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

基本信息

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
项目类别：
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

项目摘要

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）：晚期无法切除的结直肠病患者的治疗选择有限。最近的关键研究强制执行确定和适当应用预测和预后标记（如果有），以最佳选择全身化疗。 AKT是一种丝氨酸/苏氨酸激酶，可促进细胞增殖和存活，可能会异常或组成症激活（过表达和突变），通过PI3K（突变）（突变）和/或PTEN丧失（突变，杂合性丧失，或甲基化）。 perifosine是一种口服的可生物利用烷基磷脂，可阻止Akt定位于细胞膜及其磷酸化及其体内和体内的磷酸化。钙蛋白钙替滨的引人注目的II期数据表明，转移性结直肠患者（MCRC）中，进展的时间为2至3倍（TTP），反应和总生存期（OS）。这些结果是在先前治疗的MCRC患者中进行随机，安慰剂对照，双盲，III期试验的基础。 Perifosine是第三阶段开发中的第一个假定的AKT抑制剂。将获得存档的组织，预处理和治疗（周期＃1之前和周期2）的血液和组织相关性。特定目的＃1：确定PI3K途径畸变是否预测反应，无进展生存（PFS）和OS对perifosine。包括PIK3CA，PIK3R1，AKT，RAS和RAF在内的关键致癌基因的突变状态将通过对福尔马林固定的石蜡嵌入（FFPE）档案组织的序列突变分析进行评估。 PTEN的损失将通过免疫组织化学（IHC）评估。假设：我们假设患有肿瘤畸变激活PI3K信号传导的患者（PIK3CA，PTEN突变和IHC的PTEN丢失）将从perifosine中获得显着益处。终点：与perifosine治疗有效性相关的预处理生物标志物的鉴定。特定目的＃2：确定perifosine是否抑制转移性肿瘤中的AKT信号传导，并确定该信号是否与其抗肿瘤作用相关。 1。用于评估crifosine对IHC的PI3K途径信号传导，凋亡和增殖的影响。 2。确定perifosine对PI3K途径信号传导的影响，利用反相蛋白阵列（RPPA）一种高通量，功能性蛋白质组学技术的影响。 RPPA将用于检测基线细胞信号传导，推定耐药性标记的表达以及功能蛋白质组的改变。 3。将药效学表达的变化与肿瘤组织相关联和治疗外周血单核细胞（PBMC）和富含血小板血浆（PRP）的变化与肿瘤组织。假设：我们假设perifosine治疗将导致抑制磷酸化的AKT（P-AKT）和下游信号传导，从而抑制细胞增殖并增强凋亡。终点：药物动力生物标志物的变化将与perifosine治疗的功效相关。