Targeting BRD2 to Block Therapy-Induced Reprogramming and Immune Evasion in Glioblastoma

Novel Approaches, Targets, and Therapeutics

Frank Furnari, PhD (UC San Diego)

Raghavendra Vadla, PhD (UC San Diego)

Susan Kaech, PhD (The Salk Institute)

Glioblastoma recurrence is driven by therapy-induced reprogramming and an immunosuppressive microenvironment. Building upon our published work, we hypothesize that inhibiting activity of bromodomain protein, BRD2, post-radiation therapy, offers dual benefits: disrupting cellular reprogramming toward stem-like states and augmenting anti-tumor immunity through senescence-associated secretory phenotype (SASP) activation. Using a first-in-class brain-penetrant BRD2 inhibitor as adjuvant therapy, we will interrogate its role in SASP reprogramming by epigenetic and functional assays (AIM 1), assess its immunomodulatory effects in immune-competent models by flow cytometry and IHC (Aim 2), and validate therapeutic efficacy when combined with immune checkpoint blockade (ICB) (Aim 3). We expect our results will nominate BRD2 inhibition as a therapeutic strategy to simultaneously block senescence-mediated recurrence and promote immune surveillance by priming the GBM TME to enhance ICB response.