Researchers and drug companies are ganging up for a new push against cancer.
“THERE is no treatment.” This is the conclusion of an Egyptian papyrus, written around 3000BC, that is the oldest known description of the scourge that is now called “cancer”. And so, more or less, it remained until the 20th century, for merely excising a tumour by surgery rarely eliminates it. Only when doctors worked out how to back up the surgeon’s knife with drugs and radiation did cancer begin to succumb to treatment–albeit, to start with, in a pretty crude fashion.
Now, however, that crudeness is rapidly giving way to sophistication, as a new wave of cancer treatments comes to market. In 2012 more than 500 potential cancer drugs were under investigation, according to a survey by IMS Health, an American research group–over five times as many as were being developed in the next biggest category, diabetes.
Three trends are helping to fill this cancer-drug cornucopia. One is the increase in demand as people live longer, and thus become more likely to develop cancer. According to the World Health Organisation, there were 14m new cases of cancer around the world in 2012. In 2030 there will be nearly 22m. The second trend is the rising price of cancer drugs, particularly in America, the biggest market. More expensive drugs increases profitability. The third is a rapid expansion of scientific knowledge about cancer, the result of both the plummeting cost of genetic sequencing (see chart) and a better understanding of how to recruit the immune system to attack the disease.
Or, rather, the diseases. For there are hundreds of kinds of cancer. Their common factor is that they are all caused by cells dividing interminably because something has gone wrong with the victim’s genes. The problem may be extra copies of a crucial gene, damage to a gene, modifications that affect a gene’s function, or the merger of two chromosomes to create a novel gene not seen in healthy cells. Sometimes these problems are inherited. More often they arise when cellular wear and tear goes unrepaired, a process exacerbated by certain chemicals and radiation.
Understanding the genetic changes that cause particular cancers may suggest ways to attack them with specially tailored drugs. The first example of such a targeted treatment came in 2001, when Novartis launched Gleevec, a treatment for chronic myeloid leukaemia. Gleevec blocks the activity of a protein called BCR-ABL, which is the product of an abnormal gene created by a merger of chromosomes 9 and 22. Before Gleevec, less than a third of those diagnosed with chronic myeloid leukaemia were still alive five years later. After it became available, that figure jumped to 90%.
New magic bullets
Gleevec’s success inspired others to search for targeted cancer drugs. For example, Pfizer came up with crizotinib (sold under the brand name Xalcori), for lung-cancer patients with a mutated version of a gene called ALK, which encodes a protein that instructs lung cells to divide uncontrollably. And Roche developed vemurafenib (sold as Zelboraf), which goes after another rogue protein, generated by a mutated version of a gene called BRAF. It tells skin cells to reproduce, causing melanoma.
Though much better than older cancer drugs, Gleevec and its successors are not perfect. Many cancers are driven by more than one mutation. Cells also tend to pick up new mutations as they divide. Cancer cells divide a lot, so mutations can accumulate rapidly. And sometimes, to add to the problem, one of the enabling mutations of a cancer is of a gene involved in the DNA-repair mechanism, which a healthy cell would use to deal with mutations. BRCA1 and BRCA2, both often implicated in breast cancer, are DNA-repair genes.
DNA sequencing means it is becoming possible to track mutations, one tumour at a time. This helps in understanding how cancers in different tissues work and it also holds out the hope of treatments tailored even more closely to an individual’s needs.
The International Cancer Genome Consortium (ICGC), is doing this for 50 different sorts of cancer, with a global team studying the genomes of more than 25,000 individual tumours. Researchers working on the Cancer Genome Atlas, an American effort that is part of the ICGC, published a series of papers in 2013 showing some of the complex relationships. Chris Sander of Memorial Sloan-Kettering Cancer Centre, in New York, used an algorithm based on tumours’ genetic and epigenetic characteristics to describe 31 subclasses of cancer. tumours from one type of lung cancer, for example, share traits with those of head and neck cancer. Li Ding, of Washington University, in St Louis, examined more than 3,000 tumours across 12 types of cancer. She reported 127 mutated genes that seem to propel cancer, with most tumours having between two and six mutations.
