While significant improvements have been made in recent years to the survival rates for patients with some cancers, clearly we still have a long way to go to reach our goal - a cure for all cancers. Only through research into novel and innovative approaches to treat cancer, can we move towards achieving this goal.
Cancer is a disease of uncontrolled cellular growth. Our body is made up of trillions of tiny entities called cells, each of which has a defined function in our body. Cancer develops when one cell suffers damage to its DNA. Our DNA contains all of our genes. DNA can undergo multiple types of damage - this may be due to UV radiation, exposure to carcinogens, or simply due to errors in the replication process that cells must undergo so as to replicate DNA during cell growth. In most cases, our cells have an amazing capacity to repair DNA damage. However, in some cases the damage is either too great or our DNA repair mechanisms are faulty. This results in the accumulation of DNA damage – or mutations – and ultimately leads to uncontrolled cellular growth, and hence cancer.
Genes that normally function to repair DNA damage are termed tumour suppressor genes, because their role is to ‘suppress’ tumour formation, by repairing DNA damage. Our research group has recently identified a new tumour suppressor gene - called PPP2R2A. The function of this gene is to repair DNA damage in normal cells. However, we have found that the PPP2R2A gene is ‘lost’ or ‘switched off’, in up to half of all prostate cancer, breast cancer, ovarian cancer, lung cancer, colon cancer, and pancreatic cancer patients. Because PPP2R2A normally repairs DNA damage, in cells that no longer have this protective mechanism, the DNA is highly unstable, and hence these cells are highly susceptible to cancer development. Ironically however, we believe that we can use the loss of PPP2R2A to our advantage. We have found that cancer cells with loss of PPP2R2A are highly sensitive to two specific classes of anticancer drugs: 1) PARP inhibitors - these are a class of drugs currently in clinical trials for a range of cancers. We believe that the reason these cancer cells are hyper-sensitive to these drugs is because of their unstable DNA, however this needs to be experimentally tested. 2) PP2A activating drugs - these are a class of drugs in pre-clinical development, a number of which we have developed in our own laboratory, which function to ‘switch back on’ the activity of PPP2R2A.
We hypothesize that tumours that have PPP2R2A loss would respond to chemotherapy treatment using one, or a combination, or these drugs.
This project will directly test this using pre-clinical models of a range of cancer types. To achieve this, we have generated cancer cell lines in which PPP2R2A is switched off, and we are in the process of generating a laboratory model where the PPP2R2A gene has been switched off. These are unique and powerful models to test the effectiveness of our PARP inhibitors and PP2A activating drugs as a novel therapeutic approach to treat cancer. Such studies are vital to determine which types of cancer patients would be candidates for these therapies, and are required before human clinical trials could be conducted.
Funding of this project will enable us, for the first time, to accurately model what occurs in human cancers. These models will be a unique resource to study the effects of PPP2R2A loss in a range of cancers. Testing the efficacy of PARP inhibitors and PP2A activating drugs in these models will determine if cancers with PPP2R2A loss are, as we predict, sensitive to these classes of drugs.