Purpose: The Notch pathway plays an important role in both stem cell biology and cancer. Dysregulation of Notch signaling has been reported in several human tumor types. In this report, we describe the development of an antibody, OMP-59R5 (tarextumab), which blocks both Notch2 and Notch3 signaling. Experimental Design: We utilized patient-derived xenograft tumors to evaluate antitumor effect of OMP-59R5. Immunohistochemistry, RNA microarray, real-time PCR, and in vivo serial transplantation assays were employed to investigate the mechanisms of action and pharmacodynamic readouts. Results: We found that anti-Notch2/3, either as a single agent or in combination with chemotherapeutic agents was efficacious in a broad spectrum of epithelial tumors, including breast, lung, ovarian, and pancreatic cancers. Notably, the sensitivity of anti-Notch2/3 in combination with gemcitabine in pancreatic tumors was associated with higher levels of Notch3 gene expression. The antitumor effect of anti-Notch2/3 in combination with gemcitabine plus nab-paclitaxel was greater than the combination effect with gemcitabine alone. OMP-59R5 inhibits both human and mouse Notch2 and Notch3 function and its antitumor activity was characterized by a dual mechanism of action in both tumor and stromal/vascular cells in xenograft experiments. In tumor cells, anti-Notch2/3 inhibited expression of Notch target genes and reduced tumor-initiating cell frequency. In the tumor stroma, OMP-59R5 consistently inhibited the expression of Notch3, HeyL, and Rgs5, characteristic of affecting pericyte function in tumor vasculature. Conclusions: These findings indicate that blockade of Notch2/3 signaling with this cross-reactive antagonist antibody may be an effective strategy for treatment of a variety of tumor types. Clin Cancer Res; 21(9); 2084–95. ©2015 AACR.

Deregulation of the b-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and b-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate b-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate b-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, geneexpression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited b-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of b-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis. Cancer Res; 76(3); 713-23. Ó2015 AACR.

Recently, there has been renewed interest in the role of tumor stem cells (TSCs) in tumorigenesis, chemoresistance, and relapse of malignant tumors including osteosarcoma. The potential exists to improve osteosarcoma treatment through characterization of TSCs and identification of therapeutic targets. Using transcriptome, proteome, immunophenotyping for cell-surface markers, and bioinformatic analyses, heterogeneous expression of previously reported TSC or osteosarcoma markers, such as CD133, nestin, POU5F1 (OCT3/4), NANOG, SOX2, and aldehyde dehydrogenase, among others, was observed in vitro. However, consistently significantly lower CD326, CD24, CD44, and higher ABCG2 expression in TSC-enriched as compared with un-enriched osteosarcoma cultures was observed. In addition, consistently higher CBX3 expression in TSC-enriched osteosarcoma cultures was identified. ABCA5 was identified as a putative biomarker of TSCs and/or osteosarcoma. Lastly, in a high-throughput screen we identified epigenetic (5-azacytidine), anti-microtubule (vincristine), and anti-telomerase (3,11-difluoro-6,8,13-trimethyl- 8H-quino [4,3,2-kl] acridinium methosulfate; RHPS4)-targeted therapeutic agents as candidates for TSC ablation in osteosarcoma.

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Purpose The purpose of this paper is to understand the dynamics of pleasure related to chemsex from the perspective of French gay men and other men who have sex with men (MSM). Recognising that participants in chemsex are social actors, the authors diverge from the prominent “pathology paradigm” used in public health. Design/methodology/approach In-depth interviews were conducted with gay men and other MSM engaging in chemsex via snowball sampling (n=33). The authors explored the definitions of pleasure and the role of stimulants, sexual activity, smartphones and partners in chemsex pleasures. Findings Chemsex pleasures encompass multiple dimensions that go far beyond bodily pleasures, such as love or romantic relationships, socializing with significant others and sexual discovery through disinhibition. Narratives of pleasure were also, simultaneously, stories of suffering and distress. This dissonance can pose challenges to the participants in chemsex, their entourages and care providers. Practical implications Given that the focus of care for gay men and other MSM is on risk behaviors, the findings of this paper help nurture discussions where pleasure is integrated into a new, value-neutral framework of care that incorporates chemsex pleasures. Originality/value This study examined the perspectives of those actually participating in chemsex, allowing gay men and other MSM to relate the entirety of their experiences, in which pleasure is often at the forefront, without restriction.

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Access to vaccination against a health threat such as that presented by the COVID-19 pandemic is an imperative driven, in principle, by at least three compelling factors: (1) the right to health of all people, irrespective of their status; (2) humanitarian need of undocumented migrants, as well as of others including documented migrants, refugees and displaced people who are sometimes vulnerable and living in precarious situations; and (3) the need to ensure heath security globally and nationally, which in the case of a global pandemic requires operating on the basis that, for vaccination strategies to succeed in fighting a pandemic, the highest possible levels of vaccine uptake are required. Yet some population segments have had limited access to mainstream health systems, both prior to as well as during the COVID-19 pandemic. People with irregular resident status are among those who face extremely high barriers in accessing both preventative and curative health care. This is due to a range of factors that drive exclusion, both on the supply side (e.g., systemic and practical restrictions in service delivery) and the demand side (e.g., in uptake, including due to fears that personal data would be transmitted to immigration authorities). Moreover, undocumented people have often been at increased risk of infection due to their role as “essential workers”, including those experiencing higher exposure to the SARS-CoV-2 virus due to frontline occupations while lacking protective equipment. Often, they have also been largely left out of social protection measures granted by governments to their populations during successive lockdowns. This article reviews the factors that serve as supply-side and demand-side barriers to vaccination for undocumented migrants and considers what steps need to be taken to ensure that inclusive approaches operate in practice.