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High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to its high recurrence rate and acquired chemoresistance. RAS/MEK/ERK pathway activation is linked to cell proliferation and therapeutic resistance, but the role of MEK1/2-ERK1/2 pathway in HGSOC is poorly investigated. We evaluated MEK1/2 pathway activity in clinical HGSOC samples and ovarian cancer cell lines using immunohistochemistry, immunoblotting, and RT-qPCR. HGSOC cell lines were used to assess immediate and lasting effects of MEK1/2 inhibition with trametinib in vitro. Trametinib effect on tumor growth in vivo was investigated using mouse xenografts. MEK1/2 pathway is hyperactivated in HGSOC and is further stimulated by cisplatin treatment. Trametinib treatment causes cell cycle arrest in G1/0-phase and reduces tumor growth rate in vivo but does not induce cell death or reduce fraction of CD133+ stem-like cells, while increasing expression of stemness-associated genes instead. Transient trametinib treatment causes long-term increase in a subpopulation of cells with high aldehyde dehydrogenase (ALDH)1 activity that can survive and grow in non-adherent conditions. We conclude that MEK1/2 inhibition may be a promising approach to suppress ovarian cancer growth as a maintenance therapy. Promotion of stem-like properties upon MEK1/2 inhibition suggests a possible mechanism of resistance, so a combination with CSC-targeting drugs should be considered.

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This review summarizes the evidence on antiphospholipid (aPL) antibodies and related thromboembolic events in patients with solid tumors. Data sources included Medline, EMBASE, Web of Science, PubMed ePubs, and the Cochrane Central Register of Controlled Trials through August 2019 without restrictions. Observational studies that evaluated patients with solid tumors for the presence of aPL antibodies were included. Data were extracted and quality was assessed by one reviewer and cross-checked by another. Thirty-three studies were identified. Gastrointestinal (GI) and genitourinary (GU) cancers were the most frequently reported. Compared with healthy patients, patients with GI cancer were more likely to develop anticardiolipin antibodies (risk ratio [RR], 5.1; 95% confidence interval [CI], 2.6-9.95), as were those with GU (RR, 7.3; 95% CI, 3.3-16.2) and lung cancer (RR, 5.2; 95% CI, 1.3-20.6). The increased risk for anti-β2-glycoprotein I or lupus anticoagulant was not statistically significant. Patients with lung cancer who had positive aPL antibodies had higher risk of developing thromboembolic events than those who had negative antibodies (RR, 3.8%; 95% CI, 1.2-12.2), while the increased risk in patients with GU cancer was not statistically significant. Deaths due to thromboembolic events were more common among patients with lung cancer who had elevated aPL antibodies. A limitation of this review is that the results are contingent on the reported information. We found an increased risk of developing aPL antibodies in patients with GI, GU, and lung cancers resulting in thromboembolic events and death. Further studies are needed to better understand the pathogenesis and development of aPL antibodies in cancer.

Congenital central hypoventilation syndrome (CCHS) is a rare autosomal dominant disease that affects the autonomic regulation of breathing. Patients present with respiratory symptoms such as sleep apnea and dependency on mechanical ventilation during sleep or nonrespiratory symptoms such as orthostatic hypotension and sinus bradycardia. CCHS in the neonates are linked but not limited to Hirschsprung disease, neural crest cell tumors, and esophageal dysmotility. Literature about CCHS management in pregnancy is scarce. Several studies have shown that pregnant CCHS patients are at risk of adverse pregnancy outcomes such as preterm delivery, low birth weight, and maternal complications including increased dependency on the mechanical ventilation and sometimes cardiopulmonary arrest. A multidisciplinary approach has been shown to be associated with better pregnancy outcomes. In this case report, we present a case of a patient with CCHS who had her prenatal care at our high-risk pregnancy unit and delivered a healthy baby. We encourage having a thorough discussion with such high-risk patients throughout their prenatal care or even preconception about their pregnancy expectations and outcomes in order to provide them and their babies with the care needed in the postpartum period.

