pathways to cancer therapy

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Dan Jones September 2008 saw the publication of three landmark genomic analyses of cancer, two in Science 1,2 and one from the Cancer Genome Atlas Research Network in Nature 3 . These in-depth genomic views of the alterations underlying specific solid tumours (pancreatic cancer and glioblastomas) show that there are many genetic routes to the same end point: a perturbed cellular pathway leading to cancer. These studies have also reiterated the great genetic variation that exists even among a given type of cancer; for example, tumours in two patients with pancreatic cancer will frequently have unique genetic features. However, while tumours of the same type often show genetic variation between people, they commonly share features at the protein pathway level, says Bert Vogelstein of the Johns Hopkins School of Medicine in Baltimore, Maryland, USA, and an author on both Science papers 1,2 . The complicated picture of cancer that these genome scans have revealed calls for a reorientation of perspective on approaching cancer, says Vogelstein. “The only way to handle this complexity is to change the way we think about cancer, from gene-centric to pathway-centric.” Emmanuel Petricoin, Co-Director of the Centre for Applied Proteomics and Molecular Medicine at George Mason University, Virginia, USA, agrees. “Cancer is a protein-pathway disease, and these genomic studies prove it,” he says. “While genetic mutations obviously underpin cancer, the manifestation of these is at the pathway, functional signalling level.” Petricoin sees this as a fantastic outcome for the field, with a clear implication for approaching cancer Pathways to cancer therapy New studies have affirmed the complexity of genetic changes in solid tumours, but also revealed common alities in the associated pathways, suggesting that a pathway-oriented perspective could aid cancer drug discovery and therapy. NATURE REVIEWS | DRUG DISCOVERY VOLUME 7 | NOVEMBER 2008 | 1 NEWS & ANALYSIS

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Page 1: Pathways to cancer therapy

Dan Jones

September 2008 saw the publication of three landmark genomic analyses of cancer, two in Science1,2 and one from the Cancer Genome Atlas Research Network in Nature3. These in-depth genomic views of the alterations underlying specific solid tumours (pancreatic cancer and glioblastomas) show that there are many genetic routes to the same end point: a perturbed cellular pathway leading to cancer.

These studies have also reiterated the great genetic variation that exists even among a given type of

cancer; for example, tumours in two patients with pancreatic cancer will frequently have unique genetic features. However, while tumours of the same type often show genetic variation between people, they commonly share features at the protein pathway level, says Bert Vogelstein of the Johns Hopkins School of Medicine in Baltimore, Maryland, USA, and an author on both Science papers1 ,2.

The complicated picture of cancer that these genome scans have revealed calls for a reorientation of perspective on approaching cancer, says Vogelstein. “The only way to

handle this complexity is to change the way we think about cancer, from gene-centric to pathway-centric.”

Emmanuel Petricoin, Co-Director of the Centre for Applied Proteomics and Molecular Medicine at George Mason University, Virginia, USA, agrees. “Cancer is a protein-pathway disease, and these genomic studies prove it,” he says. “While genetic mutations obviously underpin cancer, the manifestation of these is at the pathway, functional signalling level.”

Petricoin sees this as a fantastic outcome for the field, with a clear implication for approaching cancer

Pathways to cancer therapyNew studies have affirmed the complexity of genetic changes in solid tumours, but also revealed common alities in the associated pathways, suggesting that a pathway-oriented perspective could aid cancer drug discovery and therapy.

NATURE REViEWS | drug discovery VolUME 7 | NoVEMBER 2008 | 1

News & aNalysis

Page 2: Pathways to cancer therapy

treatment: “it points towards a future where if we consider therapeutic intervention, we can really start to think about this as drugging entire signalling pathways rather than just one aberration at a time,” he says.

