Determinants of Efficacy to the Akt Inhibitor Perifosine in Colorectal Cancer

Akt 抑制剂哌立福辛治疗结直肠癌疗效的决定因素

• 批准号: 8294604
• 负责人: Cathy Eng
• 金额: $ 10.31万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294604
• 关键词: Alkylphosphocholine Compound; Apoptosis; Apoptotic; Archives; Autophagocytosis; Bioavailable; Biological Markers; Biological Products; Biopsy; Blood; Blood Platelets; Blood specimen; Breast; Cancer Patient; Cell Proliferation; Cell Survival; Cell membrane; Cells; Clinical Data; Clinical Trials; Codon Nucleotides; Colorectal; Colorectal Cancer; Correlative Study; Data; Detection; Development; Doctor of Medicine; Double-Blind Method; Down-Regulation; Drug resistance; EGFR inhibition; Employee Strikes; FDA approved; Fluorouracil; Formalin; Foundations; Hematologic Neoplasms; Immunohistochemistry; In Vitro; KRAS2 gene; Knowledge; Loss of Heterozygosity; MAPK8 gene; Malignant Neoplasms; Methylation; Molecular; Mutation; Mutation Analysis; NF-kappa B; Neoplasm Metastasis; Nuclear; Oncogenes; Oral; Ovarian; PI3K/AKT; PIK3CA gene; PTEN gene; Paraffin Embedding; Pathway interactions; Patient Selection; Patients; Perifosine; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Phosphorylation; Placebo Control; Plasma; Prognostic Marker; Progression-Free Survivals; Protein Array; Protein-Serine-Threonine Kinases; Proteome; Proteomics; Proto-Oncogene Proteins c-akt; Publications; Qualifying; Randomized; Raptors; Ras/Raf; Reporting; Research; Resistance; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Techniques; Therapeutic; Time; Tissues; Transcriptional Activation; Treatment Efficacy; Tumor Tissue; Unresectable; base; cancer cell; capecitabine; cell growth; chemotherapy; double-blind placebo controlled trial; experience; human FRAP1 protein; in vivo; inhibitor/antagonist; metastatic colorectal; molecular marker; novel; overexpression; placebo controlled study; response; therapy development; transcription factor; tumor

DESCRIPTION (provided by applicant): Advanced surgically unresectable colorectal patients have limited treatment options. Recent pivotal research enforces the necessity of identification and appropriate application of predictive and prognostic markers (if available) for optimal selection of systemic chemotherapy. Akt is a serine/threonine kinase that promotes cell proliferation and survival and may be abnormally or constitutively activated (overexpression and mutation), altered by PI3K (mutation), and/or loss of PTEN (mutation, loss of heterozygosity, or methylation). Perifosine is an orally bioavailable alkylphospholipid that blocks localization of Akt to the cell membrane and its phosphorylation in-vitro and in-vivo. Striking phase II data of perifosine capecitabine demonstrated a 2- to 3-fold superior time to progression (TTP), response, and overall survival (OS) in metastatic colorectal patients (MCRC). These results are the foundation for a randomized, placebo-controlled, double blinded, phase III trial of capecitabine perifosine (X-PECT) in previously treated MCRC patients. Perifosine is the first putative Akt inhibitor in phase III development. Archived tissue, pre- and on-treatment (before cycle #1 and at cycle #2) blood and tissue correlatives will be obtained. Specific Aim #1: To determine whether PI3K pathway aberrations predict response, progression-free survival (PFS) and OS to perifosine. Mutation status of key oncogenes including PIK3CA, PIK3R1, Akt, ras, and raf, will be evaluated through Sequenom mutation analysis on formalin-fixed paraffin embedded (FFPE) archival tissue. Loss of PTEN will be assessed by immunohistochemistry (IHC). Hypothesis: We hypothesize that patients having tumor aberrations activating PI3K signaling (PIK3CA, PTEN mutations, and PTEN loss by IHC) will derive significant benefit from perifosine. Endpoint: Identification of pretreatment biomarkers that correlate with efficacy of perifosine therapy. Specific Aim #2: To determine whether perifosine inhibits Akt signaling in metastatic tumors and determine whether this correlates with its anti-tumor effect. 1. To assess effect of perifosine on PI3K pathway signaling, apoptosis, and proliferation by IHC. 2. To determine effect of perifosine on PI3K pathway signaling utilizing reverse phase protein array (RPPA) a high-throughput, functional proteomic technique. RPPA will be used for detection of baseline cell signaling, expression of putative drug resistance markers, and alterations in the functional proteome. 3. To correlate changes in pharmacodynamic expression in pre- and on-treatment peripheral blood mononuclear cell's (PBMC's) and platelet-rich plasma (PRP) with tumor tissue. Hypothesis: We hypothesize that perifosine treatment will result in inhibition of phosphorylated Akt (p-Akt) and downstream signaling thereby inhibiting cell proliferation and enhancing apoptosis. Endpoint: Pharma- codynamic biomarker changes will correlate with efficacy of perifosine therapy.

描述（由申请人提供）：晚期手术不可切除的结直肠患者的治疗选择有限。最近的关键性研究强调了识别和适当应用预测和预后标志物（如果可用）以最佳选择全身化疗的必要性。Akt是一种丝氨酸/苏氨酸激酶，其促进细胞增殖和存活，并且可以被异常或组成性激活（过表达和突变）、被PI 3 K改变（突变）和/或PTEN缺失（突变、杂合性缺失或甲基化）。哌立福辛是一种口服生物可利用的烷基磷脂，其在体外和体内阻断Akt定位于细胞膜及其磷酸化。哌立福新卡培他滨的惊人II期数据显示，在转移性结直肠患者（MCRC）中，进展时间（TTP）、缓解和总生存期（OS）均上级2- 3倍。这些结果是在先前治疗的MCRC患者中进行卡培他滨哌立福新（X-PECT）的随机、安慰剂对照、双盲、III期试验的基础。哌立福新是第一个公认的Akt抑制剂在III期开发。将获得存档的组织、治疗前和治疗中（第1周期前和第2周期时）的血液和组织相关物。具体目标#1：确定PI 3 K通路畸变是否预测对哌立福新的反应、无进展生存期（PFS）和OS。将通过对福尔马林固定石蜡包埋（FFPE）存档组织进行Sequenom突变分析，评价关键癌基因（包括PIK 3CA、PIK 3R 1、Akt、ras和raf）的突变状态。将通过免疫组织化学（IHC）评估PTEN的丢失。假设：我们假设具有激活PI 3 K信号传导的肿瘤畸变（PIK 3CA、PTEN突变和通过IHC的PTEN损失）的患者将从哌立福新获得显著益处。终点：与哌立福新治疗疗效相关的治疗前生物标志物的鉴定。具体目标#2：确定哌立福新是否抑制转移性肿瘤中的Akt信号传导，并确定这是否与其抗肿瘤作用相关。1.通过IHC评估哌立福新对PI 3 K通路信号传导、凋亡和增殖的影响。2.利用反相蛋白质阵列（RPPA）这一高通量功能蛋白质组学技术确定哌立福新对PI 3 K通路信号传导的影响。RPPA将用于检测基线细胞信号传导、推定耐药标志物的表达和功能蛋白质组的改变。3.将治疗前和治疗中外周血单核细胞（PBMC）和富血小板血浆（PRP）中的药效学表达变化与肿瘤组织相关联。假设：我们假设哌立福新处理将导致磷酸化Akt（p-Akt）和下游信号传导的抑制，从而抑制细胞增殖并增强细胞凋亡。终点：药物共动力学生物标志物变化将与哌立福新治疗的疗效相关。