Defects in EMSY Gene Spur Ovarian Cancer Growth

Angelica Welch

Douglas A. Levine, MD

Douglas A. Levine, MD

BRCA1/2 mutations have long been attributed to the development ovarian cancer; however, women with healthy BRCA genes are still receiving a cancer diagnosis.

A study was conducted to investigate whether changes in the EMSY gene attributed to cancer cell growth in patients with ovarian cancer who have healthy BRCA genes.

In the study, the full-length EMSY gene was overexpressed, resulting in suppression of homologous recombination, much like BRCA2. However, these changes in EMSY contribute to cancer growth independently as there is no direct interaction with BRCA2, says senior study author Douglas A. Levine, MD.

Levine, who is director of the Division of Gynecologic Oncology at NYU Langone Medical Center and Perlmutter Cancer Center, says that with this study, therapies can now be designed to target the specific activity of these EMSY cells. For example, PARP inhibitors are being explored as a potential treatment option for EMSY-driven cancer, as they have been shown to be effective in patients with mutated BRCA genes.

In an interview with OncLive, Levine discussed the relationship between EMSY and BRCA, the potential to target EMSY amplified tumors with PARP inhibitors, and the future of ovarian cancer treatment.

OncLive: Could you provide a brief overview of the study?

Levine: The EMSY gene was discovered probably 15 years ago and it was thought to interact with BRCA2 and suppress it as well as sort of mimic the function of BRCA2. In this study, we wanted to see if it truly has the biological effects that BRCA2 suppression would have.

We discovered, through some of our prior work in ovarian cancer, that EMSY is amplified in more than 10% of cases, which is important to know in treating the disease. First, we overexpressed the full length of the gene—which no one has been able to do before. By overexpressing the full-length gene, we are able to show that it does indeed suppress DNA repair—a specific type of DNA repair called homologous recombination. That is the type of repair in which BRCA2 also causes suppression; this is called homologous recombination deficiency.

Although it did suppress that type of DNA repair to a lesser extent than BRCA2 does by itself, our second question was, “Does the protein directly interact with BRCA2?” This has been reported in at least 1 study. We demonstrated that there was no direct interaction between EMSY and BRCA2.

Once we showed that there was no direct interaction, our next question was, “How does EMSY suppress homologous recombination if there is no direct interaction?” By reviewing the literature and having some internal discussions, we started to look for some various binding sites and we found a phosphorylation site at a new location in the protein. When this binding side was mutated, it could no longer carry out the function of suppression of DNA repair.

In short, we identified routes to overexpress the full-length protein, showed that it doesn’t directly interact with BRCA2, that it affects homologous recombination, and that a specific phosphoric site that we identified mediates it.

As of now, is there an effective way to identify these defective EMSY genes?

It’s an amplification of a gene; it’s kind of a copy number alteration and so it’s relatively easy to do this. We haven't done it on individual clinical specimens; however, there are several standard ways to look for amplified genes that we do for various other genes. We just have to use the right antibody and we could stain tissues using fluorescent markers, but we did not do that for this study because we were working in cell lines.

We had done the discovery in human tissue using whole-genome approaches, which was done prior to this report becoming the basis for our work. In a clinical specimen, you would do some sort of fluorescent-antibody approach or now we can do droplet pathological complete response, as well. It would not be difficult, but we have not done that for clinical purposes yet. 

Could you speak to the successes of PARP inhibition both in this study and in ovarian cancer overall?

For 10 years, we have known that tumors that are defective in homologous recombination are very sensitive to DNA damage agents, such as platinum-based chemotherapy. More importantly, they are exquisitely sensitive to PARP inhibitors. Our next step in the process is to figure out if EMSY amplification does indeed result in sensitivity to PARP inhibitors.

PARP inhibitors are now approved in the United States for the treatment of patients with ovarian cancer, specifically approved for those with defective BRCA genes. This is because if you have a defective BRCA gene, you can’t perform homologous recombination.

