The Laura J. Fogarty Endowed Chair for Uterine Cancer Research
Location: Cleveland Clinic Main Campus
There is a dearth of targeted therapies for women’s cancers and our projects seek to address this shortage by a focused approach on novel new pathways that we recently discovered. We focus on the most therapeutically challenging triple negative breast and gynecologic cancers. Due to limited available therapies, less than 50% of women survive more than 5 years with these cancers.
Complement independent signaling in ovarian cancer.
In the U.S., ovarian cancer is the second most common gynecologic malignancy, but the top cause of gynecologic cancer death, and is responsible for 5% of all cancer deaths in women. In 2017, 22,440 new cases and 14,080 deaths are estimated to occur. Of these, 10% of ovarian cancers demonstrate an appearance of endometrioid tumor (ET) subtype.
Treatment for gynecologic malignancy is traditionally comprised of debulking surgery and platinum/taxane-based chemotherapy. Patients initially respond to cytotoxic chemotherapy, however for many the tumor recurs and becomes resistant to platinum. As such, there is a significant unmet medical need to treat ETs. An underlying cause of this resistance is the presence of a cancer stem cell population that contributes to tumor growth, recurrence, and treatment resistance and has been observed in ETs. CSCs offer a potential target population for therapeutic intervention. In published studies, we identified the cell surface protein CD55 as a therapeutic target for ET cancer stem cells and platinum-resistant disease. Our studies focus on defining mechanisms for overcoming resistance and targeting cancer stem cells.
Connexin/Focal Adhesion Kinase/NANOG complex in Triple Negative Breast Cancer.
Triple-negative breast cancer is the most aggressive breast cancer subtype and is resistant to therapies. Our objective is to identify unique, targetable mechanisms to neutralize cancer stem cells, which are thought to underlie resistance to chemotherapeutics, as well as recurrence and metastasis, and minimize collateral damage to surrounding cells. To identify key processes that are important for cancer stem cell function, we developed a reporter system to track and study these cells in real time. With this reporter, we identified that the protein connexin 26 (Cx26) is necessary and sufficient for the survival of cancer stem cells in triple-negative breast cancer models. While Cx26 was previously proposed to be a tumor suppressor, epidemiological studies suggest otherwise, as patients with high Cx26 had a poorer prognosis. Our studies indicate that Cx26 promotes cancer stem cell survival by forming a protein complex with the transcription factor NANOG, a master regulator of cancer stem cell function, and focal adhesion kinase in triple-negative breast cancer but not in other breast cancers. Our objective is to prevent this complex from forming and thereby inhibit cancer stem cell survival and growth.
Reizes, O., Lincecum, J., Wang, Z., et al. Transgenic expression of syndecan-1 uncovers a novel control of feeding behavior by hypothalamic syndecan-3. Cell 2001, 106: 105-116.Strader, A.D*, Reizes, O.* et al. Syndecan-3 null mice are resistant to diet induced obesity. J. Clin. Invest. 2004, 114: 1354-1360.Thiagarajan PS, Sinyuk M, Turaga SM, Mulkearns-Hubert EE, Hale JS, Rao V, Demelash A, Saygin C, China A, Alban TJ2, Hitomi M, Torre-Healy LA, Alvarado AG, Jarrar A, Wiechert A, Adorno-Cruz V, Fox PL, Calhoun BC, Guan JL, Liu H, Reizes O, Lathia JD. Cx26 drives self-renewal in triple-negative breast cancer via interaction with NANOG and focal adhesion kinase. Nat Commun. 2018 Feb 8;9(1):578. doi: 10.1038/s41467-018-02938-1.Saygin C, Wiechert A, Rao VS, Alluri R, Connor E, Thiagarajan PS, Hale JS, Li Y, Chumakova A, Jarrar A, Parker Y, Lindner DJ, Nagaraj AB, Kim JJ, DiFeo A, Abdul-Karim FW, Michener C, Rose PG, DeBernardo R, Mahdi H, McCrae KR, Lin F, Lathia JD, Reizes O. CD55 regulates self-renewal and cisplatin resistance in endometrioid tumors. J Exp Med. 2017 Sep 4;214(9):2715-2732. doi: 10.1084/jem.20170438. Epub 2017 Aug 24.
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Reassessing antibiotic dosage and type could improve survival rates in deadliest gynecologic malignancy, Cleveland Clinic research finds.