Fine Lab
organoid

Research

A Novel Approach to Glioblastoma

What is GBM?  

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults. It is characterized by treatment resistance, high recurrence rate, and low survival: median survival rates have remained largely unchanged for 30 years, with a 5-year survival rate of less than 5% (Stupp et al., 2005). 

This may be attributed to the cancer’s infiltrative nature into the brain parenchyma and transcriptionally-distinct cellular states, most commonly recognized as: the astro-cyte (AC)-like, mesenchymal (MES)-like, oligodendrocyte progenitor cell (OPC)-like, and neural pro-genitor cell (NPC)-like states (Neftel et al., 2019). 

Modeling GBM

I. GLICO – a novel Glioma Cerebral Organoid Model

Our most recent initiative is the creation of cerebral organoids to use these “in vitro human brains” as 3-D platforms for growing and studying how primary patient-derived glioblastoma tumor stem cells proliferate, invade, migrate and destroy human brain tissue. We have developed a novel model system (GLICO) whereby we retro-engineer patient-derived primary brain tumors (gliomas) into iPSC/hESC-derived human cerebral organoids, ultimately forming tumors that closely phenocopy patient glioblastomas. Evidence generated by our laboratory and others has shown that patient-derived glioma stem cells (GSCs) are the most biologically and phenotypically relevant cells to the parental tumor in patients. Using hESC-derived cerebral organoids and patient-derived GSCs, we demonstrate a powerful tool for modeling human GBM within a primitive, human brain microenvironment. (Linkous & Fine (2020) (Pine, Cirigliano et al., 2023) 

How are we optimizing and employing GLICO? 

II. Patient-specific Neuro-Immune Mouse Avatar Model (PSNiM)

The PSniM-Avatar model aims to create a next-generation patient-specific model of glioblastoma that captures the complex interactions between tumor cells, human neural tissue, immune components, and the vascularized brain microenvironment. The PSniM-Avatar model is designed to uncover actionable vulnerability hubs that may drive glioblastoma adaptation, resistance, and therapeutic response.

How are we validating PSNiM?

Treating GBM

I. State-Selective Lethality & Glioblastoma Cellular Plasticity

We are investigating how anti-cancer therapies reshape glioblastoma cellular states, (Neftel et al., 2019), and how this plasticity can be exploited therapeutically. We have found that different therapies can induce distinct and partially reversible state shifts, with HDAC inhibitor panobinostat promoting mesenchymal-like programs and PI3K inhibitor paxalisib promoting astrocyte-like programs.

Can we induce particular cell states more responsive to GBM treatment? 

Read our pre-print! 

II. Radiation & Treatment Recurrence 

There exists a hiatus period between initial glioblastoma treatment and eventual recurrence (~90% of patients). How can the current standard-of-care, particularly radiotherapy, contribute to recurrence, and what interventions might disrupt this progression?

Recent Publications

Glioblastoma: Not Just Another Cancer.
Microenvironment-Driven Dynamic Chromatin Changes in Glioblastoma Recapitulate Early Neural Development at Single-Cell Resolution.
Three-dimensional regulatory hubs support oncogenic programs in glioblastoma.