Abstract A080: Activation of hSSB2/1 by BCN077 Induces Tumor-Selective Mitotic Catastrophe While Protecting Irradiated Epithelium: A New Therapeutic Paradigm for Expanding the Cancer Treatment Window

Abstract

The failure of current DNA damage response strategies to adequately distinguish tumor from normal tissue remains a major barrier to durable cancer control. BCN077 is a first-in-class small-molecule activator of human single strand DNA-binding protein 2 (hSSB2), a conserved single-stranded DNA binding complex that coordinates replication stress responses, DNA repair, and checkpoint recovery. We hypothesized that pharmacologic activation of hSSB2 would create a therapeutically exploitable divergence: lethal replication stress in genomically unstable tumors, but epithelial protection in normal tissues exposed to radiation or chemotherapy. BCN077 was evaluated across cancer cell lines, the NCI-60 panel, and in vivo tumor and radiation injury models. Mechanistic studies assessed DNA damage, replication stress, spindle checkpoint signaling, and mitotic catastrophe using γH2AX, phospho-H3, BUB1, MAD2L1, comet analysis, clonogenic survival, and morphologic criteria. Tumor efficacy was tested in aggressive and treatment-resistant models, including BRAF V600E colorectal cancer, and normal tissue protection was assessed in irradiation settings relevant to gastrointestinal injury. BCN077 demonstrated broad anti-tumor activity across diverse cancer types and selectively triggered mitotic catastrophe in checkpoint-defective tumor cells characterized by unresolved DNA damage, aberrant mitotic entry, and loss of proliferative capacity. In contrast, normal cells with intact checkpoint function were comparatively spared. In vivo, BCN077 enhanced tumor control and showed marked protective activity in irradiated or chemo exposed normal epithelium, preserving intestinal architecture and improving survival after radiation exposure. These findings support a mechanism in which hSSB2 activation intensifies genotoxic stress beyond the tolerable threshold in cancer cells while reinforcing recovery and survival programs in normal tissues. hSSB2 is an emerging druggable vulnerability with a compelling dual therapeutic profile. BCN077 may define a new class of agents that simultaneously improve tumor control and reduce treatment-limiting toxicity, representing a genuine translational opportunity to expand the therapeutic window of radiation and chemotherapy. This strategy is especially relevant for malignancies in which checkpoint failure and replication stress are common, including triple-negative breast cancer not amenable to PARP inhibition and head and neck cancers where improved tumor ablation must be balanced against epithelial sparing. Andrew J. Norris, Elizabeth M. Singer, Rishi Man Chugh, Payel Bhanja, Julian P. Whitelegge, William H. McBride, Jesus M. Rodriguez, Natalie Isaghulian, Alexander M. Varady, Subhrajit Saha. Activation of hSSB2/1 by BCN077 Induces Tumor-Selective Mitotic Catastrophe While Protecting Irradiated Epithelium: A New Therapeutic Paradigm for Expanding the Cancer Treatment Window [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A080.