A receptor for the dopamine neurotransmitter promotes growth and spread of pancreatic cancer -- and schizophrenia drugs, which block the function of this receptor, slowed tumor growth and metastatic spread in mice, according to researchers at McGill University and the German Cancer Research Center.
Cancer of the pancreas is an extremely aggressive disease with a dismal prognosis. “While the overall five-year survival rate of all cancer patients stands at 63%, it is only about 5% for pancreatic cancer – a number that has remained largely unchanged for the last three decades,” notes Yasser Riazalhosseini, professor of Human Genetics at McGill and corresponding author of the new study, published in the journal Gastroenterology.
“The tumors do not cause any signs or symptoms for a long time and are therefore diagnosed late,” says Jörg Hoheisel from the German Cancer Research Center (Deutsches Krebsforschungszentrum, or DKFZ) in Heidelberg, who co-led the study with Riazalhosseini. “In addition, the tumor biology is very aggressive, i.e., the cancer starts spreading metastases early on. And to make things even worse, pancreatic cancer rapidly develops resistance against available chemotherapy drugs.”
Along with colleagues from Heidelberg, Tübingen, Liverpool, and Verona, the McGill and DKFZ researchers undertook a large-scale analysis of gene activities in 195 pancreatic cancer cases. “We leveraged quantitative and computational biology approaches that we have established in order to identify genes that may play a central role in several pancreatic cancer-relevant signaling pathways. We found that the gene for the dopamine receptor DRD2 was significantly more active in cancer cells than in healthy pancreatic cells,” says Riazalhosseini, who is also head of Cancer Genomics at the McGill University and Genome Quebec Innovation Centre. “And the levels of DRD2 protein found in the cancer cells were four times normal levels.”
Blocking the dopamine receptor inhibits cancer growth
The dopamine receptor mediates the effect of dopamine, a brain chemical that increases motivation and drive. How can a receptor protein known to clinicians primarily for its role in schizophrenia and psychotic disorders influence the malignant characteristics of cancer cells? The researchers pursued this question in pancreatic cancer cell lines in which they had turned off the DRD2 gene. They observed that these cells in fact grew more slowly and formed smaller tumors when transferred to mice.
DRD2, a key molecule in schizophrenia, is targeted by numerous psychopharmaceutical agents. Drugs that block the function of DRD2 (“dopamine antagonists”) have been available since the 1950s. Among them are the antipsychotics pimozide and haloperidol, medications often prescribed to treat schizophrenia. Using these substances, the researchers succeeded in substantially slowing the growth and impeding the mobility of pancreatic cancer cell lines.
The researchers transferred human pancreatic cancer cells to mice and allowed them to grow into tumors. After treating the animals with haloperidol they developed smaller tumors and, more importantly, fewer metastases than untreated animals.
This study was an international and multidisciplinary endeavor supported by expertise in oncology, genomics, computational, cell and molecular, and animal biology. “The fact that we show established medications that inhibit DRD2 have promising results for treating pancreatic cancer paves the way for a faster translation of our findings into the clinic through a drug repositioning strategy, Riazalhosseini said . “At the initial step of this strategy, we are examining the efficacy of different doses of DRD2 inhibitors in different animal models before moving on to patients.”
Funding for the work was provided by the German Federal Ministry of Education and Research, Heidelberger Stiftung Chirurgie,the Integrated European Platform for Pancreas Cancer Research, the Canadian Institutes of Health Research, the Ministère de l’économie, de l’innovation et de l’exportation du Québec, the Canada Research Chairs program, the Italian Association for Cancer Research, theItalian Cancer Genome Project, and the Fonds de Recherche du Québec – Santé (FRQS).
“Expression of DRD2 is Increased in Human Pancreatic Ductal Adenocarcinoma and Inhibitors Slow Tumor Growth in Mice”, Pouria Jandaghi, Hamed S. Najafabadi, Andrea S. Bauer, Andreas I. Papadakis, Matteo Fassan, Anita Hall, Anie Monast, Magnus von Knebel Doeberitz, John P. Neoptolemos, Eithne Costello, William Greenhalf, Aldo Scarpa, Bence Sipos, Daniel Auld, Mark Lathrop, Morag Park, Markus W. Büchler, Oliver Strobel, Thilo Hackert, Nathalia A. Giese, George Zogopoulos, Veena Sangwan, Sidong Huang, Yasser Riazalhosseini, Jörg D. Hoheisel. Gastroenterology, published online Aug. 28, 2016