Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer
| Autor: | Daniel A. Laheru, Anirban Maitra, Alison P. Klein, Ana De Jesus-Acosta, Ralph H. Hruban, Maria Cristina Villarroel, Manuel Hidalgo, N. V. Rajeshkumar, Siân Jones, Ross C. Donehower, James R. Eshleman, Ignacio Garrido-Laguna |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Cancer Research DNA damage Mitomycin Mice Nude Biology Bioinformatics medicine.disease_cause PALB2 Gene Deoxycytidine Article Metastasis Mice Pancreatic cancer medicine Neoplasm Animals Humans DNA Breaks Double-Stranded Precision Medicine Mutation business.industry Tumor Suppressor Proteins Cancer Nuclear Proteins Middle Aged medicine.disease Xenograft Model Antitumor Assays Gemcitabine Pancreatic Neoplasms Oncology Drug Resistance Neoplasm Cancer research Disease Progression Female Personalized medicine business Fanconi Anemia Complementation Group N Protein |
| Zdroj: | Molecular cancer therapeutics. 10(1) |
| ISSN: | 1538-8514 |
| Popis: | Metastasis and drug resistance are the major causes of mortality in patients with pancreatic cancer. Once developed, the progression of pancreatic cancer metastasis is virtually unstoppable with current therapies. Here, we report 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 xenograft generated from the patient's surgically resected tumor. Mitomycin C treatment, selected on the basis of its robust preclinical activity in a personalized xenograft generated from the patient's tumor, resulted in long-lasting (36+ months) tumor response. Global genomic sequencing revealed biallelic inactivation of the gene encoding PalB2 protein in this patient's cancer; the mutation is predicted to disrupt BRCA1 and BRCA2 interactions critical to DNA double-strand break repair. This work suggests that inactivation of the PALB2 gene is a determinant of response to DNA damage in pancreatic cancer and a new target for personalizing cancer treatment. Integrating personalized xenografts with unbiased exomic sequencing led to customized therapy, tailored to the genetic environment of the patient's tumor, and identification of a new biomarker of drug response in a lethal cancer. Mol Cancer Ther; 10(1); 3–8. ©2010 AACR. Mol Cancer Ther; 10(1); 3–8. ©2010 AACR. |
| Databáze: | OpenAIRE |
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