TY - JOUR
T1 - Personalizing cancer treatment in the age of global genomic analyses
T2 - PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer
AU - Villarroel, Maria C.
AU - Rajeshkumar, N. V.
AU - Garrido-Laguna, Ignacio
AU - De Jesus-Acosta, Ana
AU - Jones, Siân
AU - Maitra, Anirban
AU - Hruban, Ralph H.
AU - Eshleman, James R.
AU - Klein, Alison
AU - Laheru, Daniel
AU - Donehower, Ross
AU - Hidalgo, Manuel
PY - 2011/1
Y1 - 2011/1
N2 - Metastasis and drug resistance are the major causes of mortality in patients with pancreatic cancer. Once developed, the progression of pancreatic cancermetastasis 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 revealedbiallelic inactivation of the gene encoding PalB2 protein in this patient's cancer; themutation 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.
AB - Metastasis and drug resistance are the major causes of mortality in patients with pancreatic cancer. Once developed, the progression of pancreatic cancermetastasis 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 revealedbiallelic inactivation of the gene encoding PalB2 protein in this patient's cancer; themutation 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.
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U2 - 10.1158/1535-7163.MCT-10-0893
DO - 10.1158/1535-7163.MCT-10-0893
M3 - Article
C2 - 21135251
AN - SCOPUS:78751559414
SN - 1535-7163
VL - 10
SP - 3
EP - 8
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 1
ER -