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Simple Summary: Glycosylation is an important post-translational modification made on mammalian proteins and lipids. In cancer cells, the disruption of several glycosylation patterns, such as the O-glycosylation, has been observed. The expression of incomplete/truncated O-glycans in cancer cells occurs in both solid and liquid tumors and is correlated with poor prognosis and tumor progression. The employment of monoclonal antibodies (mAbs) targeting truncated O-glycans in cancer cells could serve as an effective strategy to counteract tumor growth. In previous studies, we reported that the IgG1-humanized mAb NEO-201 binds specifically to tumor-associated variants of CEACAM5 and CEACAM6 expressed by colon, ovarian, pancreatic, non-small cell lung, head and neck, cervical, uterine and breast cancers but is not reactive against most normal tissues. Since CEACAMs are highly glycosylated proteins, in this article, we evaluated whether the epitope recognized by NEO-201 is an O-glycan. This study demonstrated that NEO-201 binds to core 1 O-glycans and targets and kills cancer cells expressing core 1 and extended core 1 O-glycans. Usually, GalNAc residue can be added on to threonine and serine to form O-glycans, suggesting that NEO-201 binds to core 1 and extended core 1 O-glycans attached to any protein carrying amino acid regions containing serine and threonine Truncated O-glycans expressed in cancer cells support tumor progression, and they may serve as potential targets to improve the monitoring and treatment of cancers. Previously, we reported that NEO-201 binds to several tumors expressing tumor-associated CEACAM5 and CEACAM6 variants but does not bind to those expressed in healthy tissues. This specific binding may be associated with the presence of truncated O-glycans attached on the protein sequence of these variants. To evaluate the glycosylation pattern targeted by NEO-201 we performed an O-glycan array consisting of 94 O-glycans. O-glycan profiles were elucidated from the human pancreatic cancer cell line CFPAC-1, human hematological neoplastic cells (HL-60, U937, K562) and human neutrophils. The O-glycan array analysis showed that NEO-201 interacts with core 1-4 O-glycans and that the binding to a specific core 1 O-glycan was the strongest. The O-glycan profiling of the NEO-201-reactive cells CFPAC-1, HL-60, U937 and human neutrophils showed that cells recognized by NEO-201 express mostly core 1 and/or extended core 1 O-glycans. In addition, NEO-201 mediates antibody-dependent cell-mediated cytotoxicity (ADCC) against tumor cells expressing core 1 or extended core 1 O-glycan profiles. These results demonstrated that NEO-201 binds to core 1 and extended core 1 O-glycans expressed in its target cells. Since GalNAc residue can be added onto threonine and serine to form O-glycans, it is very likely that NEO-201 recognizes these O-glycans attached to any protein with amino acid regions containing serine and threonine. [ABSTRACT FROM AUTHOR]

The Gynecologic Oncology Group has historically performed ground-breaking, practice-changing clinical trials in women's cancers. The current standard of care for initial treatment of ovarian, endometrial, cervical, and trophoblastic cancers was determined by clinical trials completed within this cooperative group structure. For example, trial GOG-0111 set the standard for combining platinum and taxane chemotherapy in ovarian cancer, and more recently GOG-0240 provided evidence for adding bevacizumab to chemotherapy for women with advanced cervical cancer. The landscape of clinical trial design has markedly changed in recent decades, with a clear emphasis on streamlining drug development towards specific patient populations and indications for investigational agents. Translational science in gynecologic cancers can set the stage for rapid and efficient introduction of new therapies for our patients. The gynecologic oncology community of researchers and clinicians is well positioned to enter into the new era of drug development, with breakthrough discoveries increasing each year. It is clear that we must incorporate smarter clinical trial design to get the right drugs to the right patients expeditiously, so we can continue to improve outcome for women with gynecologic cancers. [ABSTRACT FROM AUTHOR]

Background. Worse chemotherapy response for neurofibromatosis type 1- (NF1-) associated compared to sporadic malignant peripheral nerve sheath tumors (MPNST) has been reported. Methods. We evaluated the objective response (OR) rate of patients with AJCC Stage III/IV chemotherapy-naive NF1 MPNST versus sporadic MPNST after 4 cycles of neoadjuvant chemotherapy, 2 cycles of ifosfamide/doxorubicin, and 2 cycles of ifosfamide/etoposide. A Simon optimal two-stage design was used (target response rate 40%). Results. 34 NF1 (median age 33 years) and 14 sporadic (median age 40 years) MPNST patients enrolled. Five of 28 (17.9%) evaluable NF1 MPNST patients had a partial response (PR), as did 4 of 9 (44.4%) patients with sporadic MPNST. Stable disease (SD) was achieved in 22 NF1 and 4 sporadic MPNST patients. In both strata, results in the initial stages met criteria for expansion of enrollment. Only 1 additional PR was observed in the expanded NF1 stratum. Enrollment was slower than expected and the trial closed before full accrual. Conclusions. This trial was not powered to detect differences in response rates between NF1 and sporadic MPNST. While the OR rate was lower in NF1 compared to sporadic MPNST, qualitative responses were similar, and disease stabilization was achieved in most patients. [ABSTRACT FROM AUTHOR]

