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

基本信息

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
项目类别：
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

项目摘要

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.

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 年估计死亡人数超过 49,920 人。尽管过去十年 FDA 批准了多种新疗法，但 5 年生存率仍然极低。此外，虽然人们对结合 KRAS 基因密码子 12/13 检测 EGFR 靶向抗体的“靶向”患者感到非常兴奋，但这一发现是在 FDA 批准这些药物 5 年后才发现的，导致数十亿美元的浪费的美元（以及副作用）“治疗”受益机会为 0% 的患者。迫切需要新方法和新疗法。为此，我们创建了一种源自患者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。一个有前途的药物靶点是非受体激酶 Src。这种蛋白调节多个级联反应，影响细胞粘附、迁移和侵袭，当这些因素失调时，肿瘤细胞就会破坏其微环境，不依赖于正常的调节信号，迁移到远处并侵入宿主组织。这种表型的结果是转移，这是癌细胞导致器官功能障碍并最终死亡的关键机制。我们发现了对 Src 抑制敏感的人类结直肠肿瘤细胞系和外植体的子集。使用基因测序、基因微阵列（最高得分对分析）和 FISH，我们开发了一种推定的综合基因组预测器，用于在开始治疗之前选择敏感肿瘤/患者。下一步是在扩大的临床前测试（包括新型小鼠肝转移模型）中完善预测因子，并进行两阶段的 II 期临床试验。我们组建了一支由国家认可的 Src 抑制剂和临床生物标志物开发专家组成的团队，他们完全有资格执行这项工作。目标是证明，使用存档的肿瘤组织，接受萨拉卡替尼治疗的生物标志物阳性患者队列将比同时入组的生物标志物阴性患者组具有更高的缓解/无进展率。我们还将对一部分患者进行连续的肿瘤活检，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，可以验证和扩展结直肠癌人类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 Src 抑制剂合理组合研究的丰富来源。此外，人类外植体异种移植模型的效用也具有更广泛的影响，目前全球范围内正在对许多癌症类型进行探索，作为癌症诊所的模拟器。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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

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
影响因子：
0
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