Engineering novel methods to study metastases and reduce systemic treatment toxicity in breast cancer patients - Project Summary
Preventative screening has brought hope to many women diagnosed with breast cancer (BrCa), as there are
currently 2.5 million BrCa survivors. Yet for every life saved, one in three women will suffer from medical
interventions that offer little or no benefit but still carry all the potential for harm. African American (AA) women
carry the highest BrCa burden of any racial or ethnic group in the U.S. A variety of factors (economic, genetic,
and behavioral) contribute to the high rate of BrCa mortality among AAs including a higher prevalence of triple
negative breast cancer (TNBC) and obesity. TNBC currently has no targeted therapies, thus systemic chemo-
therapy is the only option, and survival is poor. Compared to systemic chemotherapy, localized delivery offers
the greatest potential impact as a therapeutic option against early stage breast cancer with isolated disease.
Local delivery of chemotherapy could sterilize the surgical tissue margin and thereby reduce the incidence of
loco-regional tumor recurrence. Local delivery would also effectively extend the surgical margins to include the
depth of therapeutic agents penetrating into the surrounding tissue. Few studies have examined if local
treatment of the primary tumor environment could prevent metastasis from occurring. To this end, we propose
a trans-disciplinary study that offers a two-prong approach to evaluate the efficacy of local delivery of chemo-
therapeutics to BrCa. First, we propose highly translational studies enabled by a recently pioneered thermo-
responsive injectable drug delivery system, “LiquoGel™”, which delivers therapeutics by independent modes
(entrapment and covalent linkage) directly to the tumor site. The distinguishing feature is this system's flexibility
to accommodate a modality of drugs eliminating the need to synthetically re-design each time the drug
candidate is altered. Second, we balance our translational studies with mechanistic molecular studies focused
on determining whether reducing the stiffness of the tumor-associated extracellular matrix via exogenous
biologicals alters BrCa metastases. This is critical to address as matrix-degrading therapies to enhance intra-
tumor drug delivery are currently entering clinical trials. Our hypothesis is that drug delivery by injection,
entrapment, and controlled release into breast lesions will stop cancer growth, enhance tumor eradication, and
decrease toxicities and mortalities compared to systemic chemotherapeutics. In Aim 1, we will evaluate the
efficacy of LiquoGel™ enabled chemo-delivery in pre-clinical in vitro models. In Aim 2, we will administer
localized chemotherapy with(out) LiquoGel™ and evaluate cell death, tumor regression, and metastasis
compared to systemic chemotherapeutic delivery in pre-clinical in vivo models. Last, Aim 3 we will evaluate the
effect of LiquoGel™ enabled localized delivery of matrix-degrading biologicals on BrCa metastasis. Our studies
have strong potential to lead to clinical trails that may reduce systemic toxicities and associated mortalities
BrCa patients. Further, this AREA grant will provide an opportunity for underrepresented students to receive
intensive biomedical research training, attend meetings, and become co-authors on research publications.
