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，仍然无法治愈，中位总生存期为5-6年，大多数患者死于疾病进展。然而，WM患者的生存率和治疗结局差异很大，根据WM的国际预后评分系统（IPSS），WM患者的5年生存率从高危WM的36%到低危WM的87%不等。因此，开发新的治疗方法，改善这种疾病的患者的结果是至关重要的，但更重要的是，设计专门定制的治疗方法的基础上的风险分层可能会改善这些患者的反应，并减少不必要的毒性低风险患者。 PI 3 K/mTOR和NF-kB通路在淋巴组织增生性疾病中作为细胞凋亡、细胞周期和肿瘤增殖的关键调节因子。初步数据表明，Akt和NF-kB在WM细胞中被激活。 这种激活可能是由于遗传或表观遗传畸变或由于骨髓微环境的外部刺激。RAD 001和硼替佐米/利妥昔单抗在WM的2期临床试验中显示出高活性，并且这些药剂的组合的临床前研究在体外显示出高细胞毒性活性并抑制通过PI 3 K/mTOR和NF-κ B途径的信号传导。基于这些发现，申请方假设通过骨髓环境的组成性调节或外部刺激激活PI 3 K和NF-κ B通路导致对治疗的抵抗。 申请人提出，这些途径的激活可能是由于1）恶性细胞内的组成性激活或2）通过骨髓微环境的外部刺激。 该提出的假设将在3个目的中进行测试：目的1是在基于根据IPSS-WM分期系统的患者风险分层的1/2期临床试验中检查RAD 001/利妥昔单抗或RAD 001/硼替佐米/利妥昔单抗组合的体内活性和安全性。临床试验将包括一项I期研究，以确定AD 001/利妥昔单抗和RAD 001/利妥昔单抗/硼替佐米组合的最大耐受剂量（MTD）。随后将进行2组II期试验。A组将包括基于IPSS他汀类药物系统的低风险WM患者，其中患者将接受RAD 001和利妥昔单抗的组合。组B将包括具有中-高风险WM的患者，其中患者将接受RAD 001/硼替佐米/利妥昔单抗的组合。这些II期研究的主要目的是评估WM患者的缓解深度。目的2是确定PI 3 K和NF-kB通路的遗传和表观遗传调节因子及其在WM治疗耐药中的作用，目的3是确定骨髓微环境通过PI 3 K和NF-kB通路赋予治疗耐药的作用。 虽然罕见，但与其他淋巴增生性疾病相比，WM的生物学畸变更为同质，因此，它可能成为其他低度淋巴瘤和浆细胞恶液质的模型疾病，其中使用新型治疗药物鉴定和功能验证了异常分子途径。

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.