Targeting the host immune system to fight back against cancer has seen recent breakthroughs. The protein Heme Oxygenase-1 (HO-1) has recently been shown to suppress the immune system in breast cancer and that inhibiting HO-1 had therapeutic benefit. In this project, we will show that HO-1 is important in osteosarcoma and that inhibiting HO-1 with already-approved drugs can block osteosarcoma development and metastasis.

Project summary

Osteosarcoma is a devastating malignancy that affects patients of all ages. Chemotherapy and limb-sparing surgery has improved over the past years, however, the 5-year survival rate has not changed in nearly 30 years. This is because one of the most difficult complications is cancer spread and metastasis, and in the case of osteosarcoma, this is mainly to the lungs. There are great efforts made to understand the genetic basis of osteosarcoma and metastasis, but there are still many unanswered questions about what signals are present in the tumours that are driving cells to leave the primary tumour and metastasise to the lungs.

One of the current breakthroughs in the cancer field is in understanding how the immune system can be boosted to help fight back against the cancer. This is important because the standard chemotherapy treatment suppresses the immune system, allowing the cancer to escape attack from immune cells.

There has been intensive research into special cells called macrophages, normally present in all of us, which are important for our normal development. In cancer, macrophages are hijacked and altered by the cancer cells. Once hijacked, these cells are called Tumour Associated Macrophages (TAMs). It is these TAMs that are largely responsible for allowing cancer cells to evade attack by the host immune system, and these TAMs are generally present in all tumours, including in osteosarcoma. Therefore, in order to “kick-start” the body’s own defence system, these TAMs need to be targeted.

Professor Grigoriadis has been encouraged by recent work conducted by a collaborator (Professor James Arnold) at Kings College London, who recently demonstrated that TAMs in breast cancer make factors called Fibroblast Activation Protein (FAP) and Heme Oxygenase-1 (HO-1), and that HO-1 can promote the growth of tumours by blocking the immune system. Therefore, it would be of great benefit to block HO-1. Fortunately, there are already drugs being used against HO-1. HO-1 is important in neonatal jaundice, and a drug called SnMP is used routinely to treat this. A breakthrough published recently shows that in pre-clinical models, treatment with SnMP was more effective at reducing tumour growth when compared to chemotherapy alone. This is very exciting and suggests there is scope for human cancer treatment.

Encouraged by this data, Professor Grigoriadis and his team established a collaboration with Professor Arnold to see if a similar mechanism might be operating in osteosarcoma. Preliminary experiments suggested that osteosarcoma also expresses high levels of FAP and HO-1. This prompted Professor Grigoriadis and his team to propose a simple initial study to confirm if these proteins are functional in osteosarcoma, and if the SnMP drug, either with or without chemotherapy, will reduce osteosarcoma growth and metastasis. This would represent a significant advance in the osteosarcoma field.

How will it improve the lives of patients?

One of the goals of fundamental basic research is to discover and provide information on novel targets that are relevant to specific cancers, and that can be targeted in a therapeutic setting to treat cancer. It has also become evident in recent years that drugs that are already on the market and used for treating other diseases might provide therapeutic benefit for additional diseases – this is referred to as drug re-purposing. This project will investigate one such target, HO-1 for which there is already an inhibitor being used for neonatal jaundice, and the goal is to show that this would be effective in osteosarcoma. This work would be performed using pre-clinical studies, which are essential before translating to a human setting. It is anticipated that once this fundamental question is proven, that rapid progress can be made with patients that have bone cancers such as osteosarcoma.

The Bone Cancer Research Trust would like to thank the Clive and Sylvia Richards Charity for helping to make this project a reality.