#KSDNA Plenary Speaker Stephen Jackson: PARP Inhibitors, Synthetic Lethality & Lynparza

Hello from sunny, scenic, British Columbia!


I’m blogging after my first day at an awesome scientific conference: The Keystone Symposia joint meeting covering DNA Replication & Recombination and Genomic Instability & DNA Repair. The talks today were all top-notch. I wanted to give a run-down of some of the radical research I’ve seen thus far, but I don’t want to hit you, my readers, with a firehose of data, so instead I think I’ll summarize the plenary session, and leave the rest of the genomic gymnastics for another post.

There were CRISPRs...get stoked
There were CRISPRs…get stoked

Our first speaker, Stephen Jackson, kicked off the conference with an exhortation for collaboration. He encouraged scientists working on similar topics to reach out and promote synergy rather than trying to scoop each other. I really appreciated his message of cooperation: the point of conferences is the productive exchange of ideas, not a giant scientific pissing match. Jackson made a point to acknowledge all of the other researchers who contributed to the work he presented during his talk. He mentioned that a night in the bar with Alan Ashworth led to the screen of small molecule DNA-repair inhibitors against many mutant cell lines that gave rise to a recently approved cancer drug

Jackson gave a retrospective of 25 years of research leading to one of the hottest new cancer drugs on the market right now: Lynparza (olaparib).This compound is exciting because it is a first-in-class PARP-inhibitor drug especially for personalized cancer medicine. Traditional cancer treatments, like chemotherapy and radiation, kill cancer by destroying any rapidly dividing cells within the body. This blunt approach works reasonably well for fast growing tumors, but it causes NASTY side effects. Hair, skin, and cells in the gut all also happen to also be fast-growing, which is why Chemo hits people like a sledgehammer. Additionally, chemotherapy and radiation don’t take into account the innate differences between different types of tumors. These approaches won’t work on all tumors (like Chondrosarcomas…Hi Mom!) On the surface it’s obvious that breasts and bones and brains are RADICALLY different body parts, and therefore treating cancers of each organ identically is insane. We wouldn’t wear brassieres as hats, why would we treat a breast and a brain tumor with the same drug? However, even within a single type of tissue, different genetic mutations can give rise to different kinds of cancers. The premise behind personalized medicine is that each type of tumor carries its own particular set of changes that contribute to causing disease.  

As we get better and better at sequencing genomes we’ve started to better understand the underlying causes of different kinds of cancers; concomitantly,  clinicians are becoming more and more adept at targeting these specific differences to destroy tumor cells. One particularly aggressive type of cancer is distinguished by defects in the BRCA genes. The BRCA genes are vital for DNA break-repair. Lynparza inhibits a different DNA repair protein called PARP; PARP inhibitors are highly effective for treating cancers with BRCA mutations. The concept of treating cancer with a drug that prevents DNA repair is, at first glance, a shocking strategy. After all, isn’t cancer CAUSED by DNA damage? Don’t defects in DNA repair genes (like BRCA) LEAD TO cancer? Wont there be lots MORE DNA damage in cancer cells if you treat them with this inhibitor?

The fact that cancers carrying BRCA mutations are defective for DNA repair is precisely the phenomenon behind Lynparza’s success. The idea behind this strategy is that normal human cells have many different pathways to deal with DNA damage; there are back-up mechanisms in place if Lynparza takes down PARP. Cancer cells, by contrast, have lost most of their repair capability (due to mutations in BRCA, or other genes) and thus don’t have many options to fix their DNA. Therefore, DNA repair inhibitors become potent poisons specifically for cancer cells. This concept, where a particular deficiency only becomes a problem in the context of another defect is called synthetic lethality.

Jackson talked about the extensive findings that helped uncover Lynparza’s synthetic lethal effect for cancers with BRCA mutations, and showed the data from phase II clinical trials demonstrating its dramatic efficacy. Not only did the researchers observe prevention of disease progression in 34% of patients, the side effects associated with Lynparza are a walk in the park compared to conventional chemotherapy. The FDA just granted accelerated approval status to Lynparza for treatment of advanced ovarian cancers, based on promising results from these Phase II clinical trials.

The talk, of course, contained lots more mechanistic details about which components of the DNA Damage Response do what, and how scientists in Stephen’s group (and others) figured all of this out. I really enjoyed seeing a multi-decade long story where basic science (mechanisms of DNA repair) eventually led to an awesome new cancer drug.

I could go on, and on, and ON about what else I saw today (There were TWO Plenary speakers…a whole session on single-molecule studies of the replisome…a workshop on genome editing…CRISPRS! I’m in DNA-nerd heaven). However, after explaining synthetic lethality, I think that I want to go to bed so that I’m bright eyed and bushy tailed for my poster presentation tomorrow.

I’ll keep writing up some of the cool stuff I see all this week (I might even sneak in some skiing as well).

Skis, snacks, passport...all VITAL things to bring to a conference in Canada
Skis, snacks, passport…all VITAL things to bring to a conference in Canada

In the meantime, I hope everybody’s having a killer Monday!


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