A new molecular signature to orient patients towards the treatment which will be most effective for their tumor.
Results from Juan Iovanna’s team at the Centre de Recherche en Cancerologie de Marseille just published in the Journal EMBO Molecular Medicine describe the identification of a new molecular signature which allow pancreatic cancer patients’ response to targeted therapies which are more efficient than standard chemotherapy.
Pancreatic ductal adenocarcinoma (PDAC) has the worst mortality rate and the
lowest overall survival of all cancers (less than 5% at 5 years). Surgery is the most
effective treatment but the mean life expectancy of the 15-20% of patients eligible
for surgery, and even for those patients, aggressive metastasis often appears post-operation and survival of patients with metastatic disease is only 3 to 6 months. Chemotherapy and radiotherapy offer limited benefit for patients undergoing surgery in metastatic disease.
Like other malignant diseases, pancreatic cancer results from a complex combination of genetic, epigenetic and environmental factors which gives rise to a particularly heterogeneous disease, with patients having different sets of symptoms, predisposition to early metastasis, and therapeutic responses. This heterogeneity highlights the necessity to stratify patients – distinguish different subgroups of patients depending on their molecular and/or pharmacological profiles- with the goal of better predicting responses to therapies.
Dr Iovanna’s team identified a biomarker which is specific to patients whose tumors are sensitive to a drug called JQ1. JQ1 inhibits the deregulation of gene expression by the c-Myc protein, which is necessary for the progression of one third of pancreatic cancer tumors.
Two groups of patients could thus be distinguished, one with a characteristic profile of upregulation of 10 genes, which allows the identification of tumors with high levels of c-Myc and high sensitivity to JQ1, and one group with a characteristic profile of upregulation of 6 other genes, which allows the identification of tumors with low levels of c-Myc and resistance to JQ1.
This molecular signature should allow low cost assays to be developed for the molecular profiling of patient biopsies, and an alternative treatment to be offered to the patients most likely to respond better to c-Myc targeted therapy than to standard chemotherapy.
Gene Expression Profiling of Patient-Derived Pancreatic Cancer Xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1: Implications to individualized medicine efforts.
Bian B, Bigonnet M, Gayet O, Loncle C, Maignan A, Gilabert M, Moutardier V, Garcia S, Turrini O, Delpero JR, Giovannini M, Grandval P, Gasmi M, Ouaissi M, Secq V, Poizat F, Nicolle R, Blum Y, Marisa L, Rubis M, Raou JL, Bradner JE, Qi J, Lomberk G, Urrutia R, Saul A, Dusetti N, Iovanna J.
EMBO Molecular Medicine, 2017. doi: 10.15252/emmm.201606975