Recently, someone very close to me went through chemotherapy for a fairly common yet very scary cancer. One night as we were going over her treatments and how they were going to affect the rest of her body I compared our cancer treatments to using the biggest hammer possible, hitting a building and hoping that it remains standing while only the broken windows fall down.
She laughed but that idea stuck with me. Current treatments are banking on the idea that the cancer is going to replicate faster than the normal tissue and will therefore be more sensitive to drugs that target proliferative processes. An example of such drug is taxol, a common and potent chemotherapeutic agent that blocks progression of mitosis thus inducing cell death.
For years, I have thought that the ideal treatment for any disease is to exploit what separates that disease from the normal tissue. It is the reason that cancer biology as a discipline has exploded in recent decades but has yielded very few distinguished targets. The personalized cancer therapy we have been promised is yet to be delivered. A new family of drugs is bringing us closer to that goal by building on years of basic biology research and targeting one of the most abundant nuclear proteins, PARP-1.
We have known for a long time that PARP-1 is important in a variety of cellular processes from replication to transcription and we are still in the process of identifying various PARP family members.
One of the most common activities of PARP-1 protein is its role in the base excision repair process that repairs single-strand breaks that occur on the DNA as a product of normal cell metabolism. If unrepaired, single-strand breaks can stall replication forks and create single-ended double-strand breaks, a highly toxic lesion repairable only by homologous recombination. Homologous recombination is one of the most commonly inactivated repair mechanisms in cancer, especially in breast and ovarian (BRCA1 and BRCA2 mutations) as well as prostate tumors. Inability of a cell to repair a single-ended double-strand break will lead to activation of apoptosis and cell death.
The pathway of oxidative damage to single-strand break to double-strand break to homologous recombination is now being used to selectively kill cancer cells. A cancer deficient in homologous recombination is going to be more sensitive to PARP-1 inhibition and formation of single-strand breaks than normal tissues.
In normal tissues, inactivating PARP-1 will produce single-strand breaks that will get converted to double-strand breaks during replication but with active homologous recombination this damage will be easily repaired and the cell will survive and continue proliferating. In BRCA2 mutant tumors, for example, inactivating PARP-1 will also produce the same type of damage but at the last stage the cell will be unable to repair it because it lacks the homologous recombination activity. Thus, inactivating PARP-1 will selectively kill cancer cells but not normal tissue, providing a silver bullet for that type of tumor.
A recent report in New England Journal of Medicine described this exact effect in BRCA2 deficient tumors during a phase I study of AZD2281, a highly selective and potent PARP-1 inhibitor.
As a scientist, I hope that soon we can hear of more therapeutic success stories that came from basic research foundations. Judging by published data, we have certainly been productive and it is now time to assess which of those avenues will be crucial as we move forward to develop new treatments that will be more potent and yet have fewer side-effects than what we currently offer.
It would be wonderful to have a treatment that would be like a skilled carpenter: able to go into a house, take out the broken window and leave without anybody waking up.
Reference:
Fong, et. al., 2009. Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers. NEJM; 361: 123-34.
