Exposing a New Achilles Heel for GBM « Charlie Teo Foundation

Exposing a New Achilles Heel for GBM

Researcher name: A/Prof David Nathanson and A/Prof Scott Dixon

Institution: UCLA and Stanford University (collaborative grant), U.S.

Grant Name: More Data Grant

Grant amount (AUD): Up to $372k

Grant Awarded: 2024

Status: Ongoing

Meet the Researcher

A/Prof David Nathanson is an Associate Professor of Molecular and Medical Pharmacology in the David Geffen School of Medicine at UCLA. The Nathanson laboratory focuses on identifying the key molecular and functional processes driving glioblastoma with the goal of developing new therapeutic strategies to treat this deadly disease.

A/Prof Scott Dixon is an Associate Professor of Biology at Stanford University. The Dixon laboratory has a major focus of understanding the interaction between intracellular metabolism and cell death.

Charlie Teo Foundation is proud to award this collaborative More Data grant between the Nathanson lab at UCLA and Dixon lab at Stanford, where they will effectively combine their expertise in GBM biology, drug discovery, and chemical biology to develop more effective therapies for brain cancer patients.

Most current drugs tested in Glioblastoma (GBM) try to kill these brain tumour cells by activating a mechanism of cell death named apoptosis. Apoptosis, the conventional mechanism of cell death, isn't the only way cells can die, and GBM cells often resist treatments that rely on triggering this form of cell death. The Nathanson and Dixon Labs are exploring alternative cell death mechanisms and have discovered a new one called palmoptosis, which involves disrupting the fat molecule composition of these tumour cells. Recent data from the Nathanson and Dixon labs show that GBM cells are more sensitive to palmoptosis than apoptosis. They have identified an existing drug that is already safe for human use and can trigger palmoptosis. This research will investigate how palmoptosis works in GBM and determine which patients might benefit most from this treatment.

This project is game-changing because it challenges the conventional approach of treating GBM with therapies that only induce apoptosis, a common cell death mechanism. Therapies that rely solely on triggering apoptosis is doomed to fail, as GBM cells often resist this type of cell death. We now know that apoptosis is just one of many ways a cell can die, and over the past decade, researchers have shown that alternative forms of cell death can also be induced. The Nathanson and Dixon Labs have discovered a new mechanism called palmoptosis, which could serve as a 'back door' to kill GBM cells resistant to apoptosis.

This project can help people with brain cancer by offering a new way to kill GBM cells, which are resistant to traditional treatments. The Nathanson and Dixon labs have discovered that a drug called tegavivint, already proven safe for humans, can penetrate the brain and kill cancer cells through activating a unique cell death mechanism called palmoptosis. Unlike the usual cell death process, apoptosis, palmoptosis provides a novel way to selectively target and kill GBM cells.

GBM is notoriously resistant to existing therapies, which primarily induce cell death through apoptosis. GBM cells often express high levels of anti-apoptotic proteins, rendering these treatments ineffective. Research from the Nathanson and Dixon labs indicate that therapies relying solely on apoptosis are destined to fail. Apoptosis is just one of many cell death mechanisms, and the combined research of the Nathanson and Dixon labs over the past decade has demonstrated the potential of triggering non-canonical forms of cell death. Both labs in collaboration have identified a novel mechanism, palmoptosis, which requires the lipid palmitate and related metabolic enzymes. Their preliminary data show that the drug tegavivint, currently in clinical trials, can selectively trigger palmoptosis in GBM cells. This collaborative grant between the Nathanson and Dixon labs combines expertise in GBM biology and drug discovery (Nathanson) with cell biology and chemical biology (Dixon) to establish palmoptosis as a new therapeutic approach for GBM.

The overarching aims of this collaborative grant includes:

Aim 1. Assess the role of lipid metabolism in mediating palmoptosis in glioblastoma.

Aim 2. Identify the molecular features of GBMs susceptible to palmoptosis

Aim 3. Evaluate the pharmacokinetics, anti-tumour efficacy of Tegavivint in orthotopic patient-derived xenograft models.