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Specific antiviral reagents are particularly needed for HPV-related oropharyngeal cancers (HPV\n                      <jats:sup>+<\/jats:sup>\n                      OPCs) whose incidence is increasing and for which there are no early diagnostic tools available. We and others have demonstrated that the estrogen receptor alpha (ER\u03b1) is overexpressed in HPV\n                      <jats:sup>+<\/jats:sup>\n                      OPCs, compared to HPV-negative cancers in this region, and that these elevated levels are associated with an improved disease outcome. Utilizing this HPV\n                      <jats:sup>+<\/jats:sup>\n                      -specific overexpression profile, we previously demonstrated that estrogen attenuates the growth and cell viability of HPV\n                      <jats:sup>+<\/jats:sup>\n                      keratinocytes and HPV\n                      <jats:sup>+<\/jats:sup>\n                      cancer cells\n                      <jats:italic>in vitro<\/jats:italic>\n                      . Expansion of this work\n                      <jats:italic>in vivo<\/jats:italic>\n                      failed to replicate this sensitization. The role of stromal support from the tumor microenvironment (TME) has previously been tied to both the HPV lifecycle and\n                      <jats:italic>in vivo<\/jats:italic>\n                      therapeutic responses. Our investigations revealed that\n                      <jats:italic>in vitro<\/jats:italic>\n                      co-culture with fibroblasts attenuated HPV\n                      <jats:sup>+<\/jats:sup>\n                      -specific estrogen growth responses. Continuing to monopolize on the HPV\n                      <jats:sup>+<\/jats:sup>\n                      -specific overexpression of ER\u03b1, our co-culture models then assessed the suitability of the selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen, and showed growth attenuation in a variety of our models to one or both of these drugs\n                      <jats:italic>in vitro<\/jats:italic>\n                      . Utilization of these SERMs\n                      <jats:italic>in vivo<\/jats:italic>\n                      closely resembled the sensitization predicted by our co-culture models. Therefore, the\n                      <jats:italic>in vitro<\/jats:italic>\n                      fibroblast co-culture model better predicts\n                      <jats:italic>in vivo<\/jats:italic>\n                      responses. We propose that utilization of our co-culture\n                      <jats:italic>in vitro<\/jats:italic>\n                      model can accelerate cancer therapeutic drug discovery.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Human papillomavirus-related cancers (HPV\n                      <jats:sup>+<\/jats:sup>\n                      cancers) remain a significant public health concern, and specific clinical approaches are desperately needed. In translating drug response data from\n                      <jats:italic>in vitro<\/jats:italic>\n                      to\n                      <jats:italic>in vivo<\/jats:italic>\n                      , the fibroblasts of the adjacent stromal support network play a key role. Our study presents the utilization of a fibroblast 2D co-culture system to better predict translational drug assessments for HPV\n                      <jats:sup>+<\/jats:sup>\n                      cancers. We also suggest that this co-culture system should be considered for other translational approaches. Predicting even a portion of treatment paradigms that may fail\n                      <jats:italic>in vivo<\/jats:italic>\n                      with a co-culture model will yield significant time, effort, resource, and cost efficiencies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01024-24","type":"journal-article","created":{"date-parts":[[2024,9,13]],"date-time":"2024-09-13T09:14:51Z","timestamp":1726218891000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Fibroblast stromal support model for predicting human papillomavirus-associated cancer drug responses"],"prefix":"10.1128","volume":"98","author":[{"given":"Claire D.","family":"James","sequence":"first","affiliation":[{"name":"Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University (VCU), Richmond, Virginia, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel L.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University (VCU), Richmond, Virginia, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexis L.","family":"Fakunmoju","sequence":"additional","affiliation":[{"name":"Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University (VCU), Richmond, Virginia, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Austin J.","family":"Witt","sequence":"additional","affiliation":[{"name":"Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University (VCU), Richmond, Virginia, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aya H.","family":"Youssef","sequence":"additional","affiliation":[{"name":"Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University (VCU), Richmond, Virginia, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Wang","sequence":"additional","affiliation":[{"name":"Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University (VCU), Richmond, Virginia, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nabiha M.","family":"Rais","sequence":"additional","affiliation":[{"name":"Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University (VCU), Richmond, Virginia, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2266-7247","authenticated-orcid":true,"given":"Apurva T.","family":"Prabhakar","sequence":"additional","affiliation":[{"name":"Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University (VCU), Richmond, Virginia, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. 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