{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:24Z","timestamp":1792787304876,"version":"4.5.0"},"reference-count":56,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"unspecified","delay-in-days":6,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NIH DF\/HCC SPORE in Breast Cancer","award":["P50 CA168504"],"award-info":[{"award-number":["P50 CA168504"]}]},{"name":"Canadian Institute of Health Postdoctoral Fellowship","award":["194068"],"award-info":[{"award-number":["194068"]}]},{"name":"NIH NCI","award":["P50 CA168504"],"award-info":[{"award-number":["P50 CA168504"]}]},{"name":"NIH NCI","award":["R01 CA307291"],"award-info":[{"award-number":["R01 CA307291"]}]},{"name":"NIH NCI","award":["R37 CA 269499"],"award-info":[{"award-number":["R37 CA 269499"]}]},{"name":"Susan G. Komen Foundation","award":["CCR18547597"],"award-info":[{"award-number":["CCR18547597"]}],"id":[{"id":"https:\/\/ror.org\/02nadbe75","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Duke Street Bio Ltd","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"The Terri Brodeur Breast Cancer Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"https:\/\/ror.org\/02g6a6a54","id-type":"ROR","asserted-by":"crossref"}]},{"name":"The Harvard Ludwig Center","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100001558","name":"Concern Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100001558","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,9,23]]},"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Poly (ADP-ribose) polymerase inhibitors (PARPis) have improved outcomes of BRCA-associated breast cancer; however, treatment-related toxicity remains a major clinical challenge. Currently approved PARPis broadly inhibit multiple members of the PARP protein family. However, preclinical studies suggest that inhibition of PARP1 alone is sufficient to drive antitumor efficacy. In contrast, inhibition of PARP2 has been implicated in hematological toxicities seen in patients receiving PARPi therapy. Therefore, selectively inhibiting PARP1 may reduce toxicity for patients. Here, we characterize and test the PARP1-selective inhibitor DSB1559 in preclinical models of Brca1-associated triple-negative breast cancer (TNBC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Pharmacokinetic\/pharmacodynamic assays were performed to examine DSB1559 potency, selectivity, and in vivo behavior. Immunocompetent FVB\/n mice bearing Brca1-deficient TNBC (CMV-Cre;Brca1\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      ;Trp53\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      ) tumors were treated with olaparib or DSB1559 and followed for survival. Flow cytometry and bulk RNA-sequencing were performed to measure the effects on the tumor microenvironment (TME).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>DSB1559 had superior selectivity for PARP1 and increased overall survival compared with olaparib. Analysis of the TME revealed a significant increase in cytotoxic T-cells, activated dendritic cells, and genes associated with antitumor immunity in mice treated with DSB1559.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Taken together, DSB1559 is a highly selective PARP1 inhibitor that demonstrates superior efficacy and antitumor immune response compared with olaparib. A structurally related, clinical lead compound (DSB2455) is now being tested in a phase Ia\/Ib clinical trial (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT06458712\">NCT06458712<\/jats:ext-link>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-014578","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:00:28Z","timestamp":1791385228000},"page":"e014578","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["PARP1-selective inhibitor DSB1559 demonstrates superior efficacy and antitumor immunity in triple-negative breast cancer"],"prefix":"10.1136","volume":"14","clinical-trial-number":[{"clinical-trial-number":"nct06458712","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06458712","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06488378","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06458712","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Adam","family":"Nelson","sequence":"first","affiliation":[{"name":"Division of Breast Surgery, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA"},{"name":"Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly F","family":"Zheng","sequence":"additional","affiliation":[{"name":"Division of Breast Surgery, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Wagner S","family":"Wanderley","sequence":"additional","affiliation":[{"name":"Division of Breast Surgery, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA"},{"name":"Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7816-3924","authenticated-orcid":false,"given":"Daniel E","family":"Michaud","sequence":"additional","affiliation":[{"name":"Division of Breast Surgery, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA"},{"name":"Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip M","family":"Cowley","sequence":"additional","affiliation":[{"name":"Duke Street Bio Ltd, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian M","family":"Campbell","sequence":"additional","affiliation":[{"name":"Duke Street Bio Ltd, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bose","family":"Kochupurakkal","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Jiao","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0577-7797","authenticated-orcid":false,"given":"Carman Man-Chung","family":"Li","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6615-7076","authenticated-orcid":false,"given":"Filipa","family":"Lynce","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, Massachusetts, 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