The Science Behind GLIOBREAK
GLIOBREAK combines targeted protein degradation with biomarker-enabled patient stratification to move a first-in-class GBM therapeutic concept toward clinical readiness.
What glioblastoma is
Glioblastoma (GBM) is the most common and aggressive primary brain tumour in adults, arising from glial cells in the cerebral cortex. It is classified as WHO Grade 4 — the highest malignancy grade — accounting for roughly 50% of all malignant brain tumours.
GBM grows rapidly and diffusely into surrounding brain tissue, making complete surgical resection impossible. Extensive intratumoural heterogeneity — multiple co-existing cancer cell populations — drives early resistance to any single treatment.
Around 3–4 people per 100,000 are diagnosed each year. Median age at diagnosis is ~64 years, and survival outcomes are dramatically worse than almost any other solid tumour.
Outcomes remain poor
Median overall survival (OS) ~15 months — unchanged since temozolomide approval (1999). Immunotherapies have largely failed in GBM.
Why new approaches are needed
Incremental improvements to existing agents have not moved the survival needle. Overcoming the immunosuppressive microenvironment requires genuine mechanistic innovation — new targets, not better dosing of failed drugs.
Epigenetic reprogramming is a compelling frontier: GBM co-opts chromatin complexes including LSD1/CoREST to silence immune-activating genes and endogenous retroviral elements, enabling immune evasion. Targeting this axis can restore immune visibility.
Targeted protein degradation offers a qualitative step-change: degraders dismantle entire repressive complexes — both catalytic and scaffolding functions — overcoming resistance that limited earlier LSD1 inhibitors. Paired with predictive biomarkers, this approach can match treatment to patients most likely to benefit.
LSD1 / CoREST role in GBM biology
Lysine-specific demethylase 1 (LSD1, also known as KDM1A) is a histone demethylase that removes activating methyl marks from H3K4me1/2. In GBM, LSD1 is overexpressed and drives tumour growth through both its catalytic activity and as a structural scaffold within the CoREST repressor complex.
The LSD1/CoREST complex acts as a master epigenetic repressor: it silences tumour suppressor genes, restricts differentiation, and maintains the glioma stem cell state that underpins treatment resistance and recurrence after standard therapy.
Critically, non-catalytic (scaffolding) functions of LSD1, independent of its demethylase activity, contribute substantially to GBM survival signalling. This explains why early-generation catalytic LSD1 inhibitors showed insufficient single-agent efficacy in the clinic.
Immune-epigenetic framing
Beyond cell-intrinsic oncogenic roles, LSD1/CoREST orchestrates immune evasion in GBM. The complex represses transcription of immune-stimulatory genes, including type I interferon pathway components, and silences endogenous retroviral elements (ERVs) that would otherwise act as immunogenic double-stranded RNA.
ERV silencing by LSD1/CoREST is a key mechanism by which GBM avoids innate immune detection. When this silencing is relieved, dsRNA sensing activates the MAVS/STING pathway, triggering interferon responses that render tumour cells visible to the immune system.
Dismantling the LSD1/CoREST complex therefore remodels the tumour epigenome in two ways simultaneously: re-activating anti-tumour immune gene programmes and de-repressing ERV-mediated innate immune signalling, a dual immuno-epigenetic mechanism unique to this approach.
Connection to tumour-host interactions
GBM does not exist in isolation: the tumour microenvironment (TME) is populated by immunosuppressive macrophages, Tregs, and dysfunctional T cells shaped by signals from the cancer cells themselves. LSD1/CoREST activity in GBM cells directly programmes this suppressive immune landscape.
By reactivating interferon and immune-checkpoint-ligand pathways within tumour cells, BEA-17 can shift the TME from immunosuppressive to immune-permissive, making GBM visible and accessible to cytotoxic T cells and potentially synergising with checkpoint blockade strategies.
The GLIOMATCH project established that tumour-host immune interactions in GBM are measurable by single-cell multi-omics. GLIOBREAK deploys BEA-17 to intervene in this axis and captures the resulting immune remodelling through companion biomarkers.
First-in-class degrader framing
BEA-17 is the first small molecule designed to degrade the entire LSD1/CoREST complex rather than inhibit catalysis alone. Degradation removes both enzymatic and scaffolding functions of LSD1 simultaneously, the non-catalytic roles that first-generation inhibitors left intact and that sustained tumour survival signalling.
Targeted degraders operate catalytically: a single molecule destroys multiple target copies before recycling, enabling potency well below stoichiometric concentrations. No approved or clinical-stage LSD1 degrader exists for GBM, BEA-17 occupies an entirely vacant therapeutic niche.
Companion biomarker strategy
LSD1 inhibitor trials have shown that patient selection is decisive: tumours with high baseline LSD1/CoREST expression and immune-suppressive transcriptional signatures respond best, while unselected populations dilute clinical signal. GLIOBREAK embeds biomarker science from the outset to avoid this pitfall.
KU Leuven contributes single-cell multi-omics profiling of matched pre- and post-treatment GBM biopsies, characterising the epigenetic and immune state at baseline and capturing BEA-17 remodelling of the tumour microenvironment. This generates a companion diagnostic hypothesis as an integral programme output.
Path toward clinical evaluation
GLIOBREAK is structured to deliver a complete CTA-ready preclinical package: GLP toxicology, bioanalytical method qualification, IMPD preparation, and CNS-penetrant formulation. The 30-month EIC Transition timeline is aligned to IND/CTA submission at project close.
Phase I will target newly diagnosed or first-recurrence IDH-wildtype GBM, with BEA-17 evaluated alone and in combination with temozolomide/radiotherapy or anti-PD-1. Success creates a platform for expansion into neuroendocrine tumours and SCLC, where LSD1 inhibitors have shown clinical proof-of-concept.
BEA-17: How it works
Immune genes silenced
In GBM, the LSD1/CoREST protein complex acts as a master silencer. It switches off the genes that would normally alert the immune system to the tumour and suppresses retroviral elements that would trigger an innate immune alarm. The cancer becomes invisible to the patient's own defences.
BEA-17 destroys the complex
BEA-17 is a small molecule that disrupts the LSD1/CoREST complex, triggering the cell's own disposal machinery to break down both proteins entirely. Unlike earlier LSD1 inhibitors that only block the enzyme's catalytic activity, BEA-17 eliminates the whole complex, removing both its enzymatic and scaffolding functions.
Tumour becomes immune-visible
Once LSD1/CoREST is gone, silenced immune genes reactivate and retroviral elements trigger innate immune sensors (the STING/MAVS pathway). The tumour cell starts broadcasting alarm signals it had previously blocked. Cytotoxic T cells can now recognise and attack the cancer.