The AACR-AstraZeneca Breast Cancer Fellowship for Endocrine Therapy Research represent a joint effort to encourage and support postdoctoral or clinical research fellows to conduct breast cancer research and to establish a successful career path in this field. Proposed research projects are restricted to basic, clinical, translational or epidemiological projects that substantially advance the field of endocrine therapy in breast cancer.

2024 Grantees

 Research

Emerging evidence suggests that dysregulated gut microbiota may contribute to the development and recurrence of estrogen receptor-positive (ER+) breast cancer (BC). Despite the success of oral endocrine therapies, recurrence remains a risk up to 10 years post-diagnosis. Preliminary data indicate that manipulating the gut microbiome through short-chain fatty acids (SCFAs) may improve treatment outcomes. In mouse models, SCFA supplementation increased tumor-free survival and reduced tumor growth. Additionally, metagenomic sequencing of postmenopausal BC patient samples revealed increases in SCFA-producing microbial species following aromatase inhibitor (AI) treatment. Dr. Arnone aims to explore whether SCFA supplementation can improve the efficacy of oral endocrine therapy using an ER+ bone trophic mouse model. Plasma samples from AI-treated BC patients will also be analyzed to assess AI’s impact on the gut metabolome.

Biography

Dr. Arnone’s graduate work focused on how diet, the gut microbiome, and endocrine therapies influence estrogen receptor-positive breast cancer. She is currently a postdoctoral research fellow in the Department of Cancer Biology at Wake Forest University School of Medicine. She has extensive experience in mammary gland and breast cancer research, particularly the role of the microbiome in breast cancer development. Her current research investigates the potential of microbial-derived metabolites as adjuncts to improve the efficacy of endocrine therapy.

Acknowledgment of Support

“Receiving the 2024 AACR-AstraZeneca Breast Cancer Fellowship for Endocrine Therapy Research will significantly propel my research on gut microbiome manipulation to enhance endocrine therapy efficacy. This support will strengthen my path toward becoming an independent investigator, enabling me to expand translational research that improves outcomes for estrogen receptor-positive breast cancer patients.”

Research

The development of selective kinase inhibitors, particularly for the cyclin dependent kinases (CDK), has been challenging. FDA-approved breast cancer therapies targeting CDK4 (e.g., palbociclib) also target CDK6. However, the neutropenia side-effects limiting the clinical use of CDK4/CDK6 inhibitors are attributed to off-target CDK6 inhibition. Therefore, developing authentic CDK4-selective inhibitors and degraders has been a longstanding goal for the CDK cancer biology field.

Using activity-based protein profiling, Dr. Potter-Engelskirger has identified covalent ligands targeting an isotype-restricted cysteine on CDK4. This liganding event is remarkably selective, with only 8 other cysteines out of 8,000 quantified cysteines showing more than 50% competitive engagement. Among these ligands, he identified one that displayed excellent potency. CDK4 engagement with this molecule leads to the monofunctional degradation of CDK4. Dr. Potter-Engelskirger’s work aims to optimize and understand the mechanism-of-action for allosteric covalent ligands targeting CDK4.

Biography 

Dr. Potter-Engelskirger began his training as a chemical biologist in 2015 as a research technician at the Scripps Research Institute. After completing his doctoral training in 2023 at the University of Washington, Dr. Potter-Engelskirger re-joined the Scripps Research Institute as a postdoctoral research associate. At Scripps, Dr. Potter-Engelskirger has combined his interests in protein allostery, chemical proteomics, and covalent ligand discovery to interrogate difficult-to-drug, cancer-relevant protein targets.

Acknowledgment of Support

“The 2024 AACR-AstraZeneca Breast Cancer Fellowship for Endocrine Therapy Research affords me the creative freedom, confidence, and financial support needed to pursue an independent research career. As someone whose family has been directly impacted by cancer, receiving such a distinguished award to support the fight against this disease is extraordinarily meaningful.”