THE DEVELOPMENT OF NOVEL THERAPEUTICS IN PANCREATIC AND BREAST CANCERS: POTENTIAL ROLE OF MUC1

Pancreatic ductal adenocarcinoma (PDA) is the 4th leading cause of cancer-related deaths in the US, and breast cancer (BC) contributes to ~40,000 deaths annually. The development of novel therapeutic agents for improving patient outcome is of paramount importance. Importantly, MUC1 is a mucin glycoprotein expressed on the apical surface of normal glandular epithelia but is over expressed and aberrantly glycosylated in >80% of human PDA and in >90% of BC. In the present study, we first utilize a model of PDA that is Muc1-null in order to elucidate the oncogenic role of MUC1. We show that lack of Muc1 significantly decreased proliferation, invasion, and mitotic rates both in vivo and in vitro. Next, we evaluated the anticancer efficacy of oncolytic virus (OV) therapy that utilizes viruses to kill tumor cells. The oncolytic potential of vesicular stomatitis virus (VSV) was analyzed in a panel of human PDA cell lines in vitro and in vivo in immune compromised mice. Our results demonstrate that VSV has potential as an OV against human PDA cells. Next, we tested oncolytic VSV in an immunocompetent mouse model. In agreement with our in vitro results, in vivo administration of live VSV resulted in the significant growth reduction of PDA tumors, with an enhanced efficacy when used in combination with a chemotherapeutic drug, gemcitabine. Finally, we tested a MUC1 specific tumor vaccine with targeted inhibition of immune suppression in a model of BC. Our results indicate that Indomethacin in combination with a MUC1 vaccine resulted in a significant reduction in tumor burden. These data, therefore, may have implications in the future design of MUC1-targeted therapies for BC and OV therapies for PDA

Systemic neutralization of IL-17A significantly reduces breast cancer associated metastasis in arthritic mice by reducing CXCL12/SDF-1 expression in the metastatic niches

BACKGROUND: IL-17A is a pro-inflammatory cytokine that is normally associated with autoimmune arthritis and other pro-inflammatory conditions. Recently, IL-17A has emerged as a critical factor in enhancing breast cancer (BC)-associated metastases. We generated immune competent arthritic mouse models that develop spontaneous BC-associated bone and lung metastasis. Using these models, we have previously shown that neutralization of IL-17A resulted in significant reduction in metastasis. However, the underlying mechanism/s remains unknown. METHODS: We have utilized two previously published mouse models for this study: 1) the pro-arthritic mouse model (designated SKG) injected with metastatic BC cell line (4T1) in the mammary fat pad, and 2) the PyV MT mice that develop spontaneous mammary gland tumors injected with type II collagen to induce autoimmune arthritis. Mice were treated with anti-IL-17A neutralizing antibody and monitored for metastasis and assessed for pro-inflammatory cytokines and chemokines associated with BC-associated metastasis. RESULTS: We first corroborate our previous finding that in vivo neutralization of IL-17A significantly reduced metastasis to the bones and lungs in both models. Next, we report that treatment with anti-IL17A antibody significantly reduced the expression of a key chemokine, CXCL12 (also known as stromal derived factor-1 (SDF - 1)) in the bones and lungs of treated mice. CXCL12 is a ligand for CXCR4 (expressed on BC cells) and their interaction is known to be critical for metastasis. Interestingly, levels of CXCR4 in the tumor remained unchanged with treatment. Consequently, protein lysates derived from the bones and lungs of treated mice were significantly less chemotactic for the BC cells than lysates from untreated mice; and addition of exogenous SDF-1 to the lysates from treated mice completely restored BC cell migration. In addition, cytokines such as IL-6 and M-CSF were significantly reduced in the lung and bone lysates following treatment. The data presented suggests that systemic neutralization of IL-17A can block the CXCR4/SDF-1 signaling pathway by reducing the expression of SDF-1 in the metastatic niches and significantly reducing metastasis in both mouse models. CONCLUSION: In our model, neutralization of IL-17A regulates SDF-1 expression in the metastatic niches either directly or indirectly via reducing levels of IL-6 and M-CSF