NF-KB and mTOR regulation in Waldenstrom Macroglobulinemia

描述(由申请人提供)： WM是一种罕见的惰性低级别B细胞淋巴瘤，目前仍无法治愈，总体生存时间中位数为5-6年，大多数患者死于疾病的进展。然而，西医患者的生存率和治疗结果差异很大，根据国际西医预后评分系统(IPSS)，西医患者的5年生存率可能从高危西医的36%到低危西医的87%不等。因此，开发新的治疗方法来改善这种疾病患者的预后是至关重要的，但更重要的是，基于风险分层的专门定制治疗方案的设计可能会改善这些患者的反应，并减少低风险患者的不必要毒性。 在淋巴组织增生性疾病中，PI3K/mTOR和NF-kB通路在细胞凋亡、细胞周期和肿瘤增殖中起着重要的调节作用。初步数据表明，在WM细胞中Akt和NF-kB被激活。这种激活可能是由于遗传或表观遗传异常或由于骨髓微环境的外部刺激。RAD001和Bortezomib/rituximab在WM的第二阶段临床试验中显示出高活性，这些药物的临床前研究显示出高的体外细胞毒活性，并通过PI3K/mTOR和NF-KB途径抑制信号转导。基于这些发现，申请人假设，通过结构性调节或骨髓环境的外部刺激激活PI3K和NF-kB通路会导致治疗抵抗。申请人提出，这些途径的激活可能是由于1)恶性细胞内的结构性激活或2)通过骨髓微环境的外部刺激。 这一提出的假设将在3个目标中进行验证：目标1是根据IPSS-WM分期系统，在基于患者风险分层的1/2期临床试验中，检查RAD001/rituximab或RAD001/bortezomib/rituximab组合的体内活性和安全性。临床试验将包括一期研究，以确定AD001/rituximab和RAD001/rituximab/bortezomib的组合的最大耐受量(MTD)。在此之后，将进行2个手臂的第二阶段试验。ARM A将包括基于IPSS状态系统的低风险WM患者，其中患者将接受RAD001和利妥昔单抗的组合。B组将包括中高危WM患者，患者将接受RAD001/bortezomib/rituximab的联合治疗。这些2期研究的主要目标是评估西医患者的反应深度。目的2是确定PI3K和NF-kB通路的遗传和表观遗传调节因子及其在西医耐药中的作用，目的3是确定骨髓微环境在通过PI3K和NF-kB通路诱导耐药中的作用。 虽然罕见，但与其他淋巴增生性疾病相比，WM在生物学上的畸变率更高，因此，它可能成为其他低度恶性淋巴瘤和浆细胞癌的模式疾病，在这些疾病中，异常的分子途径被识别出来，并使用新的治疗药物进行功能验证。

DESCRIPTION (provided by applicant): WM is a rare indolent low-grade B-cell lymphoma that remains incurable with a median overall survival of 5-6 years, and most patients succumb to disease progression. However, the survival and outcome of therapy in patients with WM varies widely and the 5-year survival of patients with WM may range from 36% in high risk WM to 87% in low risk patients based on the International Prognostic Scoring System (IPSS) in WM. Therefore, development of novel therapeutics that improve the outcome in patients with this disease is critical, but more importantly the design of specifically tailored therapies based on risk stratification may improve responses in these patients and decrease unwarranted toxicity in low-risk patients. The PI3K/mTOR and NF-kB pathways act as critical regulators of apoptosis, cell cycle, and tumor proliferation in lymphoproliferative disorders. Preliminary data indicate that Akt and NF-kB are activated in WM cells. This activation may be due to genetic or epigenetic aberrations or due to external stimulation by the bone marrow microenvironment. RAD001 and bortezomib/rituximab showed high activity in Phase 2 clinical trials in WM and the preclinical studies of the combination of these agents shows high cytotoxic activity in vitro and inhibits signaling through the PI3K/mTOR and NF-KB pathways. Based on these findings, the applicant hypothesizes that activation of the PI3K and NF-kB pathways through constitutive regulation or external stimulation by the bone marrow milieu leads to resistance to therapy. The applicant proposes that activation of these pathways may be due to 1) constitutive activation within malignant cells or 2) external stimulation through the bone marrow microenvironment. This proposed hypothesis is to be tested in 3 aims: Aim 1 is to examine in vivo activity and safety of the combination of RAD001/rituximab or RAD001/bortezomib/rituximab in a Phase 1/2 clinical trial based on risk-stratification of patients according to the IPSS-WM staging system. The clinical trial will include a Phase 1 study to determine the maximum tolerated dose (MTD) of the combination of AD001/rituximab and RAD001/rituximab/bortezomib. This will be followed by a Phase 2 trial with 2 arms. Arm A will include patients with low risk WM based on the IPSS stating system where patients will receive the combination of RAD001 and rituximab. Arm B will include patients with intermediate-high risk WM where patients will receive the combination of RAD001/bortezomib/rituximab. The primary objective of these Phase 2 studies is to assess the depth of response in patients with WM. Aim 2 is to determine genetic and epigenetic regulators of the PI3K and NF-kB pathways and their role in resistance to therapy in WM, and Aim 3 is to identify the role of the bone marrow microenvironment in conferring resistance to therapy through the PI3K and NF-kB pathways. Although rare, WM is more homogenous in its biological aberrations compared to other lymphoproliferative disorders, and therefore, it may become a model disease for other low-grade lymphomas and plasma cell dyscrasias where aberrant molecular pathways are identified and functionally validated using novel therapeutic agents.