Rationale: High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to high rate of recurrence and acquired chemoresistance. Mutation and activation of the RAS/MAPK pathway has been linked to cancer cell proliferation and therapeutic resistance in numerous cancers. While RAS mutations are not commonly observed in HGSOC, less is known about downstream pathway activation. We therefore sought to investigate the role of MEK1/2 signaling in ovarian cancer.Methods: MEK1/2 pathway activity was evaluated in clinical HGSOC tissue samples and ovarian cancer cell lines by using tissue microarray-based immunohistochemistry, immunoblotting, and RT-qPCR. OVCAR8 and PEO4 HGSOC cell lines were used to assess the effect of MEK1/2 inhibition on cell viability, proliferation rate, and stem-like characteristics. Xenografts were used in mice to investigate the effect of MEK1/2 inhibition on tumor growth in vivo. A drug washout experimental model was used to study the lasting effects of MEK1/2 inhibition therapy.Results: MEK1/2 signaling is active in a majority of HGSOC tissue samples and cell lines. MEK1/2 is further stimulated by cisplatin treatment, suggesting that MEK1/2 activation may play a role in chemotherapy resistance. The MEK1/2 inhibitor, trametinib, drastically inhibits MEK1/2 downstream signaling activity, causes prominent cell cycle arrest in the G1/0-phase in cell cultures, and reduces the rate of tumor growth in vivo, but does not induce cell death. Cells treated with trametinib display a high CD133 + fraction and increased expression of stemness-associated genes.Transient trametinib treatment causes long-term increases in a high ALDH1 activity subpopulation of cells that possess the capability of surviving and growing in non-adherent conditions. Conclusions: MEK1/2 inhibition in HGSOC cells efficiently inhibits proliferation and tumorgrowth and therefore may be a promising approach to suppress ovarian cancer cell growth. MEK1/2 inhibition promotes stem-like properties, thus suggesting a possible mechanism of resistance and that a combination with CSC-targeting drugs should be considered.

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Rationale: High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to high rates of recurrence and acquired chemoresistance. Recurrent tumors are suggested to originate from cancer stem-like cells (CSCs) which have been shown to have high MEK1/2 activity signaling pathway to survive and proliferate. Present work investigates the potential of selective MEK1/2 inhibition as a CSC-targeting HGSOC therapy approach. Methods: MEK1/2 pathway activity was evaluated in clinical HGSOC tissue samples and ovarian cancer cell lines using tissue microarray-based immunohistochemistry, immunoblotting and RT-qPCR. OVCAR8 and PEO4 HGSOC cell lines were used to assess the effect of MEK1/2 inhibition on cell viability, proliferation rate and stem-like characteristics in vitro. Mouse xenografts were used to investigate MEK1/2 inhibition effect on tumor growth in vivo. Drug washout experimental model was used to study the lasting effects of MEK1/2 inhibition therapy. Results: MEK1/2 signaling is active in majority of HGSOC tissue samples and cell lines and is further stimulated by cisplatin treatment. MEK1/2 inhibitor trametinib drastically inhibits activity of MEK1/2 downstream signaling, causes prominent cell cycle arrest in G1/0-phase in vitro and reduces tumor growth rate in vivo, but does not induce cell death. Cells treated with trametinib display high CD133+ fraction and increased expression of stemness-associated genes. Transient trametinib treatment causes long-term increase in high ALDH1 activity cells that possess capability of surviving and growing in non-adherent conditions. Conclusions: MEK1/2 inhibition in HGSOC cells efficiently inhibits cell proliferation and tumor growth and therefore may be promising approach to suppress ovarian cancer cell growth. As MEK1/2 inhibition promotes stem-like properties, including ALDH activity, it should be used in combination with CSC-targeting drugs, especially ALDH1 inhibitors. Citation Format: Mikhail Chesnokov, Abdelrahman Yousif, ilana Chefetz. The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A057. doi:10.1158/1535-7163.TARG-19-A057