Cancer genomes have been a hot topic at this year’s AACR. I stopped in to see a session hosted by Elaine Mardis, Washington University’s genome maven whose been an author on most of the big cancer genome papers to date. In the session, we heard from Todd Golub of the Broad Institute, who gave preliminary results on the multiple myeloma genome, which hasn’t yet been published.

It looked like it has produced several interesting new potential cancer genes to look into. Though I won’t go into too much detail, here are some of the basic stats. They looked at cancers from 38 individuals sequencing both cancer cells and normal cells. They fully sequenced 23 of the individuals, and they did what’s called whole exome sequencing for 16 (in which they just sequence protein coding regions). One patient was sequenced by both methods.

The data produced a big list of mutations, but researchers have learned tricks for paring down such lists to find the so-called ‘drivers’ of cancer. By, for example, looking for mutations that appear frequently in cancer cells from different individuals. They came up with a short list of a dozen leading candidates. Four have been well characterized. Among the others, Golub found genes involved in regulating translation, the process by which RNA is made into protein, and even a gene implicated in susceptibility to Parkinson disease.

More research presented today at AACR’s 101st annual meeting shed some light on the mind blowing complexity of cancer. At this morning’s plenary sessions, Alan Balmain of the University of California San Francisco showed how the simple model of cancer initiation leading to progression and metastasis was a vast oversimplification. Cancer cells, he says require help from otherwise normal stromal cells, blood vessels, and inflammatory cells. And while much of the research presented at this meeting has been about cataloguing mutations that are gained in cancer, he’s been trying to better understand the underlying genetic background that plays a role in intrinsic susceptibility to cancers.

It’s hard to pull such genes out from studies of humans, so he crossed two strains of mouse, one that is susceptible to cancer and one that is relatively resistant, essentially creating a heterogeneous population of offspring with variable susceptibility to cancer. On these mice he did gene expression analysis for different skin samples and tumor samples. This analytical approach helps to uncover genes that are working in concert to influence cancer susceptibility, thus exposing deeper networks of genes at play in the process that can have interlinked function. Mice that were susceptible to tumors, for example were enriched for expression of genes involved in determining an epidermal skin cell fate, as opposed to a sebaceous or follicle fate. Genes involved in mitosis were upregulated, wound healing genes were upregulated, and genes for reigning in the inflammatory response were upregulated.

Balmain went a bit more into depth on the inflammatory genes however. Generally inflammation is generally associated with increased cancer susceptibility, but anti-inflammatory drugs have different effects on the development of skin tumors. Sometimes increasing tumor spread and other times preventing against it. Balmain’s systems biology approach has indicated a number of genes related to controlling inflammation and shows how they could be related to cancer susceptibility in his mouse population. See a paper on it from last year, here. But it’s complex relationship. It’s times like this that I consider the Thermos: it keeps things hot and it keeps things cold. Whenever something seems to have an important job in biology like preventing cancer, it almost always does exactly the opposite with a subtle shift in context.

Arul Chinnaiyan kicked off the day for AACR’s 101st annual meeting in DC by talking about cancer genomes. He gave a roundup of some of the major genomes published to date, many of them in Nature. He even showed a brilliant screenshot of Heidi Ledford’s April 15 feature on the topic. Bert Vogelstein of Johns Hopkins followed up with a talk that seemed too good to be true, asserting that thanks to decades of research, cancer is essentially a known entity. He’s been comparing the genomic landscape of nearly 100 human cancer genomes that have been sequenced to date and other data to come up with 3142 genes that are mutated regularly. He applies a simple criteria to distinguish which of these three thousand genes likely suppress tumor formation as their usual function (a function which a mutation disrupts), and those that through mutation become more active and cause cancer (so-called oncogenes).

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Today there was a lot of buzz surrounding the release of results from the BATTLE trial (Biomarker-integrated Approaches of Targeted Therapy for Lung cancer Elimination), sponsored by the US Department of Defense. This trial, started in 2006 attempted to group patients by predominant biologic features of their cancer, including those that can be characterized by genetic changes in EGFR, KRas, RXR/CyclinD1 or VEGF (all predominant defining molecular signatures lung cancer) and see if they could match these patients with the optimal treatments choosing from four treatment regimens.

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The opening ceremonies of AACR started with a sombre set by the Howard University Choir, and then launched into a ear splitting techno-infused video called “It’s Our Time” flashing some stats about cancer that for researchers are both uplifting (today the survival rate for acute lymphoblastic leukemia is 85% compared to 4% in the 1960s) and challenging (85% of adults with cancer are interested in clinical trials but only 3%-4% participate).

It was seriously loud enough to blow people out of the auditorium. But folks stayed on to watch the introductory speeches from Tyler Jacks, current AACR president and Elizabeth Blackburn, president elect. The focus of talks was clearly on basic research. Indeed, the theme of the meeting is, ‘Conquering cancer through discovery.’ We can expect a strong emphasis on the contributions of basic research to oncology as well as about the future of bringing basic research into the clinic.

