ArticleJournal for immunotherapy of cancer2026
PARP1-selective inhibitor DSB1559 demonstrates superior efficacy and antitumor immunity in triple-negative breast cancer.
Article in Journal for immunotherapy of cancer, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06458712 (Phase Ia/Ib Open Label, Multi-Centre Dose Escalation Study With Expansion Cohorts to Assess the Safety, Tolerability, and Activity of DSB2455 as Monotherapy in Participants With Advanced Malignancies), which is not on this map. Not yet cited in PubMed.
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Phase Ia/Ib Open Label, Multi-Centre Dose Escalation Study With Expansion Cohorts to Assess the Safety, Tolerability, and Activity of DSB2455 as Monotherapy in Participants With Advanced Malignancies
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Abstract
backgroundPoly (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).
methodsPharmacokinetic/pharmacodynamic assays were performed to examine DSB1559 potency, selectivity, and in vivo behavior. Immunocompetent FVB/n mice bearing Brca1-deficient TNBC (CMV-Cre;Brca1
resultsDSB1559 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.
conclusionsTaken 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 (NCT06458712).
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