Biomarker-Driven Src Inhibitor Studies in Colorectal Cancer Patients

结直肠癌患者中生物标志物驱动的 Src 抑制剂研究

• 批准号: 8105230
• 负责人: Wells A. Messersmith
• 金额: $ 28.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-02 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105230
• 关键词: Acute; Adverse effects; Aftercare; Algorithms; Antibodies; Antineoplastic Agents; Biological Markers; Biology; Biopsy; Cancer Biology; Cancer Etiology; Cancer Model; Cancer Patient; Cell Adhesion; Cell Line; Cessation of life; Cetuximab; Clinic; Clinical; Clinical Protocols; Clinical Trials; Codon Nucleotides; Colorectal Adenocarcinoma; Colorectal Cancer; Colorectal Neoplasms; Country; Culture Media; Data; Data Set; Development; Diagnosis; Diagnostic; Digit structure; Disease; Distant; Drug Approval; Drug Delivery Systems; Drug usage; Enrollment; Epidermal Growth Factor Receptor; Europe; FDA approved; Faculty; Fluorescent in Situ Hybridization; Functional disorder; Gene Dosage; Genes; Genomics; Goals; Grant; Guidelines; Healthcare Systems; Hospitals; Human; Image; Immunohistochemistry; Institutional Review Boards; Invaded; KRAS2 gene; Laboratories; Liver; Malignant Neoplasms; Malignant neoplasm of pancreas; Medicine; Metastatic Neoplasm to the Liver; Methods; Modeling; Molecular; Monoclonal Antibodies; Mus; Mutation; Neoplasm Metastasis; Nude Mice; Operating Rooms; Organ; Package Insert; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Phenotype; Phosphotransferases; Play; Pre-Clinical Model; Preclinical Testing; Principal Investigator; Process; Progression-Free Survivals; Proteins; Qualifying; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; SCID Mice; SRC gene; Sampling; Savings; Second Primary Neoplasms; Signal Transduction; Site; Solid Neoplasm; Source; Spleen; Staging; Survival Rate; Testing; Tissues; Toxic effect; Translating; Travel; Tumor Cell Line; Tumor Tissue; Validation; Western Blotting; Work; Xenograft Model; Xenograft procedure; advanced disease; base; cancer cell; cancer type; cohort; design; drug development; experience; human tissue; in vivo; inhibitor/antagonist; innovation; migration; neoplastic cell; novel; novel strategies; panitumumab; patient population; pre-clinical; preclinical study; predictive modeling; public health relevance; research study; response; src Genes; subcutaneous; tool; translational clinical trial; tumor; wasting

DESCRIPTION (provided by applicant): Colorectal cancer is the second leading cause of cancer deaths annually, with over 49,920 deaths estimated for 2009. Despite multiple new FDA-approved therapies in the last decade, the 5-year survival remains extremely poor. In addition, although there has been much excitement about "targeted" patients with the incorporation of KRAS gene codon 12/13 testing for EGFR-targeting antibodies, this discovery came 5 years after the FDA approval of these drugs, resulting in the waste of billions of dollars (as well as side effects) "treating" patients who had a 0% chance of benefit. New approaches, as well as new therapies, are desperately needed. To this end, a patient-derived colorectal cancer human explant xenograft model has been created to help develop novel therapies for colorectal cancer. A promising drug target is the non-receptor kinase, Src. This protein regulates multiple cascades that impact cellular adhesion, migration and invasion, factors that when dysregulated enable tumor cells to disrupt their microenvironment, travel to distant sites and invade host tissues independent of normal regulatory signals. The result of this phenotype is metastasis, the critical mechanism by which cancer cells cause organ dysfunction and ultimately death. We have discovered a subset of human colorectal tumor cell lines and explants sensitive to Src inhibition. Using gene sequencing, gene micro-array (top scoring pairs analysis), and FISH, we have developed a putative integrated genomic predictor to select sensitive tumors/patients prior to initiating therapy. The next steps are to refine the predictor in expanded preclinical testing (including a novel mouse liver metastases model) as well as conduct a two-stage phase II clinical trial. We have assembled a team of nationally recognized experts in Src inhibitors and clinical biomarker development who are well-qualified to perform this work. The goal is to demonstrate that using archival tumor tissue, a cohort of biomarker-positive patients treated with saracatinib will have a higher response/nonprogression rate than a simultaneously enrolled group on biomarker-negative patients. We will also perform serial tumor biopsies on a subset of patients to explore Src inhibitor effects at the tumoral level. The clinical trial represents a highly unique opportunity to qualify and extend the results of the human xenograft experiments in colorectal cancer for possible phase III testing. We also expect this dataset to be a rich source with which to develop rational combination studies with Src inhibitors. Moreover, there are also broader implications with regard to the utility of human explant xenograft models, currently being explored across the globe in many cancer types, as simulators of the cancer clinic. PUBLIC HEALTH RELEVANCE: The purpose of this project is to develop and use a set of laboratory tests to find out which colorectal cancer patients will benefit from Src inhibitors. We will use several methods to analyze patient tumor samples from when they were diagnosed with colorectal cancer, and then see if we can predict whether a Src inhibitor will work. This grant also explores the theme that cancer models from the laboratory will help guide us to better use of drugs individually directed to specific patients ("personalized medicine") in the clinic.

描述（由申请人提供）：结直肠癌是每年癌症死亡的第二大原因，2009年估计有超过49,920人死亡。尽管在过去十年中有多种新的fda批准的治疗方法，但5年生存率仍然非常低。此外，尽管人们对“靶向”患者结合KRAS基因密码子12/13检测egfr靶向抗体感到非常兴奋，但这一发现是在FDA批准这些药物5年后才发现的，导致数十亿美元（以及副作用）“治疗”那些有0%机会获益的患者。我们迫切需要新的方法和新的治疗方法。为此，建立了一种患者来源的结直肠癌人类外植体异种移植模型，以帮助开发结直肠癌的新疗法。非受体激酶Src是一个很有前景的药物靶点。该蛋白调节影响细胞粘附、迁移和侵袭的多个级联反应，当这些因素失调时，肿瘤细胞可以破坏其微环境，移动到远处并入侵宿主组织，而不依赖于正常的调节信号。这种表型的结果是转移，这是癌细胞引起器官功能障碍并最终死亡的关键机制。我们已经发现了人类结直肠肿瘤细胞系和外植体的一个子集对Src抑制敏感。利用基因测序、基因微阵列（最高评分对分析）和FISH，我们开发了一种假定的集成基因组预测器，用于在开始治疗之前选择敏感肿瘤/患者。接下来的步骤是在扩大的临床前测试（包括一种新的小鼠肝转移模型）中完善预测器，并进行两阶段的II期临床试验。我们已经在Src抑制剂和临床生物标志物开发方面组建了一个国家认可的专家团队，他们非常有资格完成这项工作。目的是证明使用档案肿瘤组织，使用saracatinib治疗的生物标志物阳性患者队列比同时入组的生物标志物阴性患者具有更高的反应/不进展率。我们还将对一部分患者进行一系列肿瘤活检，以探索Src抑制剂在肿瘤水平上的作用。该临床试验代表了一个非常独特的机会，可以验证和扩展人类异种移植实验在结直肠癌中的结果，以进行可能的III期测试。我们还希望该数据集能够成为开发Src抑制剂合理联合研究的丰富来源。此外，人类外植体异种移植模型的应用也有更广泛的意义，目前正在全球许多癌症类型中进行探索，作为癌症诊所的模拟器。