Background: shRNA-mediated lethality screening is a useful tool to identify essential targets in cancer biology. Ovarian cancer (OC) is extremely heterogeneous and most cases are advanced stages at diagnosis. OC has a high response rate initially, but becomes resistant to standard chemotherapy. We previously employed high throughput global shRNA sensitization screens to identify NF-kB related pathways. Here, we re-analyzed our previous shRNA screens in an unbiased manner to identify clinically applicable molecular targets.Methods: We proceeded with siRNA lethality screening using the top 55 genes in an expanded set of 6 OC cell lines. We investigated clinical relevance of candidate targets in The Cancer Genome Atlas OC dataset. To move these findings towards the clinic, we chose four pharmacological inhibitors to recapitulate the top siRNA effects: Oxozeaenol (for MAP3K7/TAK1), BI6727 (PLK1), MK1775 (WEE1), and Lapatinib (ERBB2). Cytotoxic effects were measured by cellular viability assay, as single agents and in 2-way combinations. Co-treatments were evaluated in either sequential or simultaneous exposure to drug for short term and extended periods to simulate different treatment strategies.Results: Loss-of-function shRNA screens followed by short-term siRNA validation screens identified therapeutic targets in OC cells. Candidate genes were dysregulated in a subset of TCGA OCs although the alterations of these genes showed no statistical significance to overall survival. Pharmacological inhibitors such as Oxozeaenol, BI6727, and MK1775 showed cytotoxic effects in OC cells regardless of cisplatin responsiveness, while all OC cells tested were cytostatic to Lapatinib. Co-treatment with BI6727 and MK1775 at sub-lethal concentrations was equally potent to BI6727 alone at lethal concentrations without cellular re-growth after the drugs were washed off, suggesting the co-inhibition at reduced dosages may be more efficacious than maximal single-agent cytotoxic concentrations.Conclusions: Loss-of-function screen followed by in vitro target validation using chemical inhibitors identified clinically relevant targets. This approach has the potential to systematically refine therapeutic strategies in OC. These molecular target-driven strategies may provide additional therapeutic options for women whose tumors have become refractory to standard chemotherapy. [ABSTRACT FROM AUTHOR]

Disease recurrence is the major cause of morbidity and mortality of ovarian cancer (OC). In terms of maintenance therapies after platinum-based chemotherapy, PARP inhibitors significantly improve the overall survival of patients with BRCA mutations but is of little benefit to patients without homologous recombination deficiency (HRD). The stem-like tumor-initiating cell (TIC) population within OC tumors are thought to contribute to disease recurrence and chemoresistance. Therefore, there is a need to identify drugs that target TICs to prevent relapse in OC without HRD. RNA sequencing analysis of OC cells grown in TIC conditions revealed a strong enrichment of genes involved in drug metabolism, oxidative phosphorylation and reactive oxygen species (ROS) pathways. Concurrently, a high-throughput drug screen identified drugs that showed efficacy against OC cells grown as TICs compared to adherent cells. Four drugs were chosen that affected drug metabolism and ROS response: disulfiram, bardoxolone methyl, elesclomol and salinomycin. The drugs were tested in vitro for effects on viability, sphere formation and markers of stemness CD133 and ALDH in TICs compared to adherent cells. The compounds promoted ROS accumulation and oxidative stress and disulfiram, elesclomol and salinomycin increased cell death following carboplatin treatment compared to carboplatin alone. Disulfiram and salinomycin were effective in a post-surgery, post-chemotherapy OC relapse model in vivo, demonstrating that enhancing oxidative stress in TICs can prevent OC recurrence. [ABSTRACT FROM AUTHOR]

The article discusses research being done on taxane resistance chemotherapy. It references the study "Role of Focal Adhesion Kinase in Regulating YB-1-mediated Paclitaxel Resistance in Ovarian Cancer," by Y. Kang et al. published in the 2013 issue of the Journal of National Institute." The study examined the role of focal adhesion kinase (FAK) and YB-1 transcription factor in the mechanisms of anti-cancer activity of taxanes in patients with ovarian cancer.