Pancreas cancer drug shows promise

An experimental drug combination may provide “a new weapon against pancreatic cancer”, BBC News has reported.

In a search for new ways to fight the aggressive cancer, scientists combined an existing chemotherapy drug called gemcitabine with an experimental chemical called MRK003. The chemical can block the actions of a protein called ‘gamma secretase’ that plays a range of roles in the body. To test the effect of this combination they gave the mixture to mice genetically engineered to develop pancreatic cancer. They found that that the mice survived 26 days with the combination treatment, compared with just nine when given an inactive dummy drug. Cancer Research UK reports that a human trial of gemcitabine combined with another gamma secretase blocker are now underway.

Pancreatic cancer often has a poor prognosis as it’s usually only diagnosed at an advanced stage, by which time it is resistant to many conventional treatments. It is the fifth most common cause of cancer death in the UK, and patients with metastatic disease (where the cancer has spread) survive between two and six months on average.

This animal study has reported promising results for a new form of combination therapy. However, there are limitations to what can be learnt from animal tests, so the results of the current clinical trial will provide a much clearer indication of how safe or successful this regime is for treating patients.

 

Where did the story come from?

The study was carried out by researchers from the Cancer Research UK Cambridge Research Institute, Cambridge University and Merck Research Laboratories, USA. It was funded by the University of Cambridge and Cancer Research UK, the Li Ka Shing Foundation and Hutchison Whampoa Limited, the UK National Institute for Health Research, Cambridge Biomedical Research Centre and the collaborative research programme at Merck, a pharmaceutical company. The study was published in the peer-reviewed Journal of Experimental Medicine.

This story was covered by the BBC and Metro. The coverage was accurate and explained that the drug is part of an ongoing phase I/II clinical trial.

 

What kind of research was this?

This study examined the use of an experimental drug in a mouse model of pancreatic cancer and on cells grown in the laboratory. Animal models of disease provide a useful way to test what might happen if human patients were given a particular drug. Although the animal models don’t necessarily reflect what would happen in humans, they can be invaluable in exploring the properties of potential treatments. The mouse model in this research has already been used to test several pancreatic cancer drugs, with researchers finding that it accurately modelled the responses seen in patients with the condition.

This is the ideal study design for preliminary trials of new drugs. Drugs need to be shown to be well-tolerated and effective in the laboratory and in animals before trials on humans can take place. 

 

What did the research involve?

The researchers took mice that modelled the main subtype of pancreatic cancer, called pancreatic ductal adenocarcinoma. This type accounts for around 90% of pancreatic cancer cases. The researchers wanted to test a novel drug called MRK003, a type of “inhibitor” that blocks the ‘gamma secretase pathway’. Gamma secretase is involved in a signalling pathway between cells, which is disrupted in many cancers.

To test their theory, the researchers looked at the effect of several treatment regimes involving MRK003, administering it alone or in combination with a drug called gemcitabine that is already clinically used to treat pancreatic cancer. In particular, the researchers looked at:

  • the way treatment affected the expression of certain markers that are characteristic of pancreatic cancer
  • the effect on mice survival
  • the effect on the tumour cells

 

What were the basic results?

The researchers found that MRK003 could reduce the expression of certain pancreatic cancer markers. When given alone, MRK003 had no effect on the survival of pancreatic cancer model, but when given in combination with gemcitabine the median survival time of the mice was significantly increased, from nine days when given a placebo to 26 days when given MRK003 and gemcitabine in combination (p=0.002). The researchers found that combination treatment promotes tumour cell death and suppresses tumour growth.

 

How did the researchers interpret the results?

The researchers concluded that this research supports the further investigation of gamma secretase inhibitors (drugs like MRK003) in combination with gemcitabine for the treatment of patients with pancreatic ductal adenocarcinoma.

 

Conclusion

Patients diagnosed with pancreatic cancer can have a poor outlook, as the disease is aggressive and often advanced by the time it produces any symptoms. Despite being a relatively rare form of cancer (with around 7,800 cases diagnosed each year), it’s the fifth most common cause of cancer death in the UK. Patients with metastatic disease (where the cancer has spread) have a median survival of between two and six months.

Given the current poor outlook for pancreatic cancer patients, there is a real need for new treatment options for the condition. This experimental study, although only in mice, has produced positive results for the combination therapy involving a gamma secretase inhibitor and gemcitabine. Gemcitabine is an established treatment for pancreatic cancer, but it currently provides only modest survival results.

The combination treatment was found to promote the death of tumour cells and suppress tumour growth, and increased survival time to 26 days (compared to nine days with a placebo).

These are exciting early results in an area with a clear need for better treatments. However, it will take the results of further clinical trials, such as the phase I/II clinical trial currently underway, to tell how successful or safe this regime is for treating patients.

Analysis by Bazian

Cook N, Frese KK, Bapiro TE et al. Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma. The Journal of Experimental Medicine, February 20 2012

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