Licofelone Enhances the Efficacy of Paclitaxel in Ovarian Cancer by Reversing Drug Resistance and Tumor Stem-like Properties

Abstract

Drug development for first-line treatment of epithelial ovarian cancer (EOC) has been stagnant for almost three decades. Traditional cell culture methods for primary drug screening do not always accurately reflect clinical disease. To overcome this barrier, we grew a panel of EOC cell lines in three-dimensional (3D) cell cultures to form multicellular tumor spheroids (MCTS). We characterized these MCTS for molecular and cellular features of EOC and performed a comparative screen with cells grown using two-dimensional (2D) cell culture to identify previously unappreciated anticancer drugs. MCTS exhibited greater resistance to chemotherapeutic agents, showed signs of senescence and hypoxia, and expressed a number of stem cell-associated transcripts including and, also known as Using a library of clinically repurposed drugs, we identified candidates with preferential activity in MCTS over 2D cultured cells. One of the lead compounds, the dual COX/LOX inhibitor licofelone, reversed the stem-like properties of ovarian MCTS. Licofelone also synergized with paclitaxel in ovarian MCTS models and in a patient-derived tumor xenograft model. Importantly, the combination of licofelone with paclitaxel prolonged the median survival of mice (>141 days) relative to paclitaxel (115 days), licofelone (37 days), or vehicle (30 days). Increased efficacy was confirmed by Mantel-Haenszel HR compared with vehicle (HR = 0.037) and paclitaxel (HR = 0.017). These results identify for the first time an unappreciated, anti-inflammatory drug that can reverse chemotherapeutic resistance in ovarian cancer, highlighting the need to clinically evaluate licofelone in combination with first-line chemotherapy in primary and chemotherapy-refractory EOC. This study highlights the use of an spheroid 3D drug screening model to identify new therapeutic approaches to reverse chemotherapy resistance in ovarian cancer..

A Tumor‐on‐a‐Chip System with Bioprinted Blood and Lymphatic Vessel Pair

“…The two-dimensional (2D) cancer cell cultures are restricted in serving as adequate models for drug screening and drug development [1,2] , due to challenges associated with for example, hypersensitivity to anti-cancer drugs [3] , and inability to recapitulate the complex intricate interactions within a tumor microenvironment (TME) [4] . The TME is capable of acting as both a potential barrier and facilitator of tumor proliferation by affecting various processes including local growth resistance, immune system interactions, and the formation of distant metastases [5] .…”

Immobilization rapidly selects for chemoresistant ovarian cancer cells with enhanced ability to enter dormancy

“…Previous studies have shown that cancer cells resisting apoptosis in nonadherent conditions are also more chemoresistant (Eguchi et al, 2015; Foley et al, 2015; Wheeler et al, 2018). Additionally in ovarian cancer, nonadherent cancer spheroids either created in vitro or isolated from in vivo ascites fluid also demonstrate enhanced chemoresistance (Hirst et al, 2018; Liao et al, 2014; Wheeler et al, 2018). Moreover, ovarian cancer spheroids are thought to be a unique subpopulation of tumor cells with self‐renewal capability and enhanced chemoresistance (Liao et al, 2014).…”

Activity of Birinapant, a SMAC Mimetic Compound, Alone or in Combination in NSCLCs With Different Mutations

“…The screening of FDA-approved library is an interesting technique already used in different fields by researchers (26,27). Indeed, by examining all the drug classes on the same cellular model it is possible to find new applications for an old drug and, hence, introduce an already existing therapy to a new disease, the so called drug repurposing (28). In addition, drug repurposing allows rapid clinical impact and patient benefit at reduced cost and time requirements than de novo drug development as a result of the availability of bioactivity and safety data from clinical trials for each compound used in the screening (21).…”