Project Funding Details

Despite their capacity for relentless growth, cancer cells are poised in a life and death predicament. Pro-survival proteins such as BCL-2 (and family member MCL-1) can be co-opted to resist the induction of apoptosis following chemotherapy or targeted therapy. In breast cancer, BCL-2 is overexpressed in the majority of ER-positive (ER+) tumours, while MCL-1 expression is prominent in triple negative breast cancer (TNBC) and HER2-amplified tumours. Recently, a promising new class of drug, termed BH3 mimetics, has been developed that target and neutralise pro-survival proteins, with the BCL-2 inhibitor venetoclax showing remarkable success in blood cancers. ‍ Our team has led global efforts to trial venetoclax in breast cancer. A phase 1 study of venetoclax with tamoxifen in ER+ metastatic breast cancer (MBC) has demonstrated safety and remarkable efficacy. We now have preliminary data from patient-derived xenograft (PDX) models indicating that venetoclax can synergise with the CDK4/6 inhibitor palbociclib (a ‘gold standard’ addition to endocrine therapy), as well as the anti-HER2 drug T-DM1 in HER2-amplified tumours. We also identified MCL-1 as an important target in TNBC. ‍ The aim of this project is to advance our pre-clinical and clinical studies. Using PDX and tumour organoid models, we will evaluate tumour response and mechanisms of action of combination therapy comprising (1) venetoclax, fulvestrant and palbociclib in ER+ breast cancer, (2) BCL-2 inhibitors with T-DM1 in HER2-amplified disease, and (3) MCL-1 inhibitors in ER+ and TNBC breast cancer. In parallel, we will undertake two phase 1b clinical trials: (1) PALVEN (palbociclib, letrozole and venetoclax) in ER+ MBC, and (2) HERB (T-DM1 and venetoclax) in HER2-amplified MBC. ‍ This project will provide essential pre-clinical and clinical data to enable our goal of transferring an entirely new class of drug to the clinic for breast cancer, with potential to transform treatment strategies across all breast cancer subtypes.

Certain blood cancers are sustained by high levels of a ‘survival’ protein called BCL-2, which makes them more resistant to therapy. A new class of drug, BH3 mimetics, is showing tremendous promise in the treatment of these cancers. BH3 mimetics target a tumour’s “Achilles’ heel” by neutralising a key pathway that helps keep tumour cells alive. Laboratory and clinical studies have shown that BH3 mimetics flip a tumour control switch from ‘life’ to ‘death’. Strong inhibitors of BCL-2 and MCL-1 (a BCL-2 family member) have recently been developed, raising the prospect they could also be effective breast cancer therapies. Most ER-positive breast cancers contain high levels of BCL-2, while MCL-1 levels are prominent in HER2-positive (‘amplified’) and triple negative breast cancer (TNBC). Our team will investigate the possibility of using pre-clinical (laboratory) models and lead international efforts that directly test these inhibitors in the clinic. In this project we will evaluate tumour response and mechanisms of action when the BCL-2 inhibitor venetoclax is combined with the new ‘gold standard’ therapy for ER-positive cancer (hormone therapy with a cell cycle inhibitor). BCL-2 inhibition will also be tested in HER2-positive cancer, while a MCL-1 inhibitor will be studied in ER-positive and TNBC (including BRCA1-associated tumours). In parallel, we will undertake two clinical trials to directly test the safety and effectiveness of venetoclax for patients with advanced (metastatic) breast cancer. PALVEN will evaluate combination therapy comprising palbociclib (a cell cycle inhibitor), letrozole (an aromatase inhibitor) and venetoclax in women with ER-positive BCL-2-positive metastatic breast cancer, while HERB will evaluate the anti-HER2 drug T-DM1 (Kadcyla) with venetoclax in HER2-positive disease. This project will enable our goal of transferring this new class of drug to the clinic for breast cancer, producing deeper and more durable responses that radically improve patient outcomes.