According to the American Cancer Society, 1 in 8 women in the U.S. will develop breast cancer at some point in their life and 15-20% of these women will have triple negative breast cancer (TNBC), an aggressive subtype of breast cancer that lacks the three receptors (ER, PR, HER2) that current drug treatment targets (tamoxifen, Herceptin). Because of its aggressive nature and lack of effective treatment that specifically targets TNBC, it is responsible for 66% of all breast-cancer deaths. The only treatment options involve chemotherapeutics that destroy healthy tissue by targeting replicating cells. Being able to target TNBC tumors directly would reduce toxicity associated with these drugs and decrease mortality from TNBC, one of NeuLink?s long-term goals. Recently, folate receptor alpha (FRA) was found to be expressed on 80% of TNBC tissue with high expression correlating with poor prognosis, suggesting a target for treating TNBC. Preliminary data generated at Wayne State University demonstrates the binding of a novel FRA-binding molecule to FRA-expressing TNBC cells. Upon binding, this molecule is able to recruit and activate neutrophils (PMNs), the major white blood cell in humans, to destroy TNBC cells. These findings suggest the use of a molecule of this type could effectively kill breast tumor cells and thus represents a promising effective targeted therapeutic treatment for TNBC. The hypothesis for this Phase I STTR is that a novel FRA-binding molecule (NEU1) will stimulate PMNs, by binding to its Fc?R1 receptor, to specifically destroy TNBC cells. To test this hypothesis, the following specific aims are proposed: 1) Determine which of 3 NEU1 variants using 1 of 3 IgA Fc fragments will activate PMNs to kill > 50% of human TNBC cell subtypes and 2) Determine which NEU1 variants will decrease mean tumor volume by > 50% in Fc?R1-expressing xenograft models.
In Aim 1, 3 NEU1 variants will be synthesized and their ability to activate PMNs to kill basal-like (BL) or mesenchymal-like (ML) subtypes of human TNBC cells (cell lines or clinical isolates) by FRA binding and cross-linking of Fc?R1 on PMN?s will be measured and compared. PMN-mediated ADCC will be tested in a 51Cr-release assay and confirmed by myeloperoxidase (MPO) activity.
For Aim 2, these NEU1 variants will be tested for ability to inhibit tumor growth in xenograft models using the highest NEU1-responding TNBC cells (within both BL and ML subtype as well as clinical isolates from Aim 1). Assessment of cancer cell viability/apoptosis (Ki-67, active caspase-3) and PMN activation (MPO, CD68, Ly6G) within tumors will be determined by IHC. NEU1 stability in serum and Fc?R1 specificity using isolated mouse PMNs will also be confirmed. There is a clear need in the market for drugs specifically targeting TNBC for which no therapy is approved. To successfully bring NEU1 to market as an orphan drug, NeuLink, together with their advisory board and small business consultants, will guide NEU1 from pre-clinical to clinical trials. NeuLink?s overall strategy after IND filing is to complete Phase I clinical trials and either 1) establish a strategic alliance with a pharmaceutical partner or 2) have NeuLink acquired.
/Public Health Relevance Statement NeuLink Inc. plans to develop a drug that will elicit the immune system in a novel way to target and kill triple negative breast cancer cells. Since triple negative breast cancer is an aggressive subtype of breast cancer with a high mortality rate, this drug would be beneficial in reducing mortality associated with this aggressive disease.
| Frontera, Eric D; Khansa, Rafa M; Schalk, Dana L et al. (2018) IgA Fc-folate conjugate activates and recruits neutrophils to directly target triple-negative breast cancer cells. Breast Cancer Res Treat 172:551-560 |
