P11.12.A A PAN-CANCER ATLAS OF LEPTOMENINGEAL DISEASE REVEALS BRANCHED CHAIN KETO ACIDS DRIVE IMMUNOSUPPRESSION AND NEURODEGENERATION
Abstract BACKGROUND Leptomeningeal disease (LMD) is one of the most devastating complications of advanced cancer, resulting in severe neurological deterioration and poor survival outcomes. MATERIAL AND METHODS Using single-cell transcriptomics and multi-omics profiling of patient specimens, we created a comprehensive LMD atlas that revealed two hallmarks of LMD: an immunosuppressive cellular microenvironment and an environment promoting neurodegeneration. RESULTS We report that toxic branched-chain keto acids (BCKAs) accumulate in the cerebrospinal fluid of LMD patients and drive both immunosuppression and neurodegeneration, presenting a novel therapeutic target. Mechanistically, there is a profound BCKA-mediated disruption of T cell function and neuronal integrity. Strikingly, BCKA-reducing therapy using sodium phenylbutyrate improved survival and neurological outcomes in preclinical models while enhancing the efficacy of CAR-T cell therapy. CONCLUSION BCKA accumulation is a central mediator of LMD progression and treatment resistance and provides an actionable therapeutic opportunity through drug repurposing. Importantly, our pan-cancer atlas of human LMD delivers a framework for understanding disease mechanisms and developing novel therapeutic strategies for this urgent unmet clinical need.
Authors
- Victoria Izumi (ORCID: https://orcid.org/0000-0001-6467-9081)
- MacLean Hall (ORCID: https://orcid.org/0000-0002-5626-1619)
- John M. Koomen (ORCID: https://orcid.org/0000-0002-3818-1762)
- Michael David Jain (ORCID: https://orcid.org/0000-0002-7789-1257)
- Shari Pilon‐Thomas (ORCID: https://orcid.org/0000-0001-7785-3034)
- Ethan Vallebuona (ORCID: https://orcid.org/0000-0002-3153-9119)
- Frederick Lundry Locke (ORCID: https://orcid.org/0000-0001-9063-6691)
- Sigve Holmen (ORCID: https://orcid.org/0000-0001-9698-6625)
- Vincent Law (ORCID: https://orcid.org/0000-0002-8569-1378)
- Purves Stewart
- Brittany Evernden
- Ann Chen (ORCID: https://orcid.org/0000-0003-2143-2817)
- Salvatore Corallo (ORCID: https://orcid.org/0000-0002-6672-0233)
- Inna Smalley (ORCID: https://orcid.org/0000-0002-6796-9145)
- Gerald Wallace
- Ronak Kundalia (ORCID: https://orcid.org/0000-0002-1287-7120)
- Oscar E. Ospina (ORCID: https://orcid.org/0000-0001-5986-4207)
- M. Ben Khaled (ORCID: https://orcid.org/0009-0008-6765-1373)
- Ana P. Gomes (ORCID: https://orcid.org/0000-0003-0881-727X)
- Lancia Darville (ORCID: https://orcid.org/0000-0002-9793-3741)
- Yuan Ren (ORCID: https://orcid.org/0000-0002-3991-5342)
- Min Liu (ORCID: https://orcid.org/0000-0002-1918-9072)
- Zhengming Chen (ORCID: https://orcid.org/0000-0001-9437-6452)
- Peter Forsyth (ORCID: https://orcid.org/0000-0001-7841-7891)
- Mohammad Baraa Boozo
Institutions
- Huntsman Cancer Institute (US)
- Moffitt Cancer Center (US)
Publication Details
- Journal
- Neuro-Oncology
- Published
- 2025-10-01
- DOI
- https://doi.org/10.1093/neuonc/noaf193.351
- Primary Topic
- Brain Metastases and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00