Monday, 13 July 2015

Drug Hunting and Cancer: The future of Medical Sciences Part 2

In the second part of my triptych, I am following the logic of the New Scientist in exploring what the future holds for Drug Discovery, in particular in the area of cancer research. In many ways, the promises of successful drug hunting are a little like Elmer J Fudd's success in hunting down Bugs Bunny. He gets close, it looks a cert.... but somehow Bugs always gets away! (I also intend to cover new antibiotics, a particularly hot potato in the world of medicine and its associated politics, but the Blog was getting too long, so this will be in a supplementary section, to follow). Let me first look at a brief history of drugs, to provide some perspective on how Science has impacted on drug discovery over the last 20 years and then why microbes and tumour cells remain a major challenge.

Drugs are not new. Moreover, the spectacular advances in Molecular Life Sciences that many would say began after the first field trials of Penicillin, throughout World War II, and included Watson and Crick's structure for DNA, Sanger's sequencing of the first protein (the hormone insulin), not forgetting Kendrew and Perutz's ground-breaking work in protein crystallography. It was in fact a slightly distracted doctor who during the Victorian era picked the wrong"potion" from his shelf and inadvertently, but successfully, administered the first dose of paracetamol (well a closely related compound), to treat a patient with fever. In fact apart from the medicinal herbs mixed and formulated by village "pharmacists" that have their roots (sorry!) in traditional cures, it was the Victorians and their 20th Century proteges that in my view laid a formidable foundation for 20th and 21st century medicine. 

The antimalarial compound, artemesinin
In fact it could be argued that desperation is the mother of drug discovery! If the regulatory barriers to drug release that exist today had been in place over the last 120 years, many of the compounds we can buy over the counter may not be available. And it could be argued that the synthetic organic chemists that have been the mainstay of the pharmaceutical industry, in particular since the 1960s, would have been severely handicapped without the clues from aspirin, paracetamol, not to mention simple anaesthetics! In fact I have recently been to a number of drug discovery talks where chemists, armed with the sophistication of combinatorial instruments, molecular modelling software and the latest separation devices are revisiting Natural Products for their new ideas. It seems to me that it is the interplay between Natural Product Chemistry, Synthetic Chemistry, Synthetic Biology and Molecular Biology and its new polyomics approaches, that will provide the biggest breakthroughs.

Image result for cancerWhat is cancer? Most of you will be familiar with someone who has suffered from cancer, a disease whose name strikes fear into the heart of most. We know from experience that while many recover from cancer, the threat of its return haunts the victim (and their family and friends) and that many die from the disease. I am sure you have heard doctors say that "cancer is not one disease but many". And that the prognosis for one person can be quite different for the next. I think this tells you straight away that cancer results from some degree of disruption to the complex cellular regulatory processes that keep us healthy. Cancer can result from the inappropriate activity of one or more biological control pathways: this may take the form of  bad timing or the  bad location of a process, or alternatively it can arise from too much or too little of a key control molecule. Cancer is rarely caused by the loss of a single, isolated function, like the loss of an enzyme activity in a metabolic pathway. In fact if that appears to be the case, then that molecule usually turns out to play roles in other cellular processes, that were initially overlooked. In short the more treatable diseases are like the failure of a light bulb: fixed by replacement, but cancer is more like the failure of your electrical fuse box, which can be catastrophic.

