Regulation of the P13K/AKT pathway in Waldenstrom Macroglobulinemia

描述（由申请人提供）：瓦尔登斯特伦巨球蛋白血症（WM）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。因此，有一个强大的理论基础，新的治疗目标异常分子途径在WM。PI 3 K/AKT通路在许多淋巴增生性恶性肿瘤中作为细胞凋亡、细胞周期调节和肿瘤增殖的关键调节因子。此外，PI 3 K通路调节淋巴细胞的迁移和运输，表明它可能调节WM中的归巢。我们的初步数据表明，与正常对照相比，WM细胞中PI 3 K通路的成员上调。新型治疗剂哌立福新下调AKT导致体外WM细胞增殖的显著抑制和凋亡的诱导。此外，我们的数据表明，哌立福辛抑制WM细胞在体外的迁移和粘附和在体内归巢。基于这些发现，我们建议在II期研究中研究这种新型药物，同时进行沿着精心设计的转化研究。我们假设AKT抑制剂哌立福新将增加复发/难治性WM患者的总体缓解率，并对WM细胞归巢和粘附至骨髓微环境具有显著的抑制作用。我们将在三个具体目标中研究这一假设。目的1是确定AKT抑制剂哌立福新在复发/难治性WM患者中的安全性、肿瘤缓解率和缓解持续时间。目的2是确定对哌立福新的体内应答/抗性机制，目的3是确定PI 3 K/AKT通路在WM中的迁移和粘附调节中的作用。这些研究将有助于确定PI 3 K/AKT通路在WM中的作用，并允许设计未来针对该通路的治疗试验，以及与其他新型靶向药物的药物组合。

DESCRIPTION (provided by applicant): Waldenstrom Macroglobulinemia (WM) remains incurable with a median overall survival of 5-6 years, and most patients succumb to disease progression. Therefore, there is a strong rationale for novel therapies that target aberrant molecular pathways in WM. The PI3K/AKT pathway acts as a critical regulator of apoptosis, cell cycle regulation, and tumor proliferation in many lymphoproliferative malignancies. In addition, the PI3K pathway regulates migration and trafficking in lymphocytes indicating that it may regulate homing in WM. Our preliminary data demonstrate that members of the PI3K pathway are upregulated in WM cells as compared to normal control. Downregulation of AKT by a novel therapeutic agent, Perifosine leads to significant inhibition of proliferation and induction of apoptosis in WM cells in vitro. In addition, our data demonstrate that perifosine inhibits migration and adhesion of WM cells in vitro and homing in vivo. Based on these findings, we propose to study this novel agent in a phase II study along with carefully designed translational research studies. We hypothesize that the AKT inhibitor perifosine will increase the overall response rate in patients with relapsed/refractory WM, and have a significant inhibitory effect on homing and adhesion of WM cells to the bone marrow microenvironment. We will study this hypothesis in 3 specific aims. Aim 1 is to determine the safety, tumor response rate, and duration of response for the AKT inhibitor, perifosine in patients with relapsed/refractory WM. Aim 2 is to determine the mechanisms of response/resistance to perifosine in vivo, and Aim 3 is to determine the role of the PI3K/AKT pathway in the regulation of migration and adhesion in WM. These studies will help define the role of the PI3K/AKT pathway in WM and allow the design of future therapeutic trials targeting this pathway, and combinations of agents with other novel targeted agents.