Blocking the protein CD47, which was found at elevated levels on both pancreatic neuroendocrine tumour cells and pancreatic ductal adenocarcinoma cells, caused tumour regression in preclinical models of both these types of pancreatic cancer, according to results presented at the AACR special conference on Pancreatic Cancer: Innovations in Research and Treatment.

“Our analysis of tumour samples from patients with pancreatic neuroendocrine tumours and those with pancreatic ductal adenocarcinoma has shown that for both these types of pancreatic cancer, CD47 is expressed at elevated levels on the cells that make up the bulk of the tumours and on the tumour-initiating cells, which are the cells that propagate disease and cause metastasis,” said Geoffrey W. Krampitz, M.D., a doctoral candidate in the laboratory of Irving L. Weissman, M.D., director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University School of Medicine and the Ludwig Center for Cancer Stem Cell Research at Stanford in California.

“We also found that using a monoclonal antibody that blocks CD47 eradicates tumours in various preclinical models of both pancreatic neuroendocrine tumours and pancreatic ductal adenocarcinoma.

“We are optimistic that targeting CD47 in this way could provide a new approach for treating patients with pancreatic cancer who have a desperate need for improved treatment options,” added Krampitz, who is also a general surgery resident in the Department of Surgery at Stanford Hospital and Clinics.

Krampitz and Jeffrey A. Norton, M.D., chief of the Divisions of General Surgery and Surgical Oncology at Stanford University School of Medicine, obtained tumour samples from 39 patients with pancreatic neuroendocrine tumours who were undergoing surgery to remove their cancers.

Analysis of 19 of these samples showed that some cells in the tumours had characteristics of tumour-initiating cells and that these cells, as well as the bulk tumour cells, had elevated levels of CD47.

The researchers also obtained tumour samples from 39 patients with pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer, who were undergoing surgical resection.

As with the pancreatic neuroendocrine tumours, all the pancreatic ductal adenocarcinoma cells in the samples examined had elevated levels of CD47.

They then tested the effects of blocking CD47 function in a number of different preclinical models of pancreatic neuroendocrine tumours and pancreatic ductal adenocarcinoma.

Anti-tumour activity was observed in each model.

In one model, in which mice were transplanted with tumours from either patients with pancreatic neuroendocrine tumours or those with pancreatic ductal adenocarcinoma, treatment with a monoclonal antibody that recognises and attaches to CD47 and blocks its function caused dramatic tumour regression.

“CD47 is a ‘don’t-eat-me’ signal,” explained Krampitz.

“Most cells have this protein on their surface and it stops them from being removed by immune cells called macrophages. As cells age or become damaged, they lose expression of CD47, which leads to their elimination by macrophages through a process called programmed cell removal. Pancreatic neuroendocrine tumours and pancreatic ductal adenocarcinomas have co-opted CD47 to help them avoid removal by the immune system. We have preliminary evidence that suggests that by blocking the don’t- eat-me signal, our monoclonal antibody promotes the clearance of cancer cells by programmed cell removal.

“We need to do more preclinical studies but are hopeful that our participation in the recently announced Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Convergence Dream Team will allow us to test our approach in the clinic in the not-too-distant future,” he added.

Source: AACR