Geoffrey Lindeman, BSc (Med), MBBS (Hons), FRACP, PhD

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. Most breast cancers contain high levels of these survival proteins (including BCL2, BCL-XL, and MCL1), and a new class of drugs that inhibit them is already under active development in blood cancers, though their role in breast cancer specifically remains poorly understood.

Progress Thus Far

Dr. Lindeman’s team is conducting a phase I trial called PALVEN (NCT03900884) 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. This trial builds on the team’s earlier work showing that venetoclax was effective in preclinical models and an early-phase trial combining it with tamoxifen, where its benefit was primarily seen prior to the development of resistance to CDK4/6 inhibitor therapy, underscoring the importance of using it before resistance develops.

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. Building on earlier findings, the team has contributed to the development of a new, pharma-led phase 1 trial (with BeiGene) testing a second-generation BCL2 inhibitor together with a CDK4-selective inhibitor.

Finally, they are investigating a new approach targeting a gene called KAT6 that is often abnormally elevated in aggressive hormone-positive breast cancers, switching on abnormal estrogen signaling to promote cell growth. Their pre-clinical findings helped launch a phase 1 trial, which showed promising results, and further trials are being planned. A screen to identify mechanisms of resistance to KAT6 inhibition has also begun.

What’s next

Dr. Lindeman and his team will continue to explore newer BCL2 and CDK4 inhibitors in ER-positive breast cancer including completing patient follow-up and translational analyses from the newly launched second-generation BCL2/CDK4 inhibitor trial, which aims to identify an optimal dose for future phase 2 study. 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, extending the same approach to identify mechanisms of resistance and early markers of response to KAT6 inhibition.