PROJECT SUMMARY
Our 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, however there has been a concomitant increase in the associated their
long-term side effects, including cognitive deficits and cardiac problems. We have developed practical, biology-
based mathematical models capable of systematically investigating the timing, order, dosing, and sequencing of
combination therapies to identify therapeutic regimens that can potentially maximize response while minimizing
toxicity. Preliminary results (both experimental and mathematical) reveal that alternating the order and dosing of
combination chemotherapy (doxorubicin) and targeted therapy (Herceptin) can significantly and synergistically
enhance response while reducing the chemotherapy dose by 50%. Furthermore, using optimal control theory,
we have identified therapeutic regimens suggesting we can achieve tumor control 1.6x faster without increasing
the amount of chemotherapy. We propose to develop the mathematical formalism that allows for systematically
determining, on a patient specific basis, therapeutic regimens that maximize tumor response and minimize side
effects. We then select the most promising options and test them experimentally against established treatment
regimens and test for superior outcomes and toxicity. We 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. We plan to achieve this goal with the following Specific Aims. Aim 1 will validate
mathematical predictions for maintaining tumor control with minimal chemotherapy dose by employing optimal
control theory to identify and biologically validate (with immunohistochemistry and overall tumor burden
measurements) the three most promising combination treatment strategies. Aim 2 will implement advanced
molecular imaging to quantify toxicity changes in critical organs during therapy by employing cardiac imaging of
membrane potential (18F-TTP+-PET) and brain imaging of microglia activation (TSPO, measured with 18F-DPA-
714-PET) to determine longitudinal differences between long-term effects in animals treated with the standard
and the optimized regimens. Completion of these aims will deliver a practical, experimental-computational
approach for identifying optimal treatment strategies in pre-clinical mouse models, and appropriate for
prospective testing in phase 1 clinical trials. As toxicity is the main dose-limiting factor in cancer treatments,
developing methods to control it will dramatically effect patient health.
