This entry is part 13 of 27 in the series Our milestones
The development of the brain tumour drug temozolomide (also known as Temodar, Temodal and Temcad) is a shining example of how the public’s generous support of Cancer Research UK has directly benefited the lives of people with cancer.For Parminder, it’s meant that she’s now back at work after being diagnosed with a brain tumour in 2011. In this latest post in Our Milestones series, we look back at the history of temozolomide, and how it’s made a difference to people with brain tumours.
Temozolomide is now used worldwide to treat the most common adult brain tumour, called glioblastoma, as well as some other types. In combination with radiotherapy, temozolomide has become the international standard-of-care for thousands of people with this type of cancer.
Cancer Research UK scientists led the development of temozolomide. From early pioneering lab work, to the discovery, development and first clinical trials of the drug in people with cancer, our researchers were involved every step of way.
The undisputed ‘father’ of temozolomide is Malcolm Stevens, now Emeritus Professor at the University of Nottingham.
We spoke to him to find out more about temozolomide and its life-changing history.
The early years
The story of temozolomide starts in the late 1970s in Birmingham, where Professor Stevens was leading a team of researchers at Aston University.
Building on the earlier work of pioneering Cancer Research UK scientist, Professor Tom Connors, they were carrying out innovative lab experiments to develop new drug prototypes and test their potential against cancer.
It took almost a decade of painstaking work and rigorous testing in the lab, but by 1987 they’d made a new molecule that looked like a promising candidate. Initially known by the unattractive moniker CCRG81045, this was gradually developed, step by step, into what we now call temozolomide.
“I don’t think there was ever a ‘Eureka’ hats-in-the-air moment,” said Professor Stevens. “There was no particular moment in time when temozolomide was ‘discovered’”.
In fact, he says, all of the work he did – as a PhD student, and as lecturer at Edinburgh University – contributed to the drug’s development.
But, says Stevens, it was funding from Cancer Research UK (then known as the Cancer Research Campaign) that was vital, allowing the team to push forward with developing their new compounds, without pressing commercial or legal interests.
Watch this video to hear the rest of our interview with Professor Stevens:
Into the clinic
Cancer Research UK was again instrumental in the next phase of the drug’s journey.
Earlier in the 1980s, we formed our Phase I/II Clinical Trials Committee, the forerunner to our Drug Development Office. The committee’s aim was simple – to improve the transition of potential new cancer treatments from the lab to patients for testing in trials.
At the time, the Clinical Trials Committee didn’t have many new cancer drugs to work with, so they were eager to find potential treatments to bring forward. Professor Stevens’s exciting work convinced the Committee to set up the first ever trial of temozolomide in a small group of cancer patients at Charing Cross Hospital in London. The results of this early-stage trial were very promising, encouraging Cancer Research UK to support further clinical trials in larger groups.
But larger trials brought an additional challenge to be overcome. Temozolomide was first produced in the relatively small quantities needed for lab work at Aston University. Once clinical trials started, demand for the drug increased dramatically.
Thankfully, the researchers at our Formulation Unit at the University of Strathclyde were at hand. They developed a process to make bigger batches of temozolomide. And they manufactured and supplied the drug in capsules to treat patients in clinical trials.
Out into the world
As we had hoped, the results of the phase II trials in 1997 showed that the drug could bring significant benefits to patients with brain tumours. As well as extending survival, patients with glioblastoma benefited mentally and physically from treatment with temozolomide. The drug then progressed to the next stage –larger phase III trials. But to do this, we needed help.
Cancer Research Technology (CRT) is Cancer Research UK’s commercial and development arm, which helps to turn our scientists’ discoveries in the lab into treatments for cancer patients. CRT licensed the drug to the pharmaceutical company Schering-Plough (now merged with Merck). The company then funded a series of trials that led to the approval of temozolomide for use on the NHS in the UK and in other countries.
In 2001, NICE (the National Institute of Health and Care Excellence) ruled that temozolomide could be used for “second line” therapy for people with brain tumours that had come back after treatment, because there were so few other options available at the time. But to prove temozolomide’s worth as a first choice therapy for patients, there had to be more trials.
Dr Clive Stanway is Chief Scientific Officer at CRT. He was at the 2006 ASCO annual conference in the US, when he heard the results of the major large-scale phase III trial of temozolomide alongside radiotherapy for people with glioblastoma brain tumours:
“It was very exciting, and you could feel the atmosphere change in the room when the results were announced,” he recounts.
“We could all see that the drug could bring significant increases in survival from these aggressive tumours, and was very quickly going to make a difference to how people were treated.”
As a result of larger trials, temozolomide was approved by NICE as a front-line drug for people newly-diagnosed with brain tumours in 2007, and has now been used to treat many thousands of patients around the world.
Into the future
Worldwide sales of temozolomide have now reached $1 billion. Because of our partnership with Schering-Plough, we receive a royalty on this. The money is ploughed straight back into our research, funding new work into the prevention, diagnosis and treatment of cancer.
But the story of temozolomide doesn’t end here. The drug continues to benefit more and more people each year – people like Parminder, who was diagnosed with a brain tumour in 2011, when she was just 28.
She had surgery and radiotherapy, as well as two courses of temozolomide, and it looks like her tumour is gone for now. As well as being back on her feet – last year she ran Race For Life to support our research – she’s now back at work as an advertising sales executive.
“Personally, I found it was a hard course of treatment to have, but I am glad to have got through it”, she says. “I am so grateful for the treatment that I had and I think it is fantastic how organisations like Cancer Research UK are working on developing these treatments for the future.”
For now Parminder is doing well, and we’re all keeping our fingers crossed that things stay that way. And for many thousands of people around the world going through treatment for brain tumours, temozolomide is playing a vital role in the treatment that is helping to control their disease, giving them precious months, years and even decades more with their families.
Our scientists are now testing whether the drug can be used for other types of cancer, and continue to refine how it’s used to treat patients through clinical trials.
This includes OPARATIC, an important trial testing temozolomide in combination with new drugs called PARP inhibitors for glioblastoma. This trial, and others like it, could bring important benefits to many more people in future.
The discovery and development of temozolomide would not have been possible without the support of the public – and with your continued support, we’ll be able to carry on developing the life-saving treatments of tomorrow.
Audette R.C. et al Studies on the mechanism of action of the tumour inhibitory triazenes., Biochemical pharmacology, PMID: 4722457
Stevens M.F. et al Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine., Cancer research, PMID: 3664486
Newlands E.S. et al Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856)., British journal of cancer, PMID: 1739631
Bower M. et al Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma., Cancer chemotherapy and pharmacology, PMID: 9332462
Mirimanoff R.O. et al Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial., Journal of clinical oncology : official journal of the American Society of Clinical Oncology, PMID: 16735709