Flaviviruses such as dengue virus (DENV), Zika virus (ZIKV), and yellow fever virus (YFV) are spread by mosquitoes and cause human disease and mortality in tropical areas. In contrast, Powassan virus ...(POWV), which causes severe neurologic illness, is a flavivirus transmitted by ticks in temperate regions of the Northern hemisphere. We find serologic neutralizing activity against POWV in individuals living in Mexico and Brazil. Monoclonal antibodies P002 and P003, which were derived from a resident of Mexico (where POWV is not reported), neutralize POWV lineage I by recognizing an epitope on the virus envelope domain III (EDIII) that is shared with a broad range of tick- and mosquito-borne flaviviruses. Our findings raise the possibility that POWV, or a flavivirus closely related to it, infects humans in the tropics.
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•Sera from Mexico and Brazil neutralize POWV and TBEV, which are not known to circulate there•Monoclonal antibody P014 binds to POWV but not to endemic flaviviruses•Monoclonal antibodies P002 and P003 neutralize POWV lineage I•The P003 epitope is shared across 13 flaviviruses from tick and mosquito serocomplexes
Cervantes Rincón et al. describe antibody neutralizing activity against Powassan virus from regions of the Americas where this flavivirus transmitted by ticks is not known to circulate. Two monoclonal antibodies to the EDIII (P002 and P003) are broadly cross-reactive against tick- and mosquito-borne flaviviruses.
Chemotherapy is the treatment of choice for metastatic castration-resistant prostate cancer (mCRPC) nonresponsive to androgen receptor–targeted therapies. Nevertheless, the impact of chemotherapy on ...patient survival is limited and clinical outcome remain dismal. Bromodomain and extraterminal inhibitors (BETis) are attractive therapeutic agents and currently in clinical trials to be tested for their efficacy in prostate cancer patients.
In this study, we evaluated the activity of two clinical stage BETis, INCB054329 and INCB057643, alone and in combination with chemotherapeutics used for the treatment of mCRPC.
Drug activity was evaluated in vitro by MTT, clonogenic, prostato-sphere, and flow cytometry assays. The activity in vivo was evaluated in mice bearing prostate tumor (22Rv1) xenografts.
Cell growth data were analyzed to determine the maximum effect and the concentration that reduces by 50%. For concomitant treatments, the combination index was determined according to the Chou-Talalay method. For in vivo activity, changes in tumor size (T/Ci%), weight (T/Cd%), doubling time, and mouse body weight were monitored. Statistical significance was determined by one-way analysis of variance followed by a Student-Newman-Keuls or Turkey a posteriori test.
INCB054329 and INCB057643 had significant activity as single agents in human prostate cancer cell lines and 22Rv1 tumor xenografts. Combined treatment with INCB057643 and any of docetaxel, olaparib, or carboplatin was synergistic/additive in vitro. Notably, INCB057643, given with a low-intensity dosing schedule, greatly enhanced the anti-tumor activity of docetaxel, carboplatin, and olaparib in 22Rv1 tumor xenografts.
Collectively, these results provide the first evidence of the therapeutic benefit obtainable by combining BETis with non–androgen receptor–targeted therapies for the treatment of mCRPC.
Chemotherapy has limited efficacy in patients with metastatic castration-resistant prostate cancer. This study provides evidence of enhanced efficacy of clinically used chemotherapeutics when given in combination with the bromodomain and extraterminal inhibitor INCB057643, expanding the horizon of the current options for the treatment of prostate cancer.
Chemotherapy has limited impact in patients with advanced castration-resistant prostate cancer (CRPC). This study demonstrates the enhanced antitumor efficacy of docetaxel, olaparib, and carboplatin when combined with the bromodomain and extraterminal inhibitor INCB057643, encouraging clinical evaluation of this strategy in advanced CRPC nonresponsive to androgen receptor–targeted therapies.
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