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: 8192035
• 负责人: Cathy Eng
• 金额: $ 24.31万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8192035
• 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. PUBLIC HEALTH RELEVANCE: Perifosine is an orally bioavailable alkylphospholipid that is the only putative Akt inhibitor in phase III development for the treatment of metastatic colorectal cancer patients. Results from a randomized phase II trial of perifosine in combination with capecitabine were overwhelmingly positive for time to progression and overall survival in heavily pretreated metastatic colorectal cancer patients. However, the exact mechanism of how perifosine impacts the PI3K/PTEN/AKT/mTOR signal transduction pathway is not well understood; molecular marker analysis of archival tissue, as well as pre- and on-treatment tissue and blood specimens for predictive biomarker identification in the phase III (X-PECT) trial will provide fundamental knowledge about perifosine but also other PI3K/AKT inhibitors in development for the treatment of metastatic colorectal cancer and other malignancies.

描述（由申请人提供）：无法手术切除的晚期结直肠患者的治疗选择有限。最近的关键研究强调了识别和适当应用预测和预后标志物（如果有）的必要性，以优化全身化疗的选择。 Akt 是一种丝氨酸/苏氨酸激酶，可促进细胞增殖和存活，可能被异常或组成型激活（过度表达和突变）、PI3K（突变）和/或 PTEN 缺失（突变、杂合性缺失或甲基化）改变。 Perifosine 是一种口服生物可利用的烷基磷脂，可阻断 Akt 在细胞膜上的定位及其在体外和体内的磷酸化。帕利福辛卡培他滨引人注目的 II 期数据表明，在转移性结直肠患者 (MCRC) 中，进展时间 (TTP)、缓解时间和总生存期 (OS) 提高了 2 至 3 倍。这些结果是在既往接受过治疗的 MCRC 患者中进行卡培他滨哌立福辛 (X-PECT) 随机、安慰剂对照、双盲 III 期试验的基础。 Perifosine 是第一个处于 III 期开发的假定 Akt 抑制剂。将获得存档的组织、治疗前和治疗中（第 1 周期之前和第 2 周期）血液和组织相关物。具体目标#1：确定 PI3K 通路畸变是否可以预测哌立福辛的反应、无进展生存期 (PFS) 和 OS。将通过对福尔马林固定石蜡包埋 (FFPE) 档案组织进行 Sequenom 突变分析来评估关键癌基因（包括 PIK3CA、PIK3R1、Akt、ras 和 raf）的突变状态。 PTEN 的缺失将通过免疫组织化学 (IHC) 进行评估。假设：我们假设患有激活 PI3K 信号传导的肿瘤畸变（PIK3CA、PTEN 突变和 IHC 导致的 PTEN 缺失）的患者将从哌立福辛中获得显着益处。终点：鉴定与哌立福辛治疗功效相关的治疗前生物标志物。具体目标#2：确定哌立福辛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 评估哌立福辛对 PI3K 通路信号传导、细胞凋亡和增殖的影响。 2. 利用反相蛋白阵列 (RPPA)（一种高通量、功能性蛋白质组学技术）确定哌立福辛对 PI3K 通路信号传导的影响。 RPPA 将用于检测基线细胞信号传导、假定的耐药标记物的表达以及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）的药效学表达变化与肿瘤组织相关联。假设：我们假设哌立福辛治疗会抑制磷酸化 Akt (p-Akt) 和下游信号传导，从而抑制细胞增殖并增强细胞凋亡。终点：药效生物标志物的变化将与哌立福辛治疗的疗效相关。 公共健康相关性：Perifosine 是一种口服生物可利用的烷基磷脂，是唯一处于 III 期开发阶段、用于治疗转移性结直肠癌患者的假定 Akt 抑制剂。培立福辛联合卡培他滨的一项随机 II 期试验结果显示，对于接受过多次治疗的转移性结直肠癌患者的进展时间和总生存期而言，结果显示压倒性积极。然而，哌立福辛如何影响 PI3K/PTEN/AKT/mTOR 信号转导通路的确切机制尚不清楚；对档案组织以及治疗前和治疗中的组织和血液样本进行分子标记分析，以在 III 期 (X-PECT) 试验中进行预测性生物标记物识别，这将提供关于哌立福辛以及正在开发的其他 PI3K/AKT 抑制剂的基础知识。治疗转移性结直肠癌和其他恶性肿瘤。