BLRD Research Career Scientist Award Application

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7. Project Summary/Abstract Breast cancer (BC) is a genetically heterogeneous disease characterized by a mixed bag of cells. BC is broadly classified into luminal, HER2+, and basal-like based on differential expression of estrogen, progesterone, and HER-2 receptor proteins found inside and on the surface of the cancer cells. Basal-like, which is about 10- 20% of BC, tests negative for both hormone receptors and HER2, considered triple-negative BC (TNBC). TNBC is characterized by resistance to chemotherapy, acquisition of the stem character, and unfavorable prognoses due to its highly metastatic phenotype and more likely to recur (come back) after treatment. TNBC patients still have minimal treatment options, and chemotherapy is currently the only treatment available for metastatic TNBC. Although checkpoint inhibitors, including PD-1 and PD-L1, were found to elicit a response in TNBC in initial clinical trials, optimistic results have not yet emerged from these trials. Thus, the detection of appropriate targeted therapeutic regimens for TNBC therapy and prevention has remained an elusive challenge to many laboratories. During our program of identifying molecule(s) that could play an inhibitory role against TNBC, we found that CCN5/WISP-2, a matricellular 29-35 kDa protein and a member of the CCN family of growth factors, can modulate TNBC by imparting an inhibitory effect on tumor progression. We have demonstrated that induced expression of CCN5 or administration of human recombinant CCN5 protein in TNBC cells resulted in suppressing tumorigenic properties and induction of growth arrest. CCN5 is also known to inhibit the stemness, reverse the epithelial-mesenchymal transition (EMT) process, modulate CCN-family proteins, and activate ER-α in TNBC cells. Building on these exciting findings, we now propose creating and establishing an innovative approach to make CCN5 for a therapeutic implication of TNBC growth and metastasis by synthetic modification of CCN5 protein through the conjugation of polyethylene glycol (CCN5 PEGylation; PEG-CCN5). Our long-term goal is to translate these findings to the clinic to treat TNBC. In Aim 1, we will generate a PEGylated CCN5 derivative for TNBC therapy alone or in a combination of an anti-hormone or chemotherapy and Characterize the novel biomarkers to improve diagnosis and therapeutic outcome. In Aim 2, we will develop drug repurposing strategies for targeted activation of CCN5 for therapies to slow or arrest breast cancer initiation or progression in pre-clinical mouse models. Lastly, in Aim 3, by dissecting the effect of CCN5 on CCN-family proteins (CCN1 and CTGF), major tumorigenesis drivers in TNBC, we will determine how CCN5 governs reprogramming mesenchymal to epithelial transition (MET), apoptosis, tumor growth inhibition, and mouse survival. These studies are expected to identify an optimal PEGylated protein or a CCN5-activator that will inhibit TNBC growth and progression and sensitize TNBC cells to tamoxifen and Paclitaxel with minimal systemic toxicity or ill effects on healthy cells or organs. A novel mechanism of action of CCN5 will be found. Thus, these approaches should significantly advance knowledge on the therapeutic utility of CCN5 and its mechanistic insights in the suppression of TNBC. We will use multiple state-of-art techniques and our multi-disciplinary team's unique collective expertise to complete the goal.