Scientists at Imperial College London have launched a project to develop new drugs for patients who stop responding to cancer treatment. 

The team, led by Dr Maurits Kleijnen, has been awarded £140,000 by Leukaemia & Lymphoma Research to improve treatments for myeloma, a currently incurable blood cancer. Myeloma is diagnosed in over 3,300 people in the UK every year and causes debilitating pain in patients through bone damage.

In recent years, a drug called Velcade has proven very effective at increasing survival times for myeloma patients. Unfortunately, patients eventually develop resistance to this treatment and the cancer returns. 

Velcade is a proteasome inhibitor: a targeted drug that causes cancer cells to ‘commit suicide’, preventing the disease from spreading. Proteasomes are found in all cells including myeloma cells. They control the amounts of proteins that, in turn, regulate cell growth. When drugs such as Velcade disable the proteasome, defective proteins build up uncontrollably in the myeloma cell, causing the cell to self-destruct. 

Experts in proteasome biology, Dr Kleijnen and his team have developed new research compounds called cPE inhibitors, which are able to target proteasomes in a new way. The team has shown in the laboratory that one of these new compounds is able to kill Velcade-resistant myeloma cell populations.

Dr Kleijnen, of Imperial’s Department of Medicine, said: “We are working towards preventing the emergence of treatment resistance among myeloma patients, by developing new types of compounds that are effective against Velcade-resistant myeloma cells. cPE inhibitors are the first of their kind – they seem to engage with the proteasome in an entirely different manner to current proteasome inhibitor drugs such as Velcade.”

The grant from Leukaemia & Lymphoma Research will enable the Imperial team to look specifically at exactly how cPE inhibitors target myeloma cells, with the aim that these can be developed into drugs that can be given to patients.

Dr David Grant, Scientific Director at Leukaemia & Lymphoma Research, said: “Myeloma remains a cancer which is very difficult to cure. Many patients diagnosed with myeloma will relapse at some stage after the first course of treatment. This research offers real hope that new effective drugs can be developed to keep the cancer under control.”
 

Cancer ‘stem cells’ are something of a hot topic in research circles at the moment. Despite decades of research and clinical trials, advanced cancers, especially once they spread in the body, are notoriously difficult to control or eradicate. Professor Mel Greaves at the Institute of Cancer Research argues this month in Nature that the genetic makeup of cancer stem cells may help explain how patients become resistant to drugs.

When designing new drugs, cancer stem cells have been widely regarded as the ‘bull’s-eye’ in the target. Recent research by Prof Greaves’ team into the most common form of childhood cancer, acute lymphoblastic leukaemia (ALL), reveals that the crucial stem cells that drive the cancer have, within individual patients, many different sets of mutations. 

This work, funded by Leukaemia & Lymphoma Research, suggests that there is no single ‘bull’s-eye’ but rather multiple targets that are diverse and constantly shifting. It vividly confirms that, as long suspected, cancer clones evolve in a Darwinian fashion by genetic ‘natural selection’ in the body.

“This Darwinian perspective has important implications for leukaemia and cancer therapy,” says Professor Greaves. “Our research may help explain why advanced cancers remain so difficult to eradicate. A massive investment is being made in developing new drugs for advanced cancer that target the tumours’ specific genetic mutations as potential ‘Achilles heels’. Whilst some of the new drugs show considerable promise, it is important to recognise that these genetic mutations are constantly evolving, which has the potential to create lethal resistance.”

A cancer stem cell is created when a single healthy stem cell becomes genetically mutated. These mutated stem cells then go on to clone multiple copies of themselves, driving and sustaining the cancer. It had been assumed that leukaemia developed in a ‘linear model’, with leukaemia stem cells acquiring additional genetic mutations with successive divisions. Variations in the combinations of genetic abnormalities found within different cancer stem cells were thought to represent earlier versions of the cancer stem cell in its development.

Professor Greaves has in fact shown that in the very early stages of the disease the original cancer stem cell produces distinct ‘sub-clones’ of itself. Each of these sub-clones contains different combinations of genetic mutations and will go on to develop further sub-clones independently of each other, like branches. While some sub-clones will be destroyed by drugs, other branches may be resistant to treatment and become dominant, driving the cancer forward.

While thankfully over 90% of children now survive childhood ALL, the long term survival rates for children who relapse remain tragically much lower. The ‘Darwinian’ model of cancer development offers a convincing explanation of why children might relapse. It seems clear that developing a deeper knowledge of how leukaemia stem cells operate and how some may evade treatment is vital to making sure that all children survive in the future.

Henry Winter - Science Communications Team

On Saturday 4 February 2012 it is World Cancer Day which unites people around the globe in the fight against cancer. It’s a chance to highlight successes in medical research, as well as acknowledge that there is still much to do to improve treatment and diagnosis for all cancers.

In 1960 when Leukaemia & Lymphoma Research was founded blood cancer was a virtual death sentence. Now, just over 50 years later, the survival rates have drastically improved; most notably now more than 90 percent of children with the most common form of childhood leukaemia are cured. And treatment for patients with myeloma has been one of the fastest improving areas in cancer research in the last 10 years – amazing for a disease that was virtually untreatable only a few decades ago.

That said for some patients with blood cancer the chances of survival remain low. So there is still much work to be done.

However I am confident that these blood cancers can also be beaten. Not only is some of the best medical research being done on blood cancers, the network of experts that we have in this country, and the extent of collaborative research really is remarkable.

Our world-class research includes the whole spectrum of disciplines from basic laboratory research, which is vital for understanding how blood cancers develop, pioneering new treatments and improving diagnosis; translational research, which brings a detailed understanding of the diseases to develop and refine treatments and clinical trials, that test new treatments in patients and ultimately save more lives.

Last year we launched the Trials Acceleration Programme (TAP) in the UK, a unique network of 13 treatment centres which will speed delivery of new life-saving treatments. This will facilitate our leading researchers across the UK being able to work together to run more clinical trials for patients with blood cancers. And I am certain we can really push survival rates up for all the blood cancers in a relatively short period of time.

Professor Chris Bunce – Research Director, Leukaemia & Lymphoma Research