High-grade serous ovarian carcinoma (HGSOC) is the most aggressive type of ovarian cancer, often diagnosed at advanced stages. Molecularly, HGSOC shows high degree of genomic instability associated with large number of genetic alterations. BRD4 is the 4th most amplified gene in HGSOC, which correlates with poor patients’ prognosis. BRD4 is constitutively expressed and generates two proteins, BRD4 long (BRD4-L) and BRD4 short (BRD4-S). Both isoforms contain bromodomains that bind to lysine-acetylated histones. Amongst other functions, BRD4 participates in chromatin organization, acetylation of histones, transcriptional control and DNA damage repair. In cancer patients with amplified BRD4, the increased activity of BRD4 is associated with higher expression of oncogenes, such as MYC, NOTCH3 and NRG1. BRD4-driven oncogenes promote increased tumor cells proliferation, genetic instability, epithelial-mesenchymal transition, metastasis and chemoresistance. Ablation of BRD4 activity can be successfully achieved with bromodomain inhibitors (BETi) and degraders, and it has been applied in pre-clinical and clinical settings. Inhibition of BRD4 function has an effective anti-cancer effect, reducing tumor growth whether ablated by single agents or in combination with other drugs. When combined with standard chemotherapy, BETi are capable of sensitizing highly resistant ovarian cancer cell lines to platinum drugs. Despite the evidence that BRD4 amplification in ovarian cancer contributes to poor patient prognosis, little is known about the specific mechanisms by which BRD4 drives tumor progression. In addition, newly emerging data revealed that BRD4 isoforms exhibit contradicting functions in cancer. Therefore, it is paramount to expand studies elucidating distinct roles of BRD4-L and BRD4-S in HGSOC, which has important implications on development of therapeutic approaches targeting BRD4.

Auroliposome represents a highly effective siRNA delivery platform for in vitro and in vivo application.

Purpose: Recent studies have demonstrated that short-form Ron (sfRon) kinase drives breast tumor progression and metastasis through robust activation of the PI3K pathway. We reasoned that upfront, concurrent inhibition of sfRon and PI3K might enhance the antitumor effects of Ron kinase inhibitor therapy while also preventing potential therapeutic resistance to tyrosine kinase inhibitors (TKI). Experimental Design: We used patient-derived breast tumor xenografts (PDX) as high-fidelity preclinical models to determine the efficacy of single-agent or dual Ron/PI3K inhibition. We tested the Ron kinase inhibitor ASLAN002 with and without coadministration of the PI3K inhibitor NVP-BKM120 in hormone receptor–positive [estrogen receptor (ER)⁺/progesterone receptor (PR)⁺] breast PDXs with and without PIK3CA gene mutation. Results: Breast PDX tumors harboring wild-type PIK3CA showed a robust response to ASLAN002 as a single agent. In contrast, PDX tumors harboring mutated PIK3CA demonstrated partial resistance to ASLAN002, which was overcome with addition of NVP-BKM120 to the treatment regimen. We further demonstrated that concurrent inhibition of sfRon and PI3K in breast PDX tumors with wild-type PIK3CA provided durable tumor stasis after therapy cessation, whereas discontinuation of either monotherapy facilitated tumor recurrence. Conclusions: Our work provides preclinical rationale for targeting sfRon in patients with breast cancer, with the important stipulation that tumors harboring PIK3CA mutations may be partially resistant to Ron inhibitor therapy. Our data also indicate that tumors with wild-type PIK3CA are most effectively treated with an upfront combination of Ron and PI3K inhibitors for the most durable response. Clin Cancer Res; 21(24); 5588–600. ©2015 AACR.

We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is particularly prevalent in ovarian carcinoma and promotes highly metabolically active phenotype. Succinate dehydrogenase deficiency has been previously studied in some rare disorders. However, the role of SDHA upregulation and its impact on ovarian cancer metabolism has never been investigated, emphasizing the need for further research. We investigated the functional consequences of SDHA overexpression in ovarian cancer. Using proteomics approaches and biological assays, we interrogated protein content of metabolic pathways, cell proliferation, anchorage-independent growth, mitochondrial respiration, glycolytic function, and ATP production rates in those cells. Lastly, we performed a drug screening to identify agents specifically targeting the SDHA overexpressing tumor cells. We showed that SDHA overexpressing cells are characterized by enhanced energy metabolism, relying on both glycolysis and oxidative phosphorylation to meet their energy needs. In addition, SDHA-high phenotype was associated with cell vulnerability to glucose and glutamine deprivation, which led to a substantial reduction of ATP yield. We also identified an anti-metabolic compound shikonin with a potent efficacy against SDHA overexpressing ovarian cancer cells. Our data underline the unappreciated role of SDHA in reprogramming of ovarian cancer metabolism, which represents a new opportunity for therapeutic intervention.

(1) Background. PDX models have become the preferred tool in research laboratories seeking to improve development and pre-clinical testing of new drugs. PDXs have been shown to capture the cellular and molecular characteristics of human tumors better than simpler cell line-based models. More recently, however, hints that PDXs may change their characteristics over time have begun to emerge, emphasizing the need for comprehensive analysis of PDX evolution. (2) Methods. We established a panel of high-grade serous ovarian carcinoma (HGSOC) PDXs and developed and validated a 300-SNP signature that can be successfully utilized to assess genetic drift across PDX passages and detect PDX contamination with lymphoproliferative tissues. In addition, we performed a detailed histological characterization and functional assessment of multiple PDX passages. (3) Results. Our data show that the PDXs remain largely stable throughout propagation, with marginal genetic drift at the time of PDX initiation and adaptation to mouse host. Importantly, our PDX lines retained the major histological characteristics of the original patients’ tumors even after multiple passages in mice, demonstrating a strong concordance with the clinical responses of their corresponding patients. (4) Conclusions. Our data underline the value of defined HGSOC PDXs as a pre-clinical tumor model.

Short-form Ron (sfRon) is an understudied, alternative isoform of the full-length Ron receptor tyrosine kinase. In contrast to Ron, which has been shown to be an important player in many cancers, little is known about the role of sfRon in cancer pathogenesis. Here we report the striking discovery that sfRon expression is required for development of carcinogen-induced malignant ovarian tumors in mice. We also show that sfRon is expressed in several subtypes of human ovarian cancer including high-grade serous carcinomas, which is in contrast to no detectable expression in healthy ovaries. In addition, we report that introduction of sfRon into OVCAR3 cells resulted in epithelial-to-mesenchymal transition, activation of the PI3K and PDK1 pathway, and inhibition of the MAPK pathway. We demonstrated that sfRon confers an aggressive cancer phenotype in vitro characterized by increased proliferation and migration, and decreased adhesion of ovarian cancer cells. Moreover, the in vivo studies show that OVCAR3 tumors expressing sfRon exhibit significantly more robust growth and spreading to the abdominal cavity when compared with the parental sfRon negative OVCAR3 cells. These data suggest that sfRon plays a significant role in ovarian cancer initiation and progression, and may represent a promising therapeutic target for ovarian cancer treatment.