Benita S. Katzenellenbogen, PhD

Identifying targets for the development of drugs that suppress the growth of aggressive breast cancers to improve breast cancer outcomes.

Impact

Estrogen receptor (ER)-positive and triple-negative breast cancer (TNBC) subtypes can develop resistance to treatments and progress and metastasize. The protein FOXM1, which is expressed at high levels in many breast tumors, plays a role in breast cancer progression, resistance to endocrine and other cancer therapies, and metastasis. Dr. Katzenellenbogen aims to develop FOXM1 inhibitors to impede tumor growth and metastasis and expand treatment strategies for aggressive breast cancers.

Progress Thus Far

Dr. Katzenellenbogen has developed and optimized FOXM1 inhibitors that are very effective in suppressing the growth and metastasis of ER-positive and TNBC with high levels of FOXM1 activity. While the FOXM1 inhibitors they developed can shrink tumors and slow spread, cancers eventually adapt and resist them. She and her team found that combining these drugs with agents that trigger ferroptosis, a type of iron-driven cell death, can overcome this resistance and improve outcomes. They also uncovered a signaling network that drives resistance not only to FOXM1 inhibitors but also to commonly used CDK4/6 inhibitors, revealing new targets for therapy. In addition, the team studied mutant forms of the estrogen receptor (ER) found in many recurrent ER-positive breast cancers and demonstrated that these mutations help tumors evade treatment. By adjusting current antiestrogen therapies, the team was able to improve their effectiveness against these resistant cancers.

What’s next

Dr. Katzenellenbogen and team will test whether their combination treatment strategies can also be effective against harder-to-treat breast cancers, including luminal B and invasive lobular carcinoma (ILC) subtypes. They will evaluate new estrogen receptor-targeting drugs (SERMs and SERDs) both alone and in combination, in breast cancer models that closely mimic real tumors. In parallel, they will study how increased interferon signaling and a process called ISGylation affects tumor growth and spread across different breast cancer subtypes. By pinpointing the pathways and proteins involved, they aim to uncover new weaknesses that can be targeted to ultimately improve treatments for these aggressive forms of breast cancer.