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By Hannah Buckelew
A researcher from the University of Alabama at Birmingham Department of Biomedical Engineering recently received a $1.4 million R01 grant to research systemic toxicities in breast cancer. Toxicity is the main dose-limiting factor in cancer treatments. Developing methods to control it could dramatically impact patient health.

Anna Sorace, Ph.D., associate professor in the UAB Departments of Biomedical Engineering and Radiology and director of the Small Animal Imaging Facility, has been awarded an R01 from the National Cancer Institute based on her project submission titled, “Mathematical Modeling and Molecular Imaging to Maximize Response While Minimizing Toxicities from Systemic Therapies in Preclinical Models of Breast Cancer.” The $1.4 million award began December 1, 2022 and will run through November 30, 2025.

The study’s overarching goal is to utilize biology-based mathematical models and advanced molecular imaging to dramatically decrease systemic toxicities, while either maintaining or accelerating tumor control in preclinical models of breast cancer. Advances in systemic therapies have improved long-term survival in patients with locally-advanced breast cancer, yet there has been a naturally accompanying increase in associated long-term side-effects, including cognitive and cardiac deficiency.

Sorace has developed biology-based mathematical models capable of systematically investigating the timing, order, dosing, and sequencing of combination therapies to identify therapeutic regimens that have the potential to maximize response and minimize toxicity. Both experimental and preliminary results show that alternating the order and dosage of combination chemotherapy and targeted therapy can significantly enhance response while reducing the chemotherapy dose by 50%.

“We want to develop mathematical formulism that uses molecular imaging data that will systematically determine, on a patient specific basis, therapeutic regimens that maximize tumor response and minimize side effects,” says Sorace. “Then, we’ll select the most promising results and put them to the test against established treatment regimens, to determine superior outcomes in decreasing toxicity.”

Sorace and team also seek to develop quantitative imaging technologies capable of characterizing the temporal alterations in brain and cardiac function, organs known to be adversely affected by chemotherapies.

They plan to do so by first validating mathematical predictions for maintaining tumor control with minimal chemotherapy by employing optimal control theory, or the mathematical optimization which finds a control within a complex system over a period of time, to biologically validate the three most promising combination treatment strategies. The second will implement advanced molecular imaging to quantify toxicity changes in critical organs during therapy by employing cardiac imaging of membrane potential and brain imaging of microglial activation to determine differences between long-term effects in animals treated with both the standard and optimized regimens.

Completing both of these aims will allow the team to deliver a practical, experimental-computational approach to identifying optimal treatment strategies in pre-clinical mouse models, and prepare for prospective testing in phase 1 clinical trials. The research team has identified therapeutic regimens suggesting further efforts can achieve tumor control 1.6 times faster without increasing the dose of chemotherapy.

This study is a collaboration with Tom Yankeelov, Ph.D., and Ernesto Lima, Ph.D., at the University of Texas at Austin. Other members of the research team include co-investigators Suzanne Lapi, Ph.D., professor, UAB Department of Radiology, Eddy Yang, M.D., Ph.D., professor, UAB Department of Radiation Oncology, and Yufeng Li, Ph.D., in the UAB Department of Medicine’s Division of Preventative Medicine.