Prof Alan Ashworth updates on the phenomenon of synthetic lethality

Among the notable absences at the first day of the 101st AACR meeting, there was the one of Alan Ashworth (Cancer Research Institute, London), whose talk on innovative synthetic lethal strategies in cancer therapy was supposed to close the first plenary session devoted to "Innovations in translational medicine". Alan, as many others, has been stuck on the other side of the ocean due to Iceland and its volcanic antics.

But chairperson Frank McCormick (UCSF Comprehensive Cancer Center, San Francisco), kept the mood of the audience up by, after apologizing for Alan's important absence – and when everybody, including myself, thought that his talk would be cancelled or, even worse, read by somebody else who understood very little of his slides - announcing that Alan's talk was going to be given via teleconference, post lunch.

"It's a bit awkward to give a talk without seeing the public, it feels like talking to myself", Alan kicked off, adding "but since I do it pretty often anyway, I'll go on". His practice proved useful, as his talk turned out to be an excellent one notwithstanding frequent stopping and starting; "next slides please" etc .

The title of his presentation was "Synthetic lethal therapies. Genetic principles". The words "synthetic lethality" may well ring a dusty bell going back to the times when you were studying genetics in college.....

The words did certainly ring a bell to me, as I remember the many hours spent by my Genetics Professors in Bologna Giovanni Perini and Giuliano Della Valle teaching us young biotechnologists-to-be (or some other kind of hybrid-to-be, in my case) the genetic underpinnings of synthetic lethality in yeast.

Today, though, Alan's brief revision was very helpful: Synthetic lethality was initially discovered in yeast, when the mutation of a single gene A does not cause any phenotype, but the mutation of gene A together with gene B (i.e. their synthesis) results in the death of the mutated cell.

The explanation for the phenomenon is given in terms of the two genetic pathways being partially redundant, which is why only one of the two can be deleted without any apparent phenotype, but not both at the same time.

The phenomenon remained confined to yeast genetics and of interests only for basic scientists until the past few years, when it was subject to a second wave of interest, which included applied researchers and medical oncologists.

In his talk Alan focused on the currently most fashionable, and promising, example of synthetic lethality in cancer: PARP inhibitors and BRCA mutated genes.

PARP inhibitors are proteins involved in a particular type of DNA repair, called base excision repair. There has in the past couple of years been a wave of interest for these inhibitors, which have been employed in several clinical trials with promising results (for an excellent and up-to-date overview of the clinical development of PARP inhibitors, read Fong et al, NEJM 2009), .

Among these, its worth mentioning here the first Phase 0 trial performed at NCI with the ABT-888 inhibitor developed by Abbott laboratories (Kummar et al, JCO 2009). PARP inhibitors have also been used and are currently being tested in combination with cytotoxic agents, as they enhance the antiproliferative activity of DNA damaging agents, and several Phase I combination trials are now running or recruiting at NCI, based on the result of the ABT-888 Phase 0 study.

But the most promising results come from the use of PARP inhibitors in tumours harbouring mutations on BRCA genes. Loss of only one copy of BRCA genes does not show sensitivity to PARP inhibitors, while loss of both copies does (Farmer et al, Nature 2005), and triggers massive genomic instability. PARP inhibitors selectively kill cells deficient in BRCA1 or 2, with the proposed mechanism being that that SSBs accumulate and are converted to DBS during replication (Ashworth AJ, Clin Oncol 2008).

Prof Ashworth also discussed some preliminary data of patients with advanced endometrial tumours BRCA1/2+ , who received clinical benefits from treatment with the oral PARP inhibitor olaparib.

The horizon of synthetic lethal strategy is not limited, though, to PARP inhibitors in combination with BRCA mutated genes, even if these two players both act like a 'primadonna' on the 'cancer-gene' stage. Indeed, towards the end of his talk, Ashworth also mentioned other interactions studied by his team such as the synthetic lethal combinations of DNA polymerase with mismatch repair enzymes, which were published most recently (Martin et al, Cancer Cell 2010).

Among the challenges for the therapeutic application of synthetic lethal approaches, target identification has traditionally been considered the major one, as it was very laborious and time-consuming to identify synthetic lethal genes.

Nowadays, with high throughput screening technologies which are able to easily identify thousands of synthetic lethal combinations, target identification is no longer an issue. Not only that, but there may simply be too many identified targets to validate!

What is now the most important hurdle is resistance to synthetic lethal therapeutic approaches. Mechanisms of resistance to PARP inhibitors have been described, which interestingly enough do not arise as mutations in the PARP genes, but in the restoration or BRCA2 ORF in PARP1 resistant cell lines. For this reason, in Prof Ashworth's opinion the best results with PARP inhibitors are likely to be achieved in early/adjuvant therapy.

The phenomenon of synthetic lethality remains one of the most interesting in genetics, and now opens up an entire new universe of possible therapeutic targets in cancer. The phenomenon of resistance, however, should not be underestimated, as it could hinder the clinical application of this fantastic genetic tool.

More basic research will be needed in order to understand mechanisms of resistance, building in a virtuous circle of translational research that goes from the bench, to the bedside, and back to the bench with new questions to be answered. And which, on a side note, makes me think that medical genetics receiving classes on synthetic lethality will be taught differently from now on, and that I already belong to an old generation!