January 14, 2009 – A new paradigm for cancer-drug development is needed because the current focus on molecular-targeted compounds that act on key proteins is unlikely to have an impact on the most common cancers, according to Stephen Neidle, DSc, PhD, professor of chemical biology and director of the Center for Cancer Medicines at the School of Pharmacy, University of London, United Kingdom. A more "global" approach is needed, focusing on global differences in the biology, metabolism, or chemistry between normal and cancer cells, he believes.
"The current approach of molecular targeting is like shutting down 1 station in a railway network," he told Medscape Oncology. "This causes some disruption, but does not prevent the rest of the system from operating. What we need is something that can close down the whole system," he says.
Dr. Neidle was speaking last week at the 2010 School of Pharmacy lecture in London.
Molecular targeting has produced useful anticancer drugs, he said, citing as an example the "spectacular success" of imatinib (Gleevec, Novartis) in the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). However, he suggested that this success is unlikely to be repeated for the more common cancers.
"We now know that a small number of mostly rarer cancers, such as CML and GIST, are driven by changes in a very few key proteins involved in cell growth," he said. "Targeting these proteins is effective," he conceded. However, most common cancers are genetically complex, he pointed out, and are often diagnosed when this complexity has already spun out of control.
There are also multiple pathways of signaling involved, and blocking one pathway can easily be compensated for elsewhere. "Hitting a single target is unlikely to halt tumor progression in these cancers," he said.
As evidence of this, Dr. Neidle cited the relatively small impact that new targeted therapies have had on the most common cancers, such as colorectal and breast cancer. The addition of these targeted agents has delayed progression or improved survival, but often by only a few weeks, and these new drugs are very expensive.
This has resulted in some of these news drugs not being accepted in the United Kingdom. A number of these drugs have been deemed not to be cost-effective by the National Institute of Clinical Excellent (NICE), and thus are not available on the National Health Service (NHS). These negative decisions have been widely covered in the lay media, he said, with emotive headlines such as "Life prolonging cancer drugs to be banned because they cost too much."
But, in fact, these negative decisions have been in the minority, he pointed out. NICE has appraised 79 cancer drugs, and 59 of these (75%) have been approved for use on the NHS.
Nevertheless, the fact remains that many of the new drugs have only a small impact on the disease. "We need new drugs capable of making a very significant difference to patients' survival," he said.
More "Global" Approach
Dr. Neidle advocated a more global approach to cancer-drug development, which would focus on global differences between normal cells and cancer cells. One approach would be to focus on telomerase, the universal driver of cellular immortality, which is activated in more than 85% of all cancers, he said. Another is the intriguing finding and "long neglected" Warburg effect, first noted 90 years ago, in which glucose levels are elevated in cancer patients. "This is now known to be involved in global cancer cell growth regulation, and has led to excitement and activity over this as a target," he added.
An example of this more global approach to cancer-drug development is abiraterone for the treatment of prostate cancer (which is currently in large phase 3 trials).
It has a novel mechanism of action; it is the first drug to inhibit the synthesis of testosterone, which drives the growth of most hormone-dependent cancers. Although other treatment approaches target testosterone (e.g., androgen-deprivation therapy), these block the hormone after it has been released and work outside the cell, Dr. Neidle pointed out. In contrast, the action of abiraterone is more fundamental — it works inside the cell to stop the hormone being produced.
This drug was originally synthesized in the United Kingdom in 1995, at the Institute for Cancer Research, as a result of a rational design for an inhibitor of the enzyme involved in the biosynthesis of testosterone, Dr. Neidle explained. But at that time, the steroid pathway was not a "fashionable" target, compared with signaling and kinase pathways, and prostate cancer was "until recently relatively ignored," he said. It was difficult to obtain funding in the early 1990s, and initial clinical trials with the drug were abandoned prematurely, he said.
"Abiraterone was rescued by the efforts of Dr. Johann de Bono with a phase 1/2 trial at the Royal Marsden Hospital in patients with advanced prostate cancer," he continued. The results showed a greater than 50% decline in prostate-specific antigen in 71% of patients and marked symptom improvement in a high proportion of patients.
On the basis of these clinical data, the small company, Cobra International, which had licensed the drug from the British Technology Group, was acquired for $1 billion last year by Johnson & Johnson, which is now investigating abiraterone in worldwide clinical trials, Dr. Neidle told the audience. The drug is expected to reach the market in 2011/12 and "will make a big difference to the treatment of prostate cancer," he predicted.
New Drugs Only "Part of the Picture"
New drugs have an important role to play in the 'war on cancer,' but they are only one part of the picture, said Sir Mike Richards, MD, national cancer director at the NHS, who also spoke at the event. Also vitally important is screening for cancer, because earlier diagnosis improves outcomes, and incorporating innovations in surgery and radiotherapy into clinical practice.
Some new drugs are having a very significant impact on cancer, Dr. Richards said, and he cited as examples imatinib in CML, rituximab in non-Hodgkin's lymphoma, and trastuzumab in HER2-positive breast cancer.
"But for many other drugs, the impact on survival or mortality is at best 'modest'," he said, "although individual patients can benefit significantly."
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