Reactivating Cancer Cell Death in Metastatic Breast Cancer

Project Description: Metastatic estrogen receptor positive (ER+) breast cancer occurs in approximately 1 in 4 patients. Whilst patients initially respond well to CDK4/6 inhibitor drugs combined with anti-estrogen therapy, most women will develop resistance to treatment within one to two years. This project will test two drugs, Venetoclax and Navitoclax, which are approved and under investigation for the treatment of some blood cancers, for their ability to reactivate cancer cell death in CDK4/6 inhibitor resistant breast cancers. 

Why This Work is Needed: About 75% of all breast cancers are ER+ and these patients receive hormone therapy but 35% develop treatment resistance. While the recent introduction of combination therapy with CDK4/6 inhibitor drugs with anti-estrogen therapy was initially shown to be highly effective for most women, the cancer inevitably returns. Hence, there is an urgent need to understand the biological mechanisms of drug resistance and develop novel treatment strategies for these patients.  

Expected Outcomes: Outcomes from this study will identify novel therapeutic targets and treatment strategies for ER+ breast cancers that experience resistance to current combination treatments. By investigating the use of existing drugs, it will reduce the costs of drug development and accelerate translation to the clinic.  

Project Details  

In 2015, two new CDK4/6 inhibitor drugs (CDK4/6i; Palbociclib and Ribociclib) were approved for metastatic ER+ breast cancer. Whilst most women respond very well to these drugs, it is common for resistance to develop within 12 to 24 months.  

Associate Professor Liz Caldon, from the Garvan Institute of Medical Research, and her team have identified one way in which the cancer cells “escape” the effects of the CDK4/6i drugs. This escape mechanism can be seen in around 15% of CDK4/6i resistant cancers. 

Luckily, there are pre-existing drugs which overcome this escape mechanism, called Venetoclax or Navitoclax, drugs that target the ways in which cancer cells survive. These drugs are currently approved for use in some blood cancers. Associate Professor Caldon’s team aims to test these drugs in unique experimental models that recapitulate human disease and show that these drugs are effective for patients who fail CDK4/6i treatment.