The Walter and Eliza Hall Institute of Medical Research
Joint Division Head, Stem Cells and Cancer
Improving the effectiveness of therapies for women with estrogen receptor-positive breast cancer.
About one quarter of women with early-stage, estrogen receptor (ER)-positive breast cancer will later be diagnosed with metastatic breast cancer (MBC). A therapeutic regimen that includes endocrine therapy plus one of a class of drugs called CDK 4/6 inhibitors has dramatically extended the lives of patients with MBC, but the tumors ultimately develop resistance. Dr. Lindeman is investigating drugs that target the survival protein BCL2 as a potential treatment option for women with ER-positive breast cancer that is no longer responding to the combination therapy.
Dr. Lindeman’s team conducted laboratory studies of the combination of an inhibitor of BCL2 with hormone therapy and a cell cycle (CDK4/6) inhibitor. They have confirmed that the efficacy of triple therapy is superior to dual therapy in ER-positive breast cancer models. The team completed a phase I clinical trial testing a BCL2 inhibitor in patients with metastatic breast cancer. The trial identified a suitable dose and safety profile as well as promising activity when given before standard combination of endocrine and CDK4/6 inhibitor therapy.
Dr. Lindeman is now extending his studies by targeting other key BCL2 family members, BCLXL and MCL1, and tumor survival pathways in breast tumor patient samples. The team is exploring a similar combination therapy targeting MCL1 or BCL-XL with endocrine therapy and a CDK4/6 inhibitor, or endocrine therapy and an inhibitor of AKT, another protein important for breast cancer cell survival. So far, the tram has observed tremendous synergy with dual targeting of AKT and BCL-XL or MCL1, including in cells resistant to CDK4/6 therapy.
Dr. Lindeman, a clinician-scientist, is Joint Head of the Stem Cells and Cancer Division at the Walter and Eliza Hall Institute of Medical Research (‘WEHI’); medical oncologist at the Peter MacCallum Cancer Centre and Royal Melbourne Hospital; Professorial Fellow in the Department of Medicine, University of Melbourne; and leads the NHMRC Centre of Research Excellence in Translational Breast Cancer Research.
His laboratory is studying molecular regulators of normal mammary gland development and cancer, with a particular interest in understanding how mammary stem cells and their progeny contribute to the mammary gland development and cancer. The discovery of RANK-positive progenitor cells as a target for breast cancer prevention in BRCA1 mutation carriers influenced the establishment of an international prevention study, BRCA-P. His laboratory is also using patient derived xenograft (PDX) and tumor organoid models to test promising anti-cancer agents, including drugs that target the BCL-2 family.
He is a member of the Scientific Advisory Committee (and former Board member) of Breast Cancer Trials (formerly the Australian and New Zealand Breast Cancer Trials Group) and member of the Executive of kConfab (a familial breast cancer consortium). Awards include the Ramaciotti Medal for Excellence in Biomedical Research (2016) and Victoria Prize for Science and Innovation (2017), jointly awarded with Dr Visvader. He has been elected Fellow of the Australian Academy of Health and Medical Sciences (2015) and the Australian Academy of Science (2016)
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