There have been no new drugs licensed to treat brain cancer in adults or children for 20 years. Now, a new type of drug that targets a genetic weakness in an untreatable childhood brain cancer could become the first ever treatment designed to target the disease. Scientists at The Institute of Cancer Research, London, led research with an international team of colleagues, finding that the new drug class can kill brain cancer cells with mutations in the ACVR1 gene and shrink tumors in mice. Open science company M4K (Medicines for Kids) Pharma has taken on development of the ACVR1 inhibitor drugs – and clinical trials in children with brain cancer are expected to begin in 2021. The new type of drug targets the mutated ACVR1 protein found in the deadly childhood brain cancer labeled as diffuse intrinsic pontine glioma (DIPG). There are currently no life-extending treatments other than radiotherapy for DIPG tumors and this is never curative, with children expecting to live only nine to 12 months after diagnosis. Because they occur in the brainstem or ‘pons’ area of the brain, DIPG tumors can’t be removed by surgery, and chemotherapy simply doesn’t work. The prototype treatment could also offer hope for patients with the rare and devastating ‘stone man syndrome’ – in which muscles and ligaments turn to bone.
Curiously, indeed, ACVR1 mutations don’t exist in any other type of cancer, but they are the cause of the inherited disease, stone man syndrome, where damaged muscle remodels as bone as it heals. Technically the disease real name is fibrodysplasia ossificans progressiva (FOP), and patients with this condition do not develop DIPG, suggesting that ACVR1 mutations alone are not sufficient to drive the onset of gliomas. ACVR1/ALK2 encodes the activin A receptor, a membrane protein that binds to activin A, a growth factor belonging to the family of bone morphogenetic proteins (BMPs). Originally in 2014, scientists at The Institute of Cancer Research (ICR) discovered that ACVR1 mutations occur in a quarter of DIPG tumors and have been working on drugs that target it ever since. Following this discovery, teams at the Structural Genomics Consortium in Oxford and the ICR created a new series of molecules that target mutant forms of ACVR1. In the new study, the ICR-led team tested 11 prototype drugs with anti-ACVR1 activity, as well as other drugs previously investigated for stone man syndrome – on brain cancer cells grown in the lab. They found that two of the prototypes from the new series were particularly good at blocking signals sent out by ACVR1 and killing ACVR1-mutant cells, while having very little effect on healthy brain cells.
The researchers transplanted human DIPG tumors into mice and found the potential new drugs stopped ACVR1 activity, shrunk tumors and extended survival by 25% (from 67 to 82 days). Treatment of ACVR1 R206H mutant DIPGs with the prototype ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to the drug. LDN212854, was significantly in vitro more efficacious than LDN214117, a second ALK2 inhibitor, in both cell-lines derived from murine model and human DIPG cell-lines. Looking at cells in the lab, the new study shows that ACVR1-mutant cells respond inappropriately to activin A – which regulates embryonic events like bone or brain development – sparking a cascade of events that trigger tumor growth. A similar situation is thought to occur in stone man syndrome, with high levels of activin A occurring during inflammation in muscles and inappropriately triggering the formation of bone tissue in people born with ACVR1 mutations. The drugs have now been taken on as the first project of a new open science company called M4K Pharma, which aims to discover and develop affordable drugs for childhood diseases that are rare, where there is less market incentive and that aren’t well served by current business models.
Dr. Chris Jones, Professor of Pediatric Brain Tumor Biology at The Institute of Cancer Research, London, said: “Diffuse intrinsic pontine glioma is a relatively rare childhood brain cancer, but it is always deadly. Learning more about its biology and trying to find ways to translate that knowledge into new treatments, has been a passion of mine for years. My lab discovered that mutations in the ACVR1 gene occur in a quarter of pontine gliomas and it’s incredibly exciting to see this now lead to potential new drugs for the disease. I can’t wait to see how they perform in patients. It’s simply not good enough that we can cure some cancers, but in others we have seen no progress in decades. We owe it to children and their families to do better”.
Professor Paul Workman, ICR Chief Executive, added: “This is an important study which perfectly illustrates how gaining a detailed understanding of the biology of cancers can allow us to move very quickly to the discovery of new treatments. I’m proud that the ICR is working in an academic-industry partnership with M4K Pharma to take a drugs forward to the clinic. Where the patient population is very small, it can be difficult to get companies to take such drugs on. And even where this does happen the result is often a very expensive drug. I hope that a new drug from this research can be taken to the clinic as quickly as possible to help children with DIPG tumors, and of course it would also be excellent to see patients with stone man syndrome benefit from the treatment as well”.
The study has been funded by Abbie’s Army, Children with Cancer UK, Cancer Research UK and the DIPG collaborative. Its results are published in the journal Communications Biology.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Hoeman CM, Cordero F et al. Nat Commun. 2019; 10(1):1023.
Sekimata K et al. Chem Pharm Bull (Tokyo) 2019; 67(3):224-35.
Han HJ, Jain P, Resnick AC. Bone. 2018 Apr; 109:91-100.
Nikbakht H et al., Nazarian J. Nat Commun. 2016; 7:11185.