The new results also raise questions about the utility of looking at genetic changes in patients to determine which therapies they should receive as part of a personalized medicine approach to cancer. “it may be a better use of time and money to look directly at the protein pathways, now that it appears that cancer really is a pathway disease,” says Petricoin. “You want to get directly at the actionable information, so one could ask why we even need to look at a genomic mutational scan when you can look directly at the protein information, which does the work of the cell. What these studies really show is that at a functional level, cancer is a proteomic disease.”

it may even be that a switch from looking at cancer through the ‘gene lens’ to the ‘pathway lens’ could help resolve some problems that have beset genetically tailored cancer therapies. Gefitinib (iressa; AstraZeneca), for example, shows efficacy against non-small-cell lung cancer, but only in a small subset of patients carrying specific mutations in the epidermal growth factor receptor (EGFR) gene. Such a treatment is personalized but is limited in its applicability, posing economic obstacles to the development of similar drugs.

“The pathway view provides one way around that,” says Vogelstein. Even though each tumour in each patient is different, they all share a core group of about a dozen perturbed pathways. “i think this has important implications,” notes Vogelstein. “Drugs can be discovered that work more universally or uniformly against cancers of a given type, or even cancers of many types, than trying to target individual mutations or individual genes.”

The pathway perspective, however, does not necessarily spell the demise of personalized therapies or undermine the

value of genome scans, says Perry Nisen, Senior Vice President of Cancer Research at GlaxoSmithKline. “These studies underscore the need to understand the key pathways, and the critical, nodal events leading to cancer,” he says. “in some cancers, very few genetic alterations really drive the whole process, such as in some haematological malignancies. i predict that if you looked in chronic myeloid leukaemia you would see a whole lot of changes, but it sure looks like one mutation — the BCR–ABl translocation — is a profound driver.”

This, in turn, does not imply that development decisions must be predicated on particular mutations. “in some cases they will, in some cases they won’t,” says Nisen. “our strategy [at GlaxoSmithKline] won’t ever be driven exclusively by genetic changes, but we incorporate those where it makes sense. We have to take a holistic picture of cancer.”

Painting this holistic picture requires getting a handle on the underlying biology. “Genome scans, coupled with bioinformatics, produce an incredible amount of useful information,” says Petricoin, “but they don’t tell you which mutations are the tipping points for cancer: the mutations that are necessary and sufficient for causing the disease itself.”

Ultimately, genome scans should, by shedding light on the genomic alterations in cancers, provide a context in which to interpret protein-pathway activation and disturbances. “The challenge is for us to identify the critical driver mutations,” says Nisen. “You cannot separate genetic association data from the fundamental understanding of the biology and pathways.”

Much of this falls under the purview of systems biology, which uses computational models to capture the network dynamics of interacting genes, proteins and metabolites in health and disease. Such models could provide a new foundation on which to develop new anticancer drugs, along the lines suggested by Vogelstein: by looking at therapies that beneficially modulate key

pathways, regardless of whether they target specific mutations associated with the cancer.

This demands not only expertise in querying or interrogating systems-biology models, but ensuring that they are fit for purpose by incorporating the right sort of data. Stephen Friend, Senior Vice President of oncology at Merck, argues that a crucial aspect of creating clinically useful systems-biology or network analyses of cancer is to link genomic and pathway alterations with patient outcomes and responses to therapy. “We need to couple data on the static records of genetic variations with data that exist on patients and their outcomes,” he says. “People are not putting enough emphasis on establishing this living linkage.”

Tying all this together into a network analysis would enable clinicians to ask what all the changes in a given patient add up to. “This is when it becomes valuable for patients and health-care providers,” says Friend. And while coming years are likely to see such network and systems-biology models crop up, how clinicians would access these new insights represents a major challenge. “We do not have platforms on which to display that network information so that physicians or researchers could know what to do with variations of the network,” says Friend.

But perhaps a network of a different type could provide a solution. “i don’t think the problem will get solved by large government initiatives,” says Friend, “but by developing open-access biological platforms on which distributed networks of scientists and researchers can query the data, even if they haven’t been part of a broader initiative.”

1. Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).

2. Williams Parsons, D. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

3. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 4 Sep 2008 (doi:10.1038/nature07385).

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2 | NoVEMBER 2008 | VolUME 7 www.nature.com/reviews/drugdisc