LSD1-directed therapy affects glioblastoma tumorigenicity by deregulating the protective ATF4-dependent integrated
Stefania Faletti1, Daniela Osti1, Elena Ceccacci1
1Department of Experimental Oncology, European Institute of Oncology (IEO), IRCCS, Milan 20139, Italy.
Abstract:
Glioblastoma (GBM) is a fatal tumor whose aggressiveness, heterogeneity, poor blood-brain barrier penetration, and resistance to therapy highlight the need for new targets and clinical treatments. A step toward clinical translation includes the eradication of GBM tumor-initiating cells (TICs), responsible for GBM heterogeneity and relapse. By using patient-derived TICs and xenograft orthotopic models, we demonstrated that the selective lysine-specific histone demethylase 1 inhibitor DDP_38003 (LSD1i) is able to penetrate the brain parenchyma in vivo in preclinical models, is well tolerated, and exerts antitumor activity in molecularly different GBMs. LSD1 genetic targeting further strengthens the role of LSD1 in GBM TIC maintenance. GBM TIC plasticity supports their adaptation and survival under a plethora of environmental stresses, including nutrient deficiency and proteostasis perturbation. By mimicking these stresses in vitro, we found that LSD1 inhibition hampers the induction of the activating transcription factor 4 (ATF4), the master regulator of the integrated stress response (ISR). The resulting aberrant ISR sensitizes GBM TICs to stress-induced cell death, hampering tumor aggressiveness. Functionally, LSD1i interferes with LSD1 scaffolding function and prevents its interaction with CREBBP, a critical ATF4 activator. By disrupting the interaction between CREBBP and LSD1-ATF4 axis, LSD1 inhibition prevents GBM TICs from overcoming stress and sustaining GBM progression. The effectiveness of the LSD1 inhibition in preclinical models shown here places a strong rationale toward its clinical translation for GBM treatment.
Insights
A new drug targeting lysine-specific histone demethylase 1 (LSD1) effectively penetrates the brain and reduces glioblastoma tumor-initiating cells (TICs) by disrupting stress response pathways, offering a promising new treatment for this fatal brain cancer.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Epigenetics
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis.
- GBM tumor-initiating cells (TICs) drive tumor heterogeneity and relapse.
- Current therapies face challenges including poor blood-brain barrier penetration and treatment resistance.
Purpose of the Study:
- To evaluate the therapeutic potential of a novel lysine-specific histone demethylase 1 inhibitor (LSD1i), DDP_38003, against GBM TICs.
- To elucidate the mechanism by which LSD1 inhibition affects GBM TIC survival and aggressiveness.
Main Methods:
- Utilized patient-derived GBM TICs and orthotopic xenograft models.
- Administered DDP_38003 in vivo and assessed its brain penetration, tolerability, and antitumor activity.
- Investigated the impact of LSD1 inhibition on the integrated stress response (ISR) pathway and ATF4 activation in vitro.
- Examined the interaction between LSD1, CREBBP, and ATF4.
Main Results:
- DDP_38003 demonstrated effective brain parenchyma penetration and was well-tolerated in preclinical GBM models.
- LSD1 inhibition reduced GBM TIC maintenance and aggressiveness across different GBM subtypes.
- LSD1 inhibition blocked the induction of ATF4, the master regulator of the ISR, sensitizing GBM TICs to stress-induced cell death.
- LSD1i disrupted the LSD1-CREBBP interaction, crucial for ATF4 activation and GBM progression.
Conclusions:
- Selective LSD1 inhibition is a promising therapeutic strategy for GBM, targeting TICs and overcoming treatment resistance.
- The mechanism involves disrupting the ISR pathway by inhibiting the LSD1-CREBBP interaction.
- These findings provide a strong rationale for the clinical translation of LSD1 inhibitors in GBM treatment.
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