Titles and Affiliations
Joint Division Head, Cancer Biology and Stem Cells Division
Research area
Improving the effectiveness of therapies for women with estrogen receptor-positive breast cancer.
Impact
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 proteins that help keep cancer cells alive as a potential treatment option for women with ER-positive breast cancer that is no longer responding to the combination therapy.
Progress Thus Far
Dr. Lindeman’s team is conducting a phase I trial called PALVEN combining an inhibitor of survival protein BCL2, venetoclax (VENCLEXTA®), with CDK4/6 inhibitor and have identified a safe and tolerable dose that can be used for later phase studies. This is the first time venetoclax is being tried in a solid tumor, and the first trial to pair it with a drug that blocks the cell cycle. Early results are encouraging. Over 90 percent of participants benefited, and about half remained free of disease progression for more than two years. In parallel with the clinical trial, the team is running laboratory studies to understand how venetoclax works best and why some tumors become resistant. The team is testing combinations with other drugs, screening for new treatment targets, and exploring better ways to block the BCL2 protein family that fuels cancer cell survival. Importantly, they also studied how long-term venetoclax affects healthy blood cells. All changes they saw were temporary, with no signs of harmful effects. Finally, they are investigating a new type of drug called a KAT6 inhibitor. Their pre-clinical findings helped launch a phase 1 trial, which showed promising results, and further trials are being planned.
What’s next
Over the upcoming year, Dr. Lindeman and his team will share the results of the PALVEN trial, including detailed analyses of tumor DNA, biopsies, metabolic responses, and the impact of therapy on patients’ white blood cells, along with patient reported outcomes. They will also extend their findings to explore newer BCL2 and CDK4 inhibitors in ER-positive breast cancer. In the lab, the team will investigate dual targeting of BCL2 family proteins with other inhibitors in patient-derived tumor models, while also developing new strategies to target these proteins. Finally, they will study how cancers develop resistance by screening gene libraries to pinpoint new vulnerabilities that could lead to future treatments.
Biography
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)