Improvements in the treatment of osteosarcoma are much needed. The risk of recurrence is considerable and current treatment options carry significant toxicities.
Unfortunately, targeted treatments that address specific mutations present in osteosarcoma, still lag behind those for other cancers.
Mutations that result in the loss-of function of the Retinoblastoma tumour suppressor gene (RB1) affect the ability of cancer cells to repair DNA breaks. This mutation occurs in 40-60% of osteosarcoma patients, making it the second most mutated gene in this disease after TP53.
What are the aims of this research project?
A group of new generation anticancer medicines known as PARP inhibitors (inhibitors of poly adenosine diphosphate-ribose polymerase) prevent cancer cells from repairing the DNA breaks caused by chemotherapy and radiotherapy and are currently being used successfully (alone or in combination with other therapies) to treat several cancers, particularly ovarian tumours.
The research team led by Professor Sibylle Mittnacht at University College London have demonstrated that osteosarcoma cells with RB1 mutations are as sensitive or more to these inhibitors than tumour cells from cancers for which they are currently being used for treatment in the clinic.
The research project grant awarded to professor Mittnacht will allow the team to undertake the necessary investigations to support the design of a clinical trial utilising PARP inhibitors to treat osteosarcoma patients. Of course, this would only be applicable to osteosarcoma patients that present with the RB1 mutation, but from the available genomics information, it seems that between 40-60% of osteosarcoma patients could benefit from it.
The main aims of the project are:
- To develop a robust accurate and fast method by which to identify patients with the RB1 mutation.
- To investigate how to best integrate PARP inhibitors into the current standard-of-care for osteosarcoma patients.
- To learn more about the behaviour of osteosarcoma tumours with RB1 loss by tracking patients’ history, including response to treatment and survival.
To clarify the therapeutic context in which these therapeutics could be used, for example, if they should be used together, or in sequence with the current standard of care treatments.
How could this project improve treatment options for osteosarcoma patients?
Successful completion of this research will validate the feasibility for the genome-led, personalised use of PARP inhibitors to threat those osteosarcomas patients with RB1 loss of function that are hypersensitive to this treatment.
It could offer the opportunity to tackle disease recurrence born from residual cancer tissue that lies dormant and hence escapes killing during acute standard cancer therapy. It may also allow for a reduction in intensity of standard-of-care therapy, thereby reducing treatment associated toxicities.