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伦纳德/临床和Ari Melnick/翻译/基础 项目摘要 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。至少有30-40%的患者不能用目前的化学免疫疗法治愈 养生法这些患者迫切需要改进治疗方法。化疗耐药性和复发 在具有某些分子特征的患者中特别高，例如具有“活化B细胞（ABC）”的患者。 如基因表达特征，或具有MYC和BCL 2易位或过表达的那些 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是剧毒的， 具有诱发继发性癌症的显著风险。我们的研究旨在确定基本的生物学 驱动DLBCL存活的机制，包括其耐药亚型。沿着这些线索，我们发现， DLBCL通常对特定的应激反应蛋白上瘾。一种肿瘤富集形式的Hsp 90（TE-1）， Hsp 90）通过支持BCL 6、MYC和BCL 2的作用在DLBCL中起重要作用 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 其选择性抑制TE-Hsp 90而不影响一般Hsp 90管家功能。这个分子 PUH 71具有相应的宽治疗窗和针对DLBCL细胞的有效活性。PUH 71是 在我们的I期临床试验中耐受良好。我们开发了一种方法来精确测量肿瘤暴露 通过I124标记的PUH 71的PET成像，它可以作为伴随生物标志物来指导 个体化给药和解释临床反应。我们假设PUH 71可以作为一种有效的 用于DLBCL的治疗剂，包括具有ABC和双重命中分子特征的那些。我们预测 可以通过PUH 71成像和生物标志物预测缓解。我们预测PUH 71将服务于 作为开发有效和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YK 198，一种有效的和特异性的Hsp 70特异性变构状态的抑制剂， DLBCL细胞的凋亡至少部分是由于抗凋亡信号通路的破坏。我们假设Hsp 70 抑制剂将是DLBCL的有用治疗剂，并且可以克服可能的PUH 71诱导的Hsp 70 反馈电阻因此，我们建议在DLBCL患者中进行PUH 71 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Hsp 90的生物依赖性， DLBCL患者标本中的Hsp 70抑制剂，并设计和测试合理的组合方案 PUH 71和YK 198。

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.