A New Drug for GBM « Charlie Teo Foundation

A New Drug for GBM

Researcher name: Dr Alan Wang
Institution: MD Anderson Cancer Centre, U.S.
Grant name: Better Tools Grant
Grant amount (AUD): $55K
Grant Awarded: 2021
Status: Closed

Meet the Researcher

Dr Y. Alan Wang is a cancer biologist at one of the most prestigious comprehensive cancer centers in the U.S., MD Anderson. He trained at Harvard Medical School and his team has been responsible for identifying the cause of some types of cancers.

Brain cancer has only had 5 FDA approved treatments in the past 35 years, while some cancers have around 34, like breast cancer! We desperately need to trial more treatment options for brain cancer patients.

If the work from this project shows that this novel drug works to make the brain cancer more susceptible to attack by the immune system and extends survival in these preclinical brain cancer models, then this is the necessary data needed to get the drug into a Phase I clinical trial.

Evaluation of Pharmaxis LOX inhibitor in recurrent GBM

Glioblastoma (GBM) is the most common and lethal primary brain cancer with limited therapeutic option. Surgery and radiation are the two most common therapeutics for these patients and recurrences following these interventions almost always occur leading to a dismal 5-year survival rate of less than 5 %. Targeted therapeutic approaches on disease drivers have also generated limited success due to a lack of blood brain barrier penetrating drugs and tumour cells often develop resistance mechanisms to targeted therapy. In the past decade, our lab has been focused on the tumour microenvironment, composed mostly of tumour infiltrating macrophages in GBM. We have shown recently that PTEN (a tumour suppressor frequently lost in GBM) deficiency induced specific macrophage recruitment and we have provided concrete evidence that macrophage recruitment is largely due to the production of LOX by tumour cells. We demonstrated that inhibition of LOX at pharmacological and genetic levels can significantly extend survival of GBM-bearing animals. Immunotherapy has failed in GBM patients due, at least in part, to PTEN deficiency, and the fact that PTEN deficiency dependent infiltration of macrophage acting as an immune suppression mechanism and recurrent GBMs are often infiltrated with macrophages, we propose to test whether LOX inhibitor can significantly prevent GBM recurrence in patients undergoing surgery and chemoradiation therapy. In collaboration with Pharmaxis, we will test whether the LOX inhibitor PXS-5505, which has already shown safety profile in the phase 1 trials, would inhibit LOX mediated macrophage migration in tumour model in vivo, block GBM recurrence in GBM animal models, and synergize with immuno-checkpoint inhibitors to cure GBM in animal models.

Charlie Teo Foundation funded this project focused on GBM, investigating the impact of PTEN deficiency and LOX production on macrophage recruitment. The research initially demonstrated that inhibiting LOX extended the survival of GBM-bearing mice by preventing the recruitment of highly immunosuppressive and pro-tumourigenic macrophages to brain tumours.

With our funding and in collaboration with Pharmaxis, the research aimed to assess whether the LOX inhibitor PXS-5505 could prevent GBM recurrence and enhance immuno-checkpoint inhibitors' effectiveness in GBM animal models. After assessing the results of stage 1, it was agreed by all parties not to pursue this methodology further. Despite PXS-5505 exhibiting robust inhibition of macrophage recruitment in an in-vitro assay and lowering LOX activity in the aorta of GBM-bearing mice, it did not provide survival benefits in GBM mice. Initial findings suggest that the concentrations of PXS-5505 in the tissue and plasma of these mice varied, leading to inconclusive results.

Given the present findings, it remains uncertain whether PXS-5505 could effectively target GBM. Future investigations will necessitate refinements to the dosing schedule, administration methods, and drug formulation to evaluate the potential efficacy of PXS-5505 more accurately for GBM.

We are proud to be open and transparent about research success and failure! As Albert Einstein famously said, "Failure is success in progress!"