A Pilot Clinical Study of Treatment Guided by Personalized Tumorgrafts in Patients with Advanced Cancer

Molecular Cancer Therapeutics - Tập 10 Số 8 - Trang 1311-1316 - 2011
Manuel Hidalgo1,2, Elizabeth Bruckheimer1,3,4,5,2, N.V. Rajeshkumar1,3,4,5,2, Ignacio Garrido‐Laguna1,3,4,5,2, Elizabeth De Oliveira1,3,4,5,2, Belén Rubio‐Viqueira1,4,5,2, Steven J. Strawn1,3,4,5,2, Michael J. Wick1,3,4,5,2, James Martell1,3,4,5,2, David Sidransky1,4,5,2
1Authors' Affiliations: Departments of 1Oncology and 2Otolaryngology - Head and Neck Surgery, Johns Hopkins University School of Medicine; 3Champions Biotechnology Inc., Science and Technology Park at Johns Hopkins, Baltimore, Maryland; 4Centro Integral Oncológico “Clara Campal”; 5Clinical Research Program, Spanish National Cancer Research Center (CNIO); 6Universidad CEU-San Pablo, Madrid, Spain; 7South Texas Accelerated Research Therapeutics, San Antonio, Texas
2Universidad CEU-San Pablo, Madrid, Spain
3Champions Biotechnology Inc., Science and Technology Park at Johns Hopkins, Baltimore, Maryland
4Clinical Research Program, Spanish National Cancer Research Center (CNIO)
5South Texas Accelerated Research Therapeutics, San Antonio, Texas

Tóm tắt

Abstract Patients with many advanced solid cancers have very poor prognosis, and improvements in life expectancy are measured only in months. We have recently reported the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was later treated with DNA-damaging agents, on the basis of the observation of significant activity of this class of drugs against a personalized tumorgraft generated from the patient's surgically resected tumor. Here, we extend the approach to patients with other advanced cancers. Tumors resected from 14 patients with refractory advanced cancers were propagated in immunodeficient mice and treated with 63 drugs in 232 treatment regimens. An effective treatment regimen in the xenograft model was identified for 12 patients. One patient died before receiving treatment, and the remaining 11 patients received 17 prospectively guided treatments. Fifteen of these treatments resulted in durable partial remissions. In 2 subjects, no effective treatments were found. Overall, there was a remarkable correlation between drug activity in the model and clinical outcome, both in terms of resistance and sensitivity. The data support the use of the personalized tumorgraft model as a powerful investigational platform for therapeutic decision making and to efficiently guide cancer treatment in the clinic. Mol Cancer Ther; 10(8); 1311–6. ©2011 AACR.

Từ khóa


Tài liệu tham khảo

Potash, 2010, What can CCR do for you?, Clin Cancer Res, 16, 4069, 10.1158/1078-0432.CCR-10-1861

Winer, 2009, Clinical cancer advances 2008: major research advances in cancer treatment, prevention, and screening—a report from the American Society of Clinical Oncology, J Clin Oncol, 27, 812, 10.1200/JCO.2008.21.2134

Lynch, 2004, Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib, N Engl J Med, 350, 2129, 10.1056/NEJMoa040938

Mok, 2009, Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, N Engl J Med, 361, 947, 10.1056/NEJMoa0810699

Chin, 2011, Cancer genomics: from discovery science to personalized medicine, Nat Med, 17, 297, 10.1038/nm.2323

Jimeno, 2009, KRAS mutations and sensitivity to epidermal growth factor receptor inhibitors in colorectal cancer: practical application of patient selection, J Clin Oncol, 27, 1130, 10.1200/JCO.2008.19.8168

Dong, 2010, Patient-derived first generation xenografts of non-small cell lung cancers: promising tools for predicting drug responses for personalized chemotherapy, Clin Cancer Res, 16, 1442, 10.1158/1078-0432.CCR-09-2878

Rajeshkumar, 2009, Antitumor effects and biomarkers of activity of AZD0530, a Src inhibitor, in pancreatic cancer, Clin Cancer Res, 15, 4138, 10.1158/1078-0432.CCR-08-3021

Rubio-Viqueira, 2006, An in vivo platform for translational drug development in pancreatic cancer, Clin Cancer Res, 12, 4652, 10.1158/1078-0432.CCR-06-0113

Messersmith, 2009, Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts, Mol Cancer Ther, 8, 1484, 10.1158/1535-7163.MCT-09-0075

Yu, 2005, Gene expression profiling of the irinotecan pathway in colorectal cancer, Clin Cancer Res, 11, 2053, 10.1158/1078-0432.CCR-04-1254

Villarroel, 2011, Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer, Mol Cancer Ther, 10, 3, 10.1158/1535-7163.MCT-10-0893

Tol, 2009, Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer, N Engl J Med, 360, 563, 10.1056/NEJMoa0808268

Horstmann, 2005, Risks and benefits of phase 1 oncology trials, 1991 through 2002, N Engl J Med, 352, 895, 10.1056/NEJMsa042220

Jones, 2009, Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene, Science, 324, 217, 10.1126/science.1171202

Thông tin
Thông tin xuất bản

Molecular Cancer Therapeutics

Tập 10 Số 8

1311-1316

Thông tin tác giả