Cancer breakthroughs often get their first airing at the annual meeting of the American Society of Clinical Oncology. This year’s meeting was no exception.

One finding getting a lot of press has its origins in a pair of studies in Nature in 2005. The studies showed how to selectively kill cancer cells deficient in BRCA1 and BRCA2, genes that are mutated in some of the deadliest breast and ovarian cancers.

The agent that does the killing is called a PARP inhibitor. And trial results released last week show some pretty promising results.

Olaparib, a PARP inhibitor under development by AstraZeneca PLC, shrank tumors in more than a third of women whose breast cancers had BRCA mutations. The trial did not have a control arm, but the data look encouraging, considering the agent was given alone, without other drugs, and that the subjects had already had an average of 3 chemotherapy regimens. A similar trial showed that the drug could also shrink advanced ovarian tumors in subjects with BRCA1 or BRCA2 mutations.

A truer test of whether a drug is likely to help patients is whether it can prolong survival. A randomized, controlled trial of BS1-201, under development by Sanofi-Aventis SA, examined this question in 116 women with some pretty nasty tumors: their breast cancer had metastasized to other parts of their body and was ‘triple negative’, meaning it lacked receptors on their tumors for estrogen, progesterone and HER2, each of which are targets for current therapies. The drug prolonged survival by three and a half months, to 9.2 months, when added to a standard chemotherapy regimen.

Bigger studies are needed, but the findings so far validate a concept with deep origins in basic research. BRCA1 and BRCA2 facilitate DNA repair, a function that emerged after years of painstaking research. PARP (poly(ADP)-ribose polymerase) mediates DNA repair also, but in a distinct way. The Nature studies exposed cells lacking BRCA1 or BRCA2 to PARP inhibitors and showed that these cells get nailed: their DNA is such a fragmented mess that they die.

Mice deficient in PARP are viable, fertile and tumor-free, which bodes well for the side effect profile of these drugs. Subjects who received the drugs reported only mild side effects, including nausea and fatigue.

Other highlights at ASCO include promising findings with multikinase inhibitors, which can block several types of proteins that go astray in tumor cells. Cancer vaccine approaches also got a boost with positive findings from trials in melanoma and non-Hodgkin’s lymphoma.

“Heard it’s dark and rainy” a fellow traveller wrote in an email to me Friday, as I was finishing up preparations for the trip. Toss in a few logistical issues, including some long commutes from out in the suburbs, and you get a sober assessment: “People are not having fun.” So I wasn’t terribly surprised when I arrived this morning to find Poznan dark and rainy. To be fair, the sun has since made a brief appearance, and it’s not exactly cold. But Bali it’s not.

And I can’t yet testify as to people having fun or not, but I guess that’s not really the goal here. As for myself, I’m still recovering from a long transatlantic flight to Munich, which offered little in the way of sleep but plenty of time to catch up on reading, followed by a quick connection in a prop plane into Poznan.

I wasn’t the only Washingtonian on this particular itinerary – spotted a pair of Republican congressional staffers on the plane, representing Joe Barton, the ranking Republican on the House Energy and Commerce Committee. I also bumped into staff representing a pair of Democratic senators. All are here to watch, listen and learn, and the Democrats might even end up reporting back to President-Elect Barack Obama’s team, as requested by Obama himself.

So. I’m going to head over to the conference centre now to get my feet on the ground, but first a quick update on a related note: French President Nicholas Sarkozy failed to reach a deal yesterday with Eastern European leaders, including Polish Prime Minister Donald Tusk, on the next phase of the European Union climate plan (BBC, Reuters)

Sarkozy will get another chance later this week, but his term as EU president is up this month. After that it goes to Czech President Vaclav Havel, who is mostly famous these days for his antagonism toward not only climate regulation but frequently the EU itself. His ascendancy to the six-month rotating post isn’t likely to halt discussions, but it could make them more difficult.

“Heard it’s dark and rainy” a fellow traveller wrote in an email to me Friday, as I was finishing up preparations for the trip. Toss in a few logistical issues, including some long commutes from out in the suburbs, and you get a sober assessment: “People are not having fun.” So I wasn’t terribly surprised when I arrived this morning to find Poznan dark and rainy. To be fair, the sun has since made a brief appearance, and it’s not exactly cold. But Bali it’s not.

And I can’t yet testify as to people having fun or not, but I guess that’s not really the goal here. As for myself, I’m still recovering from a long transatlantic flight to Munich, which offered little in the way of sleep but plenty of time to catch up on reading, followed by a quick connection in a prop plane into Poznan.