Also, I should note a mistweet for all three people that actually pay attention to what I write on Twitter. This morning’s video ran a statistic from a Nature cancer genome paper on non-small-cell lung cancer that says a typical smoker gains one mutation for every 15 cigarettes smoked. I had stated that it was 15 mutations per cigarette. That would be just crazy!

I’m heading down to Washington D.C. this evening for my first American Association for Cancer Research meeting. It could have been my second. I was supposed to go to Toronto in 2003, but an outbreak of Severe Acute Respiratory Syndrome (SARS) in the city forced organizers to reschedule. I’m starting to wonder if I’m bad luck for this meeting.

This year, a giant volcanic ash cloud originating in Iceland will likely prevent a number of European participants from making it. Via Twitter, Oncology Times reports that 10% of the roughly 17,000 planned attendees hail from Europe, but an AACR spokesperson said it’s unclear how many are grounded. AACR’s travel advisory offers ways for invited speakers to deliver talks via videoconferencing and they’re offering refunds to those grounded by ash. The AACR’s twitter feed is already announcing some rescheduled and cancelled talks.

In cancer, it’s typically not the primary tumour that kills – it’s the metastases. Little wonder, then, that a major topic at the meeting was developing drugs not to shrink the primary tumour, but to stop it from spreading.

Danny Welch from the University of Alabama at Birmingham presented data on an interesting protein called KISS1. (Welch claims the protein is so named because he lived near Hershey, Pennsylvania at the time of its discovery. For you international readers, Hershey, Pennsylvania is the home of Hershey’s, the chocolate company that makes ‘Hershey’s kisses”.)

Anyway, KISS1 inhibits metastasis, but the fascinating thing is that it does so without preventing the spread of tumour cells. Instead, it keeps the metastasized cells from flourishing in their new environment. In other words, if you inject KISS1-expressing tumour cells into mice, they’ll form a primary tumour and cells from the primary tumour will migrate to the lungs. And then they’ll just sit there, lost and lonely.

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In 1889 Stephen Paget came up with the ‘seed to soil’ theory to explain why some cancers seem to spread to specific organs, rather than just invading the body at random. He said that perhaps there were features of the soil (the organ) that determined whether the seed (the cancer) took root there. Some soils simply aren’t hospitable to some seeds (having gardened in the heavy red clay of North Carolina, I can attest to that…)

Quite a few speakers evoked the seed to soil theory in talks about metastasis. One such speaker, Sara Sukumar of Johns Hopkins University, mentioned it while talking about her rapid autopsy program. The program is meant to test the assumption that the characteristics of the original ‘primary’ tumour will be shared by its metastatic offspring. There is some evidence to support this: gene expression patterns in some breast cancer tumours have been shown to resemble gene expression in their distant metastases, for example. But Sukumar says our understanding of this relationship is hindered by a lack of tissue to study because researchers often have only a single biopsy from each patient.

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NCI director John Niederhuber was around today to answer questions from conference attendees. First, though, he gave everyone the hard truth about the budget.

The data:

Number of years that funding for NCI has remained flat: 4

Rate of biomedical research inflation (apparently slightly higher than the overall rate of inflation in the United States): 3.8% per year

Percent decrease in purchasing power at the NCI since 2004: 15%

Niederhuber said that for the first few years of flat funding, NCI tried to cope with its shrinking budget by trimming the size of their grants rather than decreasing the number of awards. Those days are over, he said today, and this year NCI will offer fewer of their competing research project grants. Niederhuber also said that he was not optimistic about the possibility of any future budget increases, “no matter which party takes over the White House”.

Today’s plenary session on ‘late-breaking clinical trials’ offered up a few new promising phase III trial results for the prevention of colorectal cancer.

The first was an update on a kind of cox-2 inhibitor called celecoxib (marketed as Celebrex). You may remember the cox-2 inhibitors — they’re a class of anti-inflammatory drugs that were the center of a scandal a few years ago when it turned out they carried increased risk of cardiovascular side effects, such as heart attacks or stroke. Most of the scandal (and accusations of suppressed negative data) revolved around rofecoxib, better known as “Vioxx”, which was subsequently pulled from the market. Celecoxib is still available but carries the dreaded black-boxwarning. (The black box is the FDA’s strongest warning, and is the last stop before yanking a drug off the market entirely.)

But celecoxib had shown promise for preventing colorectal cancer in those at high risk for the disease, and I’ve heard it said on several occasions that the negative press about the drugs’ possible cardiovascular harm unfairly restricted use of what could have been a valuable cancer preventative. Today, Monica Bertagnolli of Brigham and Women’s Hospital in Boston reported that the protective effects of celecoxib have persisted in patients that stopped taking the drug 1.5 years ago, when the study was halted due to the realization that celecoxib posed a cardiovascular risk.

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