的应用，并设计和测试合理的联合方案 PUH71和YK198。

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.