Our overarching question was, “Does amplification of EMSY—which was previously thought to be a surrogate for BRCA2 dysfunction—surpass homologous recombination?” This suggests that these particular tumors—which make up 10% of ovarian cancers—may have another mechanism to be sensitive to PARP inhibition.

PARP inhibitors went from discovery to the clinic quickly. The first study, which was done about 5 or 6 years ago, showed that patients with BRCA mutations were quite sensitive to PARP inhibitors. This led to a plethora of studies that have been conducted and are ongoing now.

Basically, in the United States, there are 2 PARP inhibitors that are FDA approved for the treatment of patients with recurrent ovarian cancer. These are olaparib (Lynparza) that was approved a few years ago, and rucaparib (Rubraca), which was approved in December 2016.

Again, both approvals are specifically for treating cancers that have defective BRCA genes. Olaparib was approved only for women who had inherited a BRCA mutation, which can be detected by a blood test. Rucaparib is for women who have an inherited or germline mutation in BRCA1/2 or have a specific mutation that would develop inside their tumor called a somatic mutation, both of which can be tested through companion diagnostics. 

How does the recent approval of rucaparib affect the field of ovarian cancer research?

This is the paradigm of how we can target defects in DNA repair, and certainly olaparib was a major advance to get that approved. Rucaparib has done a couple of things based on how those studied were designed. First, it moved the FDA approval up to an earlier setting in a disease course. Olaparib was approved only after you've had 3 prior courses of treatment for ovarian cancer and rucaparib was approved after having only 2 prior courses of treatment.

More importantly, the olaparib studies that led to the FDA approval were done in women who had an inherited or germline mutation, whereas the rucaparib studies examined the somatic mutations. The rucaparib approval is for both germline and somatic mutations.

What rucaparib was doing, and what we are trying to do with these EMSY studies, is trying to expand the arena for which PARP inhibitors can be applied to the treatment of patients with ovarian cancer. By adding somatic mutations, we have now picked up another 6% to 10% of ovarian tumors that can now receive this FDA-approved therapy. The inherited mutations are present in 15% to 20% and the somatic mutations are present in another 5% to 10%, so we are slowly chipping away to find the proper therapies targeted for each specific patient with ovarian cancer. 

Has any recent research emerged regarding the use of immunotherapy in the treatment of ovarian cancer?

There have been some studies and there are a number of ongoing studies. The single-agent results of immunotherapy in ovarian cancer have not been as dramatic as they have been in some other tumor types, such as specific types of endometrial cancer, colon cancer, and lung cancer. I don't think single-agent immunotherapy is going to be as promising as it is in other tumors, but now we're trying to augment the treatment by adding 2 and even 3 agents to immunotherapy. The combination would be traditional chemotherapy, other targeted agents or therapeutics, and through that combination there is a reasonable amount of promise for immunotherapy in ovarian cancer.

What do you think is the biggest challenge in the field of ovarian cancer?

The biggest challenge now and, unfortunately for the past 20 years, has been how to overcome platinum resistance in ovarian cancer. Most ovarian cancers are exquisitely sensitive to standard treatments, which include aggressive surgeries followed by combination chemotherapy of which a platinum-containing regimen is a critical part.

Primarily, due to the sensitivity of most ovarian cancer cells to platinum chemotherapy, the tumors fortunately have a dramatic response. Unfortunately, well over half of the tumors and half of the patients will have recurrent disease. Often, we can retreat them with platinum-based therapy or similar drugs, but they are ultimately destined to become resistant to platinum agents. We have been trying to combine agents for a long time but, with some of the more targeted therapeutics, there is a better promise that we can attack platinum-resistant disease.
Jelinic P, Eccles LA, Tseng A, et al. The EMSY threonine 207 phospho-site is required for EMSYdriven suppression of DNA damage repair [published online January 13, 2017]. Oncotarget. doi: 10.18632/oncotarget.14637.
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