PROJECT SUMMARY/ABSTRACT Breast cancer prognosis varies among subtypes, and while molecularly targeted therapies haveimproved outcomes for estrogen receptor (ER)-expressing and HER2-overexpressing tumors, triple negativebreast cancers lacking these molecular targets, most of which also belong to the basal-like molecularly-definedsubtype, have a poorer prognosis. Matrix metalloproteinase-9 (MMP-9) has been implicated as a driver ofbreast cancer progression, metastasis, and angiogenesis, and offers a promising target for therapy, particularlyfor the basal-like breast cancer subtype. In earlier clinical trials of small molecule MMP inhibitors, lack ofselectivity of the inhibitors led to poor efficacy and serious side effects. We hypothesize that better results maybe attained using MMP-9 inhibitors derived from a natural protein inhibitor of MMP-9, tissue inhibitor ofmetalloproteinases-1 (TIMP-1). In this project, we propose to employ a variety of complementary methods toengineer TIMP-1 as a therapeutic protein for effective in vivo targeting of MMP-9 activity, and to evaluate thetherapeutic potential of resulting engineered TIMP-1 variants. In Aim 1, using insights from our recentlyreported crystal structures of MMP/TIMP complexes, we will take a novel directed evolution approach toenhancing the binding selectivity of TIMP-1 for MMP-9. In Aim 2, we will define TIMP-1 epitopes that areessential for MMP-independent signaling, and determine the feasibility of mutating TIMP-1 to eliminate theseoff-target activities while preserving MMP-9 and proMMP-9 affinity. In Aim 3, we will use our recently-developed methodology to PEGylate recombinant TIMP-1 variants, improving their pharmacokinetic profile,and evaluate these TIMP-1-based therapeutics in biologically relevant preclinical models of basal-like breastcancer. Our proposal is both conceptually and technically innovative in the combination of approaches towardgenerating novel MMP-9-targeted protein therapeutics. The proposed research is highly significant because ithas substantial potential to develop an entirely new class of drugs for breast cancer, targeting a key driver ofinvasion, metastasis, and angiogenesis. We expect selective MMP-9 inhibitors to be particularly useful fortreating HER2-negative, endocrine nonresponsive cancers for which other targeted therapies are ineffective.
|Effective start/end date||7/1/16 → 6/30/18|
- National Institutes of Health: $170,408.00