Cancer therapy gets personal
Paul Workman
The Institute of Cancer Research, London, UK
As our personalized medicine month continues, Paul Workman shares his thoughts on new targeted cancer drugs and the challenges involved in personalizing these therapies.
Twelve years after the draft human genome sequence was announced, extraordinary breakthroughs in molecularly targeted drugs mean that the era of personalized cancer medicine has truly begun — but considerable challenges remain.
It’s all in the sequence
When the US and UK premiers, Bill Clinton and Tony Blair, announced the draft reference sequence of the human genome on June 26th 2000, the press release referred to a “landmark achievement, which promises to lead to a new era of molecular medicine, an era that will bring new ways to prevent, diagnose, treat and cure disease”. So 12 years on — in fact eight years from the publication of the near-complete human sequence — how far have we come? In particular, for this article, what has been the progress in understanding and treating cancer, and especially towards the Holy Grail of personalized cancer medicine? How does our progress score on the spectrum of hype to hope?
From one-fits-all to personalized therapy
Cancers are usually treated with some combination of surgery, radiotherapy and drugs. Drugs are essential to eradicate metastatic cancer that has spread from the primary site and for blood cancers. Until recently, most patients with a given type of cancer — normally diagnosed by pathologists based on appearance under the microscope — were treated in the same way in a standard one size-fits-all approach. And yet there is growing recognition that the molecular drivers of superficially similar cancers are often very different — and may have more in common with genetically similar cancers arising from a different organ than with each other. It makes sense that treatments should be personalized to suit the individual biology and specific genetic determinants of outcome for a given cancer. But to do this systematically we need to understand cancers much better.
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"It makes sense that treatments should be personalized to suit the individual biology and specific genetic determinants of outcome for a given cancer."
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Progress since 2000: understanding tumour biology
By 2000, around 90 cancer genes had been identified by traditional methods, i.e. through homology to viral oncogenes, via transfection and cell transformation approaches, by positional cloning in inherited cancers and based on deleted regions in somatically acquired tumours, and also by identifying and cloning translocations in leukaemias.
Fast forward to 2012. Through the exploitation of the human genome sequence and the systematic mining of cancer genomes — including large-scale initiatives such as The Cancer Gene Atlas, the Cancer Genome Project and the International Cancer Genome Consortium — we now have close to 480 cancer genes and rising, from among the total of 21,000 protein-coding genes1. This is a massive increase in a short time.
Moreover, together with other omics efforts benefiting greatly from the sequence, this cancer gene cataloguing has massively increased our fundamental understanding of cancer biology. Importantly, we can use the information to diagnose individual cancers more accurately through their genetics, define what genes are driving each one, and figure out what would be the best drugs to use in each case. This is personalized medicine in operation in the clinic today.
Progress since 2000: drugging the cancer genome
To realize the full potential of personalized medicine, we clearly need to discover all cancer genes and develop molecularly targeted drugs that precisely match the full range of cancer genetics. Estimates of how many drugs we might require vary from one for each cancer gene to one for every major mechanistic grouping or pathway. With the recognition over the last few years — powered by next generation sequencing — that many cancers are frequently highly heterogeneous, containing multiple clones, and moreover that this heterogeneity changes with time under selective pressure of therapy leading to drug resistance, the number of drugs needed is likely to be at the higher, rather than lower, end of the estimates.
So hundreds, rather than tens, of personalized cancer drugs. But considerable progress is already being made.
Rapid progress — the example of BRAF
The first oncogene to be identified by cancer genome sequencing was the kinase BRAF in 2002. BRAF is mutated and activated in 50% of melanoma skin cancers and a smaller but still significant number of colorectal and thyroid tumours. This discovery led rapidly to the development of BRAF kinase inhibitors.
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"Against a background of doom and gloom for the pharma industry, we have seen the approval of nine oncology drugs in 2011 and five so far in 2012."
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Following promise in preclinical cancer models, the BRAF inhibitor vemurafenib completed Phase I clinical trials in 2010. Based on an astonishing 80% response rate in BRAF mutant melanomas that are thereby ‘addicted’ to the oncogene, vemurafenib received FDA and EMA approval in August, 2011 and February, 2012, respectively — just 10 years after the discovery of the mutant BRAF target and the elucidation of its biology and structure.
Also important is that resistance to vemurafenib developed in patients after several months. Nevertheless, in an extraordinarily fast time, actionable resistance mechanisms were identified by next generation sequencing and other modern molecular approaches — this led to promising trials of BRAF drugs in combination with inhibitors of MEK and other activated targets to overcome resistance.
