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.