Prof Ygal Haupt, Dr Shahneen Sandhu
Sir Peter MacCallum Department of Oncology, The University of Melbourne
During prostate cancer development, enzymes that destroy tumour suppressors become excessibely active. This allows the cancer cells to continue to grow. Our project aims to protect tumour supressors - particularly a protein called promyslocytic leukemia (PML) - to empower these to inhibit
cancer cell growth.
What is the need?
Prostate cancer is a serious men's health issue, particularly when it is at an adanced stage and has become resistant to castration, at which point survival rates are very poor. Identifying novel treatments is therefore of prime importance.
It is known that PML, an important cancer suppressor, is often lost during the progression of prostate cancer, but it hasn't so far been clear what causes this loss. In our laboratory we discovered that PML is controlled and ultimately destroyed by an enzyme called E6AP, which is found at elevated levels in prostate cancer.
We now want to test whether inhibiting EAP6 will protect PML and consequently suppress the progression of prostate cancer.
What impact will this research have?
Our findings will provide the first demonstration of E6AP's role in the initiation, development and progression of prostate cancer. We will also provide the proof of concept that targeting E6AP is a novel therapeutic approach for advanced prostate cancers.
Our laboratory test results indicat that PML is targeted by E6AP, and that high levels of E6AP in combination with low levels of PML are predictive markers for poor prognosis of prostate cancer patients following radical prostatectomy. This in turn identifies patients who are at high risk and thus likely to benefit from a treatment that inhibits E6AP. We have also found that targeting E6AP sensitises prostate cancer cells to radiotherapy. This suggests that targeting E6AP in combination with radiotherapy could be effective.
The concept of restoring tumour suppression has been in sight, but difficult to demonstrate, for more than two decades. Our experimental tools and the availability of new drugs are finally providing strong support for its proof.
Define the mechanism by which E6AP promotes prostate cancer and testing PML tumour suppressor as a prime target.
Studying the effect of E6AP on the growth of prostate cancer cells in culture (in the laboratory) and in mice.
Test the efficacy of targeting E6AP as a novel approach for the treatment of prostate cancer is in progress.
"Demonstrating this therapeutic approach will open new possibilities to combine it with existing treatments, as well as to discover new therapeutic approaches for additional tumour suppressors."