Birinapant May Reduce Chemoresistance, Recurrence in Certain Ovarian Cancers

Sanaz Memarzadeh, MD, PhD

In patients with high-grade serous ovarian cancers (HGSCs) and high levels of cellular inhibitor of apoptosis protein (cIAP) in their CA-125—negative cells, a combination regimen of birinapant and carboplatin may be more effective than either therapy alone, according to a recent preclinical trial published in Nature Communications.

The study found that approximately 50% of patients with ovarian cancer have high levels of cIAP in their tumor’s CA-125—negative cell population. This may explain the high recurrence rate and eventual therapy resistance of HGSC after initial treatment with carboplatin.

OncLive: What are the biggest challenges in ovarian cancer?

What efforts have you made in your research to better understand the causes of this problem?

To better understand the role high cIAP in CA-125—negative cells may play in carboplatin-resistance and ovarian cancer reccurrence, OncLive spoke with the trial’s lead investigator and senior author Sanaz Memarzadeh, MD, PhD, associate professor and gynecologic cancer surgeon, Department of Obstetrics and Gynecology, G.O. Discovery Discovery Laboratory, UCLA Broad Stem Cell Research Center, UCLA School of Medicine. Dr Memarzadeh: The majority of patients with ovarian cancer present with advanced stage disease and, despite undergoing radical surgeries and chemotherapy, the majority of these patients have relapse of their tumors. Up until recently, there was little understanding as to why this was the case. What we recently found in the laboratory, through analysis of multiple patient samples, was that the majority of the tumor cells in patients who presented with ovarian cancer were actually sensitive to standard chemotherapy. However, there was a small subset of tumor cells that resisted this treatment. These preexisting cancer cells that are resistant to the carboplatin therapy are there from the beginning; they did not emerge down the line.

Why is this significant?

What is interesting is that they do not express the most common biomarker used for the detection of ovarian cancer, CA-125, so they go undetected. These are also cells that have a regenerative capacity, meaning not only do they resist chemotherapy, but they can also very quickly reinitiate the cancer. When we compare the majority of the tumor cells that are CA-125—positive and are responsive to chemotherapy, to the minority that are CA-125–negative and resistant to chemotherapy, the minority actually has approximately 700-fold greater cancer initiating potential. What we believe is happening is, as we treat patients with chemotherapy, we are killing off the majority of the tumor cells, but a minority is left behind. These cells are armed with the capacity to resist carboplatin therapy. Many of these patients are thought to be in remission because their scans do not detect anything obvious. However, in reality, 85% of women diagnosed with advanced ovarian cancer have relapse of their disease. We believe that these cells, which are a small population of each tumor and have the ability to regenerate, slowly start growing and repopulating the tumor. That is how the cancers emerge.

Knowing this, we tried to understand why there were two different cell populations within the same tumor. We compared the two, and we learned that the CA-125—negative cells had a greater capacity to repair their DNA and had mechanisms that allowed them to avoid apoptosis or programed cell death. They resisted death in response to damage. As we looked for targets, we noticed that in about 50% of tested tumors there was an upregulation of cIAP. These proteins allow the cell to evade this programed cell death that would normally take place.

What were the results of these trials?

What are the next steps in this research?

We found a drug that is able to target and cause degradation of this protein. That drug is birinapant. We hypothesized that, if we combined this drug with standard chemotherapy, we could kill off the majority of cancer cells while also tackling the minority of the tumor cells that resist this chemotherapy. This was tested in preclinical trials. The results were very promising. In a subset of patients, and I think up to 50% of patients whose tumors have an upregulation of this protein would be eligible for this treatment, the cancer can be targeted with birinapant. This disarms the CA-125—negative cells and turns those cells resistant to carboplatin therapy sensitive. This could completely eliminate the cancer and prevent it from reccurring. We are in the process of trying to get this to a clinical trial. We are also exploring other mechanisms that will work in the other 50% of patients with other tumor cell types. In the next 5 to 10 years, when we operate on a patient with ovarian cancer we might be able to analyze that patient’s tumor in the lab. Then, we could tailor the treatment approach to what we learned from that analysis and pair it with standard treatment. I do think that this disease could be potentially cured with these kinds of individualized approaches.

Janzen DM, Tiourin E, Salehi JA, et al. An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer. Nat Commun. 2015;6:7956.