I wasn’t the only Washingtonian on this particular itinerary – spotted a pair of Republican congressional staffers on the plane, representing Joe Barton, the ranking Republican on the House Energy and Commerce Committee. I also bumped into staff representing a pair of Democratic senators. All are here to watch, listen and learn, and the Democrats might even end up reporting back to President-Elect Barack Obama’s team, as requested by Obama himself.

So. I’m going to head over to the conference centre now to get my feet on the ground, but first a quick update on a related note: French President Nicholas Sarkozy failed to reach a deal yesterday with Eastern European leaders, including Polish Prime Minister Donald Tusk, on the next phase of the European Union climate plan (BBC, Reuters)

Sarkozy will get another chance later this week, but his term as EU president is up this month. After that it goes to Czech President Vaclav Havel, who is mostly famous these days for his antagonism toward not only climate regulation but frequently the EU itself. His ascendancy to the six-month rotating post isn’t likely to halt discussions, but it could make them more difficult.

A ruling came in yesterday on complaints about the UK documentary The Great Global Warming Swindle. On The Great Beyond, Katharine Sanderson notes that despite very negative headlines about the ruling,

you might say that Channel 4 got off pretty lightly for their documentary that suggested that global warming wasn’t caused by humans burning fossil fuels. Ofcom [the complaint board] charged the programme with misrepresenting certain scientists, which leads to those critical headlines, but ultimately the regulators said that the programme didn’t mislead viewers.

(more…)

Despite its small size (about one millimeter long), the nematode Caenorhabditis elegans has been used to study a wide range of “”https://www.nature.com/nrd/journal/v5/n5/full/nrd2031.html">biological processes including apoptosis, cell signalling, cell cycle, cell polarity, gene regulation, metabolism, ageing and sex determination." Which is pretty amazing, as it truly is a simple organism: the adult hermaphrodite has 959 somatic cells!

In the May issue of Nature Reviews Drug Discovery, Kaletta & Hengartner wrote:

The cellular complexity and the conservation of disease pathways between C. elegans and higher organisms, together with the simplicity and cost-effectiveness of cultivation, make for an effective in vivo model that is amenable to whole-organism high-throughput compound screens and large-scale target validation.

I was surprised to learn that complex diseases can be investigated using this worm – scientists are even using it to “”https://www.nature.com/nrd/journal/v5/n5/full/nrd2031.html">identify additional mode of actions of fluoxetine [an antidepressant] and to further elucidate the molecular mechanism of depression."

C. elegans is getting a lot of attention at NPG this week: in the May 4th issue of Nature, Kwok et al. screened 14,100 small-molecules in living worms and identified 308 compounds that induced a range of phenotypes, including slow growth, lethality, uncoordinated movement and morphological defects. One of these small-molecules (a 1,4-dihydropyridine that they named nemadipine-A) induced an Egl phenotype (egg-laying defects).

The authors then screened 180,000 “”https://www.nature.com/nature/journal/v441/n7089/full/nature04657.html">randomly mutated wild-type genomes" to look for dominant genetic suppressors of the nemadipine-A-induced phenotype, and they performed a number of follow-up experiments that indicated that the protein Egl-19 (the only L-type calcium channel alpha1-subunit in C. elegans) is a target of nemadipine-A.

This isn’t completely unsurprising, as other 1,4-dihydropyridines are known to “”https://www.nature.com/nature/journal/v441/n7089/full/nature04657.html">antagonize the alpha1-subunit of L-type calcium channels“), but it’s an important demonstration that C. elegans can be used to quickly identify the targets of biologically active small-molecules – to quote Professor ”https://www.mgh.harvard.edu/cvrc/crvc/peterson/index.html">Randall Peterson, “”https://pubs.acs.org/cen/news/84/i19/8419notw8.html">[t]arget identification has been one of the thorniest problems in small-molecule screening, so this is a welcome and encouraging advance." And it’s so simple, Professor Peter Roy (the lead author of the study) said “”https://pubs.acs.org/cen/news/84/i19/8419notw8.html">I could teach a first-year undergrad to do it"…

Joshua

Joshua Finkelstein (Associate Editor, Nature)

Roscioli et al.

Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease

Arking et al.

A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization

Carninci et al.

Genome-wide analysis of mammalian promoter architecture and evolution

Comments welcome.