Preclinical Trial of High-Grade Serous Ovarian Cancer Shows Efficacy With Birinapant Plus Carboplatin

Sanaz Memarzadeh, MD, PhD

Sanaz Memarzadeh, MD, PhD

Combination therapy with birinapant and carboplatin may be more effective than either therapy alone for treatment of high-grade serous ovarian cancers (HGSCs) with high levels of cellular inhibitor of apoptosis protein (cIAP) in their CA125-negative cells, according to a recent study at University of California, Los Angeles (UCLA).¹The findings, published August 3, 2015, inNature Communicationsmay also explain a potential mechanism for the high recurrence rate and eventual therapy resistance of HGSC after initial treatment with carboplatin.

Even with radical surgery and platinum-based chemotherapy, the 5-year survival rate for advanced-stage disease is 30% to 40%.²Carboplatin is often effective as an initial treatment, but relapse occurs in 80% to 85% of patients, according to Sanaz Memarzadeh, MD, PhD, senior author of the study and gynecologic cancer surgeon at UCLA. Many experts have proposed genetic and epigenetic changes in HGSCs as potential mechanisms of resistance to platinum-based therapy. However, the UCLA authors indicated these changes do not fully explain the reasons for the resurgence of tumor growth and increasing resistance to carboplatin.

A team of researchers led by Memarzadeh and Deanna Janzen, PhD a senior scientist in the G.O. Discovery Lab at UCLA, hypothesized that a subpopulation of cells innate to the initial tumor may contribute to the recurrence of ovarian cancer after primary therapy. The team analyzed ovarian tumors from patients at UCLA and found that while most of the cells within the tumors tested positive for CA125, a biomarker that is often used to detect ovarian cancer, a small subset were CA125-negative. The CA125-negative cells were able to grow 700 times better than CA125-positive cells from the same tumor. In addition, while carboplatin eliminates differentiated CA125-positive cells, the drug was ineffective against the CA125-negative cells, highlighting a potential mechanism for innate resistance to carboplatin. Further analysis in cell culture revealed that these CA-125—negative cells had an enhanced ability to repair DNA and resist programmed cell death (ie, apoptosis).

“It was very striking that the two cell populations had such different growth potentials,” said Janzen in a press release.³“But what was more remarkable was that the CA125-negative cells were clearly resistant to the drugs normally used to treat serous cancers.”

Further investigations using genetic analysis showed that the CA125-negative cells in up to 50% of HGSCs had high levels of cIAP, which enabled them to survive platinum-based therapy and serve as a source of tumor regrowth after initial therapy.

“These cells were like little time bombs, hiding from the chemotherapy and later initiating tumor growth,” said Memarzadeh in a press release.³

Birinapant, which has been shown to cause rapid breakdown of cIAP in cultured inflammatory breast cancer cells,⁴is currently being investigated in preclinical and clinical trials for a variety of solid tumors and hematologic malignancies. Indeed, the UCLA researchers showed that combined treatment with birinapant and carboplatin significantly improved disease-free survival in a mouse model of human ovarian cancer versus either therapy alone. According to Memarzadeh, these results suggest that the combined therapy could be useful for improving long-term outcomes in either the primary or recurrent disease setting in a subset of patients.

The next step for Memarzadeh and her colleagues will be to test this combination therapy in a clinical trial. Memarzadeh estimates about 50% of patients with ovarian cancer have high levels of cIAP in their tumor’s CA125-negative cell population and would be eligible for this study. The UCLA team is also investigating potential therapeutic targets for the 50% of patients with low cIAP, as well as biomarkers other than CA125 that could be used to screen for ovarian cancer. Nevertheless, the authors indicated that further identification of mechanisms behind ovarian cancer recurrence and resistance to platinum therapy will be central to targeting therapies toward the population of resistant cells and eventually improving long-term patient outcomes.

“If this combination of drugs proves effective, we may be able to improve outcomes for this deadly disease,” said Memarzadeh. “I think it’s entirely feasible.”

References:

1. 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 Aug 3;6:7956. doi: 10.1038/ncomms8956.

2. Vaughan S, Coward JI, Bast RC Jr, et al. Rethinking ovarian cancer: recommendations for improving outcomes.Nat Rev Cancer. 2011 Sep 23;11(10):719-25. doi: 10.1038/nrc3144.

3. UCLA Health System. Combination Therapy May Be More Effective Against the Most Common Ovarian Cancer. Available at:http://www.newswise.com/articles/view/638086/?sc=mwhr&xy=10013055. Accessed August 7, 2015.

4. Allensworth JL, Sauer SJ, Lyerly HK, Morse MA, Devi GR. Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism.Breast Cancer Res Treat