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: 8676468
• 负责人: Wells A. Messersmith
• 金额: $ 29.87万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676468
• 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 Targeting; 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; 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.

简介(申请人提供)：结直肠癌是每年导致癌症死亡的第二大原因，2009年估计有超过49,920人死亡。尽管在过去的十年里，FDA批准了多种新的治疗方法，但5年存活率仍然非常低。此外，尽管随着KRAS基因密码子12/13检测EGFR靶向抗体的加入，人们对“靶向”患者感到非常兴奋，但这一发现发生在FDA批准这些药物的5年后，导致数十亿美元(以及副作用)“治疗”那些没有机会受益的患者。人们迫切需要新的方法和新的治疗方法。为此，建立了患者来源的结直肠癌人异种移植模型，以帮助开发结直肠癌的新疗法。一个很有希望的药物靶点是非受体激酶，Src。这种蛋白质调节影响细胞黏附、迁移和侵袭的多个级联反应，当调节失调时，这些因子使肿瘤细胞能够破坏其微环境，移动到遥远的部位，并独立于正常的调节信号入侵宿主组织。这种表型的结果是转移，这是癌细胞导致器官功能障碍和最终死亡的关键机制。我们发现了一组对Src抑制敏感的人类大肠肿瘤细胞株和外植体。利用基因测序、基因微阵列(得分最高的配对分析)和FISH，我们开发了一种假定的整合基因组预测因子，用于在开始治疗之前选择敏感的肿瘤/患者。下一步是在扩大的临床前试验(包括一种新的小鼠肝转移模型)中提炼预测因子，以及进行两阶段II期临床试验。我们已经组建了一支由国家认可的Src抑制剂和临床生物标记物开发专家组成的团队，他们非常有资格执行这项工作。其目的是证明，利用存档的肿瘤组织，接受萨拉卡替尼治疗的生物标记物阳性患者的队列将比同时登记的生物标记物阴性患者组有更高的反应/无进展率。我们还将对一组患者进行系列肿瘤活检，以探索肿瘤水平上的Src抑制因子的作用。这项临床试验代表着一个非常独特的机会，可以鉴定和扩大人类结直肠癌异种移植实验的结果，以进行可能的III期测试。我们还期望该数据集成为开发与Src抑制剂的合理组合研究的丰富来源。此外，关于人类外植体异种移植模型的实用性也有更广泛的影响，目前全球正在探索许多癌症类型，作为癌症临床的模拟器。

项目成果

Gene array and fluorescence in situ hybridization biomarkers of activity of saracatinib (AZD0530), a Src inhibitor, in a preclinical model of colorectal cancer.

• DOI: 10.1158/1078-0432.ccr-10-0066
• 发表时间: 2010-08-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Arcaroli JJ;Touban BM;Tan AC;Varella-Garcia M;Powell RW;Eckhardt SG;Elvin P;Gao D;Messersmith WA
• 通讯作者: Messersmith WA

Common PIK3CA mutants and a novel 3' UTR mutation are associated with increased sensitivity to saracatinib.

• DOI: 10.1158/1078-0432.ccr-11-3167
• 发表时间: 2012-05-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Arcaroli JJ;Quackenbush KS;Powell RW;Pitts TM;Spreafico A;Varella-Garcia M;Bemis L;Tan AC;Reinemann JM;Touban BM;Dasari A;Eckhardt SG;Messersmith WA
• 通讯作者: Messersmith WA