Lucy Kelliher

Navitoclax, a Bcl-2/xL Inhibitor, and YM155, a Survivin Inhibitor, in Combination with Carboplatin, Effectively Inhibit Ovarian Cancer Tumor Growth

Abstract High-grade serous ovarian cancer is generally treated with upfront chemotherapy, including carboplatin. The persistence of platinum-resistant cells drives recurrent disease. A high-throughput screen using a 3D organotypic culture assembled with extracellular matrix, primary human fibroblasts, and mesothelial cells was established and validated. Using a library of FDA-approved drugs, the 3D high-throughput screen was performed with the goal of identifying a combination of drugs that synergistically target two populations of ovarian cancer: aldehyde dehydrogenase (ALDH) high (ALDHhi) and ALDH low (ALDHlo) enzyme activity cells, which are less sensitive to carboplatin treatment than the bulk ovarian cancer cells. Initial results showed that omipalisib, verteporfin, CA3, mitoxantrone, navitoclax, venetoclax, and YM155 had significant single-drug activity in either the ALDHlo or both the ALDHlo/ALDHhi cell populations. Synergistic drug activity was identified with three drug combinations: navitoclax/omipalisib, navitoclax/YM155, and YM155/omipalisib. In vitro, the combination of navitoclax/YM155 was most efficient at blocking primary human ovarian cancer sphere formation and the proliferation of four different ovarian cancer cell lines in the 3D organotypic culture. In vivo, the combination of navitoclax/YM155/carboplatin decreased ovarian cancer metastasis, decreased the percentage of ALDHhi ovarian cancer cells in tumors, and increased survival when compared with carboplatin treatment alone in xenograft models. Our results suggest that the combination of navitoclax/YM155/carboplatin has promise as a therapy for treating ovarian cancer.

Molecular changes driving low-grade serous ovarian cancer and implications for treatment

Low-grade serous ovarian cancer was previously thought to be a subtype of high-grade serous ovarian cancer, but it is now recognized as a distinct disease with unique clinical and molecular behaviors. The disease may arise de novo or develop from a serous borderline ovarian tumor. Although it is more indolent than high-grade serous ovarian cancer, most patients have advanced metastatic disease at diagnosis and recurrence is common. Recurrent low-grade serous ovarian cancer is often resistant to standard platinum-taxane chemotherapy, making it difficult to treat with the options currently available. New targeted therapies are needed, but their development is contingent on a deeper understanding of the specific biology of the disease. The known molecular drivers of low-grade tumors are strong hormone receptor expression, mutations in the mitogen-activated protein kinase (MAPK) pathway (

Understanding Long-Term Survival of Patients with Ovarian Cancer—The Tumor Microenvironment Comes to the Forefront

High-grade serous ovarian cancer (HGSOC) is the deadliest subtype of ovarian cancer, and most patients do not survive more than 5 years after diagnosis. Yet, for reasons that are often elusive, approximately 15% of women with advanced-stage HGSOC will survive longer than 10 years. An understanding of the biological basis of long-term survival with HGSOC may elucidate novel prognostic factors and targets for treatment. Past analyses of the clinicopathologic features of these women and genetic profiles of their tumors have not revealed a unifying explanation for their increased longevity. In this issue of Cancer Research, Ferri-Borgogno and colleagues investigate the tumor microenvironment (TME) in samples from both long- and short-term survivors using spatial transcriptomics and single-cell RNA sequencing. They found that, in metastatic tumors, various populations of cancer-associated fibroblasts (CAF) in the TME play different roles in supporting the malignant phenotype of ovarian cancer cells. Higher density of CAFs, particularly αSMA+VIM+PDGFRβ+ CAFs, was associated with lower tumor immune infiltration and short-term survival. There was also marked expression of periostin and CD36 in spatially resolved CAFs, as well as a prevalence of the APOE-LRP5 ligand-receptor pair at the tumor-stromal interface in tissue from short-term survivors. These findings suggest that, in short-term survivors, CAFs are able to more effectively promote tumorigenicity, stemness, and chemoresistance in the nearby tumor.See related article by Ferri-Borgogno et al., p. 1503