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.