When Two Wrongs Make for the Right Cancer Treatment

Mutations in certain genes drive the growth of tumors, and cancer researchers have long focused on strategies to target those mutations and reverse their effects. While that approach has racked up impressive successes, an emerging strategy called synthetic lethality is now poised to push the field into a new era, offering new ways to treat cancers that have proven difficult to combat.

In this Q&A, Edmond Chan, MD, assistant professor of medicine at Columbia University Vagelos College of Physicians and Surgeons and a member of the Cancer Genomics and Epigenomics program at the Herbert Irving Comprehensive Cancer Center, discusses his current work on synthetic lethality, including an ongoing clinical trial and major new research findings.

What's the idea behind synthetic lethality?

In many cancers, there are tumor suppressors that are broken or lost, which is what allows those cancer cells to grow and spread. But it’s hard to develop therapies that fix something that’s broken; it’s much easier to break something that’s working. Synthetic lethality is a phenomenon in which loss of two specific genes is not tolerated by the cell, whereas loss of either one is. With a synthetic lethality approach, we look for a second gene that we can break in cancer cells that then kills them. It helps solve one of the major challenges in cancer research: finding treatments that kill only cancer cells. Normal cells that don't have these sensitizing mutations and are less likely to be killed via synthetic lethality, so it allows us to take a precision oncology approach.

That idea led to the recently approved PARP inhibitors, which are now used to treat certain cancers with a BRCA mutation, right?

Yes. PARP inhibitors are the only synthetic lethal drugs that are currently FDA approved, but another example that has recently come to the stage are Werner (WRN) inhibitors. The idea for these inhibitors came out of previous research into something called high microsatellite instability, including my own research. We found that cancers with high levels of microsatellite instability can be killed if we “break” their WRN gene. MSI-high cancers essentially mutate very fast, driving the cancer, and include many ovarian, endometrial, and stomach cancers. Many pharmaceutical companies are now developing WRN inhibitors; two are now in active clinical trials, including a trial open here at Columbia that I am co-leading.

In addition to the clinical trial, you're also hunting for more synthetic lethal targets in the lab. Can you talk a bit about what led to your new paper on that work in Nature?

Yes, we've turned our attention to deletions in chromosomal region 9p, because it occurs in about 13-15% of all cancers, and 9p deletions tend to be very difficult to target with immunotherapy. There's an intense need for new therapies for these cancers, especially since 9p deletions occur in some really aggressive cancers, such as glioblastoma and pancreatic cancer.

We used a tool called DepMap, which is based on the Broad Institute's Cancer Cell Line Encyclopedia, which has over 1,000 cell lines. DepMap allows us to identify particular molecular subtypes and group them together. We can look at cells that have 9p deletions versus cells that are wild-type for 9p and ask a very simple question: are there particular genes that are preferentially required when cancers lose 9p? We found that this gene called PELO ends up being quite important. It turns out that MSI-high cancers, which is a cancer type that I’m passionate about, also require PELO.

We found that these two seemingly distinct and independent cancer subtypes both rely on PELO to survive because a genetic complex known as the superkiller complex, or SKI complex, is destabilized. We also found that normal cells do not require PELO, which makes it a potential candidate for a drug target, which is particularly exciting for these cancers with a high unmet need, like pancreas cancer and glioblastoma.

These cancers have not yet benefited from the same explosion of new therapies the way that some other cancers have. I feel like we’ve been stuck on the same therapies for quite some time, and this synthetic lethality approach gives us a new tool, a new opportunity to target cancers that have historically been difficult to treat. By exploiting a vulnerability that exists only in cancer cells, we have the potential to develop more precise, effective therapies for patients who currently have limited options.