Many exciting examples
Against a background of doom and gloom for the pharma industry, we have seen the approval of nine oncology drugs in 2011 and five so far in 2012. These include several innovative molecularly targeted agents, such as the ALK inhibitor, crizotinib, for non small cell lung cancer with driver ALK translocations. Abiraterone — a drug we discovered here —which blocks synthesis of testosterone that activates the driver androgen receptor (AR) and also the potent AR antagonist, enzalutamide, were approved for castration-resistant prostate cancer. The CTLA-4 monoclonal antibody ipilimumab may be a landmark drug for the immunotherapy of melanoma.
Our own estimates reveal that drug discovery and development efforts are now underway against 150-200 cancer targets, with about 80 of these being kinases. Exciting new agents in Phase II clinical development include PI3 kinase inhibitors for cancers with mutations in the alpha isoform and other pathway-activating changes, and Hsp90 inhibitors that show promise in genetic subsets of breast and non small cell lung cancer, both of which we have discovered here with our industry partners. PARP inhibitors show great promise for treatment of cancers with BRCA gene mutations — the first example of synthetic lethality in the clinic. The enzyme isocitrate dehydrogenase, mutated in brain and other cancers, is an interesting target for modification of tumour metabolism which is a hot new research area. Epigenetic regulation is a rich source of new targets, including demethylases and bromodomains. However, targets like RAS, MYC and the WNT pathway remain undrugged — illustrating the challenge of extending technical druggability space.
What’s next? — envisaging the future
While recent figures show the benefits of investment in research on improving patient outcomes, the worldwide number for annual cancer incidence is predicted to rise to 12.7 million by 2030 — an enormous unmet need2.
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"...the worldwide number for annual cancer incidence is predicted to rise to 12.7 million by 2030..."
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Basic researchers will continue to explore the genome to undercover further secrets about gene function — as revealed by recent discoveries from the international ENCODE project aimed at uncovering regulatory elements that control when and where genes are active3. A large-scale project is underway to sequence thousands of cancer genomes from multiple organs. From such co-operative team science efforts over the next five years, we will know all the genes that predispose to and cause cancer, generating many more new drug targets. Network biology approaches will reveal how these genes conspire together, informing on heterogeneity and combinatorial treatment approaches to defeat drug resistance4.
Large numbers of cancer patients already receive personalized medicines every day, based on predictive oncogene tests for approved drugs such as trastuzumab, cetuximab, erlotinib, gefitinib, crizotinib and vemurafenib. But there are currently only a handful of such linked drug-biomarker examples in routine use. Many more are needed. The major bottleneck in routine gene testing has been recognised in the UK by the Technology Strategy Board initiative co-funded by the government’s Department of Health, Cancer Research UK, Medical Research Council, industry and others to enable implementation of cost-effective stratifying gene tests within the socialised healthcare system5. Public-private partnership involving academia, government, charities, regulatory agencies and the pharma-biotech industry, as also seen in the European Medicines Initiative, will be essential to fill the innovation gap between exciting biology and personalized cancer medicines. This includes an increasing role for non-profit drug discovery, which requires the funding and expertise to achieve proof-of-concept de-risking of pioneering new approaches prior to industry investment for late stage development.
We can envisage a future in which cancer patients routinely undergo stratifying gene tests and indeed whole genome sequencing, based upon which they will receive increasingly sophisticated personal drug cocktails that are modified in real time4. How will all this be paid for? A new business model will emerge like a phoenix from the ashes of the blockbuster, enabled by approval of boutique cancer drugs based on small, inexpensive clinical trials. There would be incredible payoffs from an open, but responsible, sharing of information on the genome sequence of every patient and their response to treatment. Patients, companies and society as a whole can only benefit from this revolution.
References
1. http://www.sanger.ac.uk/genetics/CGP/Census/
3. http://genome.ucsc.edu/ENCODE/
4. Al-Lazikani B, Banerji U, Workman P. Combinatorial drug therapy for cancer in the post-genomic era. Nat Biotechnol. 2012 Jul 10,30 (7):679-92
5. http://www.innovateuk.org/ourstrategy/innovationplatforms/stratified-medicine-.ashx
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About the author:
Professor Workman is Director of the Cancer Research UK Cancer Therapeutics Unit – the largest non-profit cancer drug discovery group in the world – and Head of the Division of Cancer Therapeutics at The Institute of Cancer Research (ICR), London. He is also Deputy Chief Executive of the ICR and Harrap Professor of Pharmacology and Therapeutics. Paul is a Fellow of the Academy of Medical Sciences and of the Royal Society of Chemistry. This year he was the recipient of the Royal Society of Chemistry’s World Entrepreneur Award and led the team that won the American Association of Cancer Research’s Team Science Award for their achievements in cancer drug discovery and development. In addition, Paul was a scientific founder of two successful biotech companies, Chroma Therapeutics and Piramed Pharma.
Website: www.icr.ac.uk
In what ways will personalized medicines continue to evolve in oncology?
