Medulloblastoma is a rapidly growing malignant primary brain tumor that originates in the cerebellum (the lower rear portion of the brain), also called the posterior fossa. This area controls balance, posture, and complex motor functions such as speech and balance.
Medulloblastoma is the most common pediatric malignant brain tumor, accounting for 20% of all brain tumors in children.
In the EU and US ~400 new patients are diagnosed annually, with boys being affected twice as much.
The peak age of incidence is 3-5 years and ~80% of patients are diagnosed before 15 years old.
Symptoms of Medulloblastoma
Common symptoms of medulloblastoma include behavioral changes, changes in appetite, symptoms of increased pressure on the brain (e.g. headache, nausea, vomiting and drowsiness, as well as problems with coordination) and unusual (jerky) eye movements.
Early “flu-like” symptoms, such as lethargy, irritability and loss of appetite, are often so non-specific that the disease may go unnoticed. In infants, increased head size and irritability may be the first symptoms.
Older children may experience morning headaches that are relieved by vomiting. As a growing tumor increases the pressure in the brain, the headaches, vomiting and drowsiness may increase.
Current treatment consists of surgically removing as much tumor as possible, followed by craniospinal (brain and spine) radiation and/or chemotherapy – generally in older children (>3 years).
Although treatment improves survival, these regimens are highly toxic to the developing brains and are associated with significant morbidity. The prognosis is worse if the child is less than 3 years old, not enough tumor is removed or if there is any spread to other regions of the brain or body.
With treatment, around 60-65% of children with high-risk medulloblastoma, and 80-90% of those with disease that has not spread, can be expected to be free of disease 5 years later. However, treatment often results in significant neurocognitive impairment in children <8 years old.
Treating Medulloblastoma with TB-403 (anti-PlGF)
In our search to improve the treatment of cancer, we see promise in the potential of anti-PlGF [placental growth factor (TB-403)] for the treatment of medulloblastoma.
This is based on the role of PlGF in the brain, published in Cell by Prof. Rakesh Jain (Massachusetts General Hospital, Harvard, Boston, US) and Peter Carmeliet (VIB/KU Leuven, Belgium) in 2013. In this landmark paper, the authors illustrated that blocking PlGF signaling in medulloblastoma mouse models resulted in tumor regression, decreased metastasis and improved survival.
PlGF is up-regulated in the majority of medulloblastoma cancers regardless of the genetic subtypes. To a large degree, the growth factor is produced by the stromal cells surrounding the tumor cells. The functional model relies on binding of PlGF to the Neuropilin receptor. Moreover, high expression of Neuropilin 1 correlates with poor overall survival in medulloblastoma patients.
Medulloblastoma tumor cells induce production of stromal PlGF to sustain a pro-survival state through paracine secretion of signalling molecules. This becomes a self-enforcing cycle. Disruption of this cycle through PlGF blockade resulted in direct anti-tumor effects in vivo, including tumor regression, decreased metastasis and increased survival
TB-403 (anti-PlGF) is a monoclonal antibody against placental growth factor (PlGF). The molecule TB-403 has the potential to be developed as one of the first targeted therapies to treat medulloblastoma.