Drug repurposing, overcoming resistance to radiotherapy and avoiding unnecessary surgery

Brain Tumour Research

2 min read

At Brain Tumour Research we have explored drug repurposing in general, and the role of metformin in particular, before on these pages, and if you scroll down this piece you can find out about a phase III clinical trial on paediatric brain tumour survivors treated with cranial radiation currently starting at 14 hospitals in Canada and Australia. This trial is the result of a study of metformin, (commonly used to treat Type 2 diabetes) that has shown that it could be possible to repair brain injury using brain cells themselves to induce brain growth and positive recovery. Lab results found that metformin enhanced the recovery of endogenous neural precursor cells (NPCs) in the dentate gyrus (DG), a part of the brain that plays a critical role in learning and memory. Interestingly the results were sex-dependent: Metformin was sufficient to rescue neurogenesis (the process by which new neurons are formed in the brain) and behaviour in females, but not males.

Next comes really important stuff because it could help stop unnecessary second brain tumour surgeries as artificial intelligence (AI) tools are being developed to help surgeons and oncologists identify the subtle but critical differences between a recurring tumour and damaged non-cancerous tissue on post-operative MRI. The potential benefit for doctors and their patients is fewer unnecessary surgeries to remove suspect tissue which now can only be confirmed to be non-cancerous after treatment. Doctors often end up performing surgeries because tissue that has been scarred and damaged--even killed--by chemotherapy or radiation resembles a recurring tumour on an MRI scan. If that can be avoided due to more effective post-operative MRI then how much of an improvement could that be for brain tumour patients?

It is still not known exactly why glioblastomas begin to grow and the study below investigated which genes were implicated in the cancer and showed that the well-known cancer gene, EGFR (epidermal growth factor receptor) can alone initiate brain tumours to grow in mice, resulting in tumours that were highly representative of human glioblastomas. Collaborators show how a mutation in the well-known cancer gene, EGFR initiates glioblastoma, and works with a selection of more than 200 other genes to drive the cancer.

Industry/Clinical trial news now;

Quadriga BioSciences, have announced the first patient starting a Phase 1 study of QBS10072S. Preclinical studies have demonstrated that QBS10072S significantly suppresses tumour growth and improves survival in a both metastatic brain tumours and primary GBM tumours. This data showed that QBS10072S was transported across the blood brain barrier and then accumulated in the brain tumour leading to reduced tumour growth. To quote directly from the article “First-in-class, dual-function, small molecule drug utilizes LAT1 amino acid transporter pathway to cross blood-brain barrier and deliver warhead directly into cancer cells, a potential breakthrough in brain cancer treatment.” What a way to describe a drug as delivering a ‘warhead directly into cancer cells’! – follow the hyperlink for full scientific detail.
Noxxon Pharma N.V, a biotechnology company focused on improving cancer treatments by targeting the tumour microenvironment (TME), announced that safety data from the initial four weeks of treatment of the first patient of the second dose cohort enrolled in the NOX-A12 plus radiotherapy brain cancer trial concluded that it is safe and appropriate to continue the recruitment of additional patients. The Phase 1/2 clinical trial is testing three dose regimens of NOX-A12 (200, 400 and 600 mg/week), each combined with external-beam radiotherapy, in newly diagnosed brain cancer patients. The clinical centres participating in the study have now initiated the recruitment of the remaining patients in the second of three escalating dose groups. Once all patients in the second cohort have received a four-weeks treatment of NOX-A12 and radiotherapy, it will then be assessed to determine whether it is safe to proceed to the highest planned dose level of NOX-A12.

A highly scientific piece here so rather than producing a lay summary for this it’s better if the title grabs you and you want to find out more click on the link – sounds promising though - TP5 alone or in association with temozolomide and radiotherapy is a promising therapeutic option for glioblastoma.

Finally news on research to make radiation therapy more effective for glioblastoma patients by targeting a critical metabolic pathway and disrupting its ability to repair the DNA damage caused by the radiation. Resistance to radiation leads to a recurrence of the cancer so, finding new ways to overcome this resistance could help improve patient outcomes. Because of the heterogeneity (variety of genetic alterations) seen in glioblastoma the search was for a way to overcome this resistance that would work across genotypes. The characteristics of 23 glioblastoma cell lines were examined looking at the metabolites produced by each cell line and measuring how resistant each was to radiation. The group found that the cell lines that were more resistant to radiation treatment also had higher levels of purines and lots of different genetic mutations that occur in glioblastoma lead to this purine pathway being activated. A research study in human patients based on this research will start enrolling soon.