Next Article in Journal
Stroma Transcriptomic and Proteomic Profile of Prostate Cancer Metastasis Xenograft Models Reveals Prognostic Value of Stroma Signatures
Next Article in Special Issue
Suppression of Metastatic Melanoma Growth in Lung by Modulated Electro-Hyperthermia Monitored by a Minimally Invasive Heat Stress Testing Approach in Mice
Previous Article in Journal
Novel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms
Previous Article in Special Issue
Predicting and Quantifying Antagonistic Effects of Natural Compounds Given with Chemotherapeutic Agents: Applications for High-Throughput Screening
Open AccessArticle

Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer

1
Women’s Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
2
Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, James Cancer Hospital and Solve Research Institute, Columbus, OH 43210, USA
3
Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD 20814, USA
4
Department of Obstetrics, Gynecology, and Reproductive Science, Division of Gynecologic Oncology, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA
5
Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Tripler Army Medical Center, Honolulu, HI 96859, USA
6
The National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(12), 3784; https://doi.org/10.3390/cancers12123784
Received: 18 October 2020 / Revised: 8 December 2020 / Accepted: 10 December 2020 / Published: 15 December 2020
(This article belongs to the Special Issue Combination Therapies in Cancers)
Recurrent ovarian cancer is difficult to treat due to the development of chemotherapy resistance. This resistance develops through multiple mechanisms to include the avoidance of cell death by cancer cells. Prior studies have shown birinapant, a second mitochondrial activator of caspases (SMAC) mimetic drug, to be promising in overcoming this acquired resistance. Despite good tolerability, however, therapy with single-agent birinapant exhibited minimal anti-cancer activity in women with recurrent ovarian cancer. By using a high-throughput drug screen we were able to identify potential therapeutic agents that augment birinapant activity, with docetaxel emerging favorably due to its marked synergy and known utility in the recurrent ovarian cancer setting. We showed that this synergy is the result of several complementary molecular pathways and hope to highlight the promising potential of this therapeutic drug combination for clinical testing where treatment options are often limited.
Inhibitor of apoptosis (IAP) proteins are frequently upregulated in ovarian cancer, resulting in the evasion of apoptosis and enhanced cellular survival. Birinapant, a synthetic second mitochondrial activator of caspases (SMAC) mimetic, suppresses the functions of IAP proteins in order to enhance apoptotic pathways and facilitate tumor death. Despite on-target activity, however, pre-clinical trials of single-agent birinapant have exhibited minimal activity in the recurrent ovarian cancer setting. To augment the therapeutic potential of birinapant, we utilized a high-throughput screening matrix to identify synergistic drug combinations. Of those combinations identified, birinapant plus docetaxel was selected for further evaluation, given its remarkable synergy both in vitro and in vivo. We showed that this synergy results from multiple convergent pathways to include increased caspase activation, docetaxel-mediated TNF-α upregulation, alternative NF-kB signaling, and birinapant-induced microtubule stabilization. These findings provide a rationale for the integration of birinapant and docetaxel in a phase 2 clinical trial for recurrent ovarian cancer where treatment options are often limited and minimally effective. View Full-Text
Keywords: ovarian cancer; SMAC mimetics; birinapant; docetaxel; synergy; TNF-α; NF-kB; microtubule stability ovarian cancer; SMAC mimetics; birinapant; docetaxel; synergy; TNF-α; NF-kB; microtubule stability
Show Figures

Figure 1

  • Supplementary File 1:

    ZIP-Document (ZIP, 4567 KiB)

  • Externally hosted supplementary file 1
    Doi: 10.5281/zenodo.4100475
MDPI and ACS Style

Noonan, A.M.; Cousins, A.; Anderson, D.; Zeligs, K.P.; Bunch, K.; Hernandez, L.; Shibuya, Y.; Goldlust, I.S.; Guha, R.; Ferrer, M.; Thomas, C.J.; Annunziata, C.M. Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer. Cancers 2020, 12, 3784. https://doi.org/10.3390/cancers12123784

AMA Style

Noonan AM, Cousins A, Anderson D, Zeligs KP, Bunch K, Hernandez L, Shibuya Y, Goldlust IS, Guha R, Ferrer M, Thomas CJ, Annunziata CM. Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer. Cancers. 2020; 12(12):3784. https://doi.org/10.3390/cancers12123784

Chicago/Turabian Style

Noonan, Anne M.; Cousins, Amanda; Anderson, David; Zeligs, Kristen P.; Bunch, Kristen; Hernandez, Lidia; Shibuya, Yusuke; Goldlust, Ian S.; Guha, Rajarshi; Ferrer, Marc; Thomas, Craig J.; Annunziata, Christina M. 2020. "Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer" Cancers 12, no. 12: 3784. https://doi.org/10.3390/cancers12123784

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop