26 June 2009
Cancer arises when a series of mutations accumulate that act together to block normal DNA repair (correction of spontaneous mutations) and deregulate normal control over cellular proliferation. A paper in the New England Journal of Medicine reports the results of a phase I clinical trial for a novel cancer therapeutic in patients with inherited BRCA1/2 mutations. Such mutations confer significantly increased susceptibility to a range of cancer sub-types, notably breast cancer (see previous news). This is because there is only one functional BRCA allele present; inactivation of this remaining allele by a non-inherited, spontaneous mutation causes a functional deficit in normal DNA repair. The BRCA1 and BRCA2 molecules are involved in the double-strandedDNA repair pathway; when this is not working properly, then more spontaneous mutations will go uncorrected and the probability of developing a tumour increases.
Cancer therapeutics attempt to selectively target tumour cells (as opposed to normal cells) for destruction; poor specificity is responsible for the toxic side-effects of chemotherapy. Increased understanding of the genetic basis of different cancers have led to the development of a new generation of molecular targeted therapeutics such as Herceptin, which targets breast cancer cells that over-express the HER2 protein. This latest drug candidate uses an approach termed synthetic lethality. This term refers to a situation where the presence of mutations in each of two separate genes is lethal to a cell, although mutation in either one of those genes is not; for further explanation see accompanying editorial [Iglehart, JD (2009) NEJM June 24,10.1056/NEJMe0903044].
The new drug candidate, olaparib (AZD2281), inhibits PARP enzymes, essential mediators of single-stranded DNA repair [Fong PC et al. (2009) NEJM June 24, 10.1056/NEJMoa0900212]. Inhibition of PARPs causes the accumulation of single-strand breaks in the DNA, which can in turn lead to double-strand breaks; in normal cells these are repaired, but in BRCA1/2-deficient cells (such as tumour cells in individuals with inherited BRCA1/2 mutations) they are not.
The researchers recruited a total of 60 patients with advanced forms of different cancer types, 22 of whom were confirmed BRCA1 or BRCA2 mutation carriers and one of whom was a suspected but unconfirmed carrier. All the patients had previously received other forms of chemotherapy. Effective PARP inhibition was detectable in samples of normal and tumour cells from the patients after treatment. The adverse (toxic) effects associated with olaparibwere generally mild compared with normal chemotherapeutics, although there were some cases of dose-limiting toxicity. Anti-tumour activity was observed solely among confirmed or suspected mutation carriers.
Of the 23 patients in this group, two could not be evaluated (one died from causes unrelated to therapy and another did not receive the full drug dose due to toxicity) and another two showed rapid progression of their tumours, both of which were a type not normally associated with BRCA-carrier status. Of the remaining 19 BRCA carriers, all of whom had ovarian, breast,or prostate cancers, 12 showed clinical benefit from treatment with olaparib. One patient is said to still be in remission more than two years on (see BBC news report)
The authors postulate that non-responding BRCA mutation carriers might have had differential sensitivity to PARP inhibition due to the exact mutation present or additional genetic or epigenetic changes that restored some BRCA function. However, they conclude that the drug candidate shows promise and suggest that changes are needed in current clinical developmentand registration processes to allow trials of drugs for cancers in different organs, but which chare common genetic origins.
Comment: These results do not necessarily herald the advent of a new miracle cancer drug; it was a very early-stage, small-scale study, the new drug was not effective in all BRCA mutation carriers, and such individuals represent a very small sub-group of all cancer patients. However, it is an exciting paper because it demonstrates the potential for further development of therapeutics that exploit the unique genetic features of tumours. The point about the potential need to reconsider the trial design and drug approval process for the new generation of molecularly targeted therapies is a good one, since this approach differs so markedly from conventional drug development.