Image result for cancer treatmentCancer has been around in the literature since the early days of medicine and has been written about by medical pioneers like Galen and Hippocrates, and until relatively recently (around 50 years ago), it was assumed to be "incurable", with surgery (early treatment), radiotherapy (from 1900 onward) and chemotherapy (from 1950s: the most successful early drug being the DNA replication inhibitor methotrexate) providing patients with limited hope. During the 1980s, the remarkable advances in microbial molecular cloning paved the way for a new understanding of the causes of cancer. The genes responsible for eliciting cancer if they are mutated, lost or rearranged, were isolated for the first time. The initial group of cancer genes were said to be dominant (take a look here) and were given the name "oncogenes". You can read about them here, but suffice to say they encode proteins that normally regulate cellular processes, and these processes are often called signalling pathways. Some of these molecules regulate the expression of families of genes, or the transduction of signals between and within cells. Again, I hope you can see where this is going, from a drug discovery perspective. If you are trying to use a drug to interrupt a simple metabolic step, catalysed by a single enzyme, you are more likely to succeed than if your drug is targeted at an oncoprotein, that modulates the activity of many cellular processes. This work, shortly followed by the discovery of recessive cancer genes, called tumour suppressors, and exemplified by p53 has provided the pharmaceutical industry on the one hand with valuable insight, but on the other has highlighted the challenge of finding a "cure for cancer".

Today, anticancer drugs are among the most sophisticated (and consequently expensive) medicines in use. Treatments with the latest drugs can be £100 000 per year, compared with methotrexate, which would cost around £100 per year. Clearly there are major economic and political challenges here, which partly led to the formation of the NICE organisation to help provide an evidence base for regulating  drug prescription. The drugs in use are the products of research that can cost nearly £1bn (usually cited as $1bn), and therefore drug companies need a means of recovering their costs. (These issues are highly controversial, but are not the topic for discussion here).  Take Herceptin (otherwise known as Trastuzumab: the -mab suffix indicates this is drug is based on a monoclonal antibody). The drug is marketed by Genentech for certain classes of breast cancer (note the web address! This shows you how long the company has been in business). Briefly, the activity of a class of epidermal growth factor (EGF) receptors (these membrane bound molecules are the triggers for cell growth when EGF binds to them), specifically HERs 1-4, are modulated by Trastuzumab. It is thought that the drug acts mainly by promoting the degradation of HER-2, leading to a reduction in cell growth, but other mechanisms are also involved that are less well known. HER-2 is hyperactive in many breast tumours and by administration of Trastuzumab, the tumour is inhibited. The drug also promotes the "intervention" of the body's immune defences, giving rise to a powerful anti cancer effect. This drug has been a major success: but at a price. Nevertheless, our understanding of the immune system is beginning to provide inroads into the treatment of an increasing number of cancers. 

Figure thumbnail fx1In the New Scientist special edition, the emergence of targeted drugs that not only treat the diseased cells and tissues, but also send a digital report on the status of the disease, are suggested to be around the corner! I shall exemplify this with the recent work published in the journal Cell on Photostatins (PST), also covered in a recent article in the Economist. If a molecule could be synthesised that interferes selectively with a Biological process and whose activity can be tuned by a non-invasive pulse of light (hv), then drugs become not only therapeutic but also diagnostics. The term "theranostics" would encompass this type of compound. In the above image, cells are shown as a blue nucleus with green radiating fibres: these are microtubules (take a look here). The addition of the PST molecule, followed by a specific pulse of light, leads to the breakdown in the microtubule network. Since microtubules are central to the cell's many growth and cell division functions, you can see how this approach has enormous potential for precision/personalised medicines. The introduction of a simple test for the over-expression of HER-2 protein: the target for Herceptin, has been approved and marketed by Dako. The company's Hercep Test is one of the earliest examples of a theranostic agent. The combination of these two functions in the form of drugs administered to treat and report on the targeted cells, is a quantum leap in the treatment of complex diseases like cancer and one that offers exciting prospects. It reminds me of the excitement I felt when at the age of around 12, I saw the film "Fantastic Voyage"; a Jules Verne type fantasy, in which a submarine and crew are miniaturised and injected into a scientist's veins to fix a life threatening blood clot. The prospect of controlled nano drones is probably more likely to be the future reality, as we begin to combine targeted intervention, reporting and surveillance. I agree with the New Scientist view that progress across these fronts will begin to transform modern medicine. However, I also believe that the biggest challenge is not whether we can innovate, but how on earth do we pay for it all!

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