Identifying common genes is only the start. Some mutations seem to play starring roles in one cancer while being supporting characters in another. For example, Dr Ding discovered that the BRAF mutation, known to be present in about half of melanomas, was also found in other cancers, such as 7% of lung adenocarcinomas and 4% of colon and rectal carcinomas.
Even though there remains more basic science to be explored, the genetic approach points to a new way of matching patients to drugs. At the moment, many targeted cancer drugs are accompanied by a diagnostic test for the relevant mutation. The falling cost of sequencing means that a patient might now be tested for hundreds of mutations or even his full “exome” (the DNA that encodes proteins, less than 2% of the total). This means that someone who became resistant to one treatment could immediately be given another, based on the results of such tests. He might even be given a cocktail of treatments in the way that a cocktail of antiretroviral drugs is used to suppress HIV.
Cheaper sequencing is also changing the way that clinical trials are conducted. In November a group of academic researchers and companies, in collaboration with America’s National Cancer Institute, announced the Master Protocol trial. This will examine five potential treatments for squamous-cell carcinoma, a type of lung cancer. Rather than hunting separately for five groups of patients with the mutations relevant to each drug, the researchers will use a test from Foundation Medicine, a company that screens patients for abnormalities in 236 genes linked to cancer. They will then match volunteers with each of the five drugs. This approach cuts the administrative time and hassle of what would otherwise be a huge undertaking.
The other novel approach to treating cancer is to rally the immune system to join the fight. Ipilimumab, a drug to treat melanoma, was launched in 2011 by Bristol-Myers Squibb, branded as Yervoy. It is a so-called “checkpoint inhibitor”, which by removing a blocking mechanism allows immune-system cells called T-lymphocytes to attack cancer cells (as they are pictured doing on the previous page). The results in some people have been remarkable, but not so in others.
Now other checkpoint inhibitors are being developed. Nivolumab, also from Bristol-Myers Squibb, MK-3475 from Merck, and MPDL3280A from Roche also unleash the immune system on cancer cells. These drugs, moreover, could be effective in more than one type of cancer. Ipilimumab may also fight lung cancer and prostate cancer. In June Roy Herbst, of Yale University, showed that MPDL3280A helped the immune system fight several different types of tumours.
Other medicines are at earlier stages of development. Bristol-Myers Squibb, for example, is testing a chemical that binds to interleukin-21 receptors on T-lymphocytes and other immune cells, helping the T-cells survive and boosting their activity. Unlike checkpoint inhibitors, which work by releasing the brakes on immune cells, this drug pushes the accelerator.
In the lab researchers are trying a variety of approaches. Luigi Naldini of the San Raffaele Telethon Institute for Gene Therapy, in Milan, and his colleagues report this week in Science Translational Medicine that they genetically modified stem cells to make white blood cells that produced a certain protein, interferon, that helped clear tumour cells in mice.
It may, indeed, be possible to combine the two approaches of targeted drugs and immunotherapy. Bristol-Myers Squibb has already tried this, testing ipilimumab in combination with Roche’s targeted melanoma treatment, vemurafenib. Researchers stopped the trial in April because of signs of liver toxicity, but that does not mean the general idea is unsound.
On December 5th, for example, GlaxoSmithKline announced partnerships with six academic research centres to develop new therapeutic drug combinations. Axel Hoos, the company’s vice-president for oncology, says the firm may soon test a targeted drug in combination with an immunotherapy from another company.
This approach could lead to prescribable treatments arriving faster if promising combinations are tested before either component had been approved for use by itself–a process recently made easier by a change in the rules by the Food and Drug Administration, America’s drug regulator.
Who is able to use these wonder drugs, if and when they become available, will depend on how deep are the pockets of those who are paying for them. In America a typical course of four doses of ipilimumab costs more than $US100,000. Like all wars, the one against cancer is going to cost a lot of money, one way or another.
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