Carcinoma of the pancreas, or pancreatic cancer (PC), is the fourth leading cause of cancer-related death in the United States. According to the American Cancer Society, 44,030 new cases and 37,660 deaths are expected in 2011. Despite advances in therapy, the 5-year survival rate is less than 4%. Current treatments of PC include surgery, radiation therapy, chemotherapy, and immunotherapy but they all only slightly prolong survival or relieve symptoms in patients with PC. The limitations in efficacy of available treatments highlight the need for new treatments. Pancreatic inflammation is known to increase the risk of PC. High macrophage infiltration into the tumor mass correlates with the promotion of tumor growth and metastasis development. As found recently, triggering receptor expressed on myeloid cells (TREM-1), an inflammation amplifier, plays a role in PC progression. Expression of TREM-1 on myeloid cells, including tumor- associated macrophages (TAMs), in patients with PC is upregulated and correlates to disease severity. We hypothesize that TREM-1 inhibition can improve survival of PC patients. Current approaches to TREM-1 suggest to block binding of ligand to TREM-1. The true nature of the TREM-1 ligand is not yet known, highly increasing the risk of failure of these approaches in clinical development. The long-term objective of the proposed project is to develop a novel, ligand-independent approach to a TREM-1-targeted treatment of PC. The major goal of the Phase I study is to demonstrate that specific inactivation of TREM-1 with novel inhibitory peptides suppresses PC tumor progression in animal model system and improves survival. Phase I specific aims are to: 1) generate and characterize injectable formulations of TREM-1 inhibitory peptides with different half-lives, and 2) test the TREM-1 inhibitory peptide formulations in a mouse model of PC. The peptides will be designed using SignaBlok's proprietary model of TREM-1 signaling. These non- toxic peptides employ novel, ligand-independent mechanisms of action and are anticipated to have less severe side effects. In order to increase peptide solubility, bioavailability and targeting to TAMs, we will utilize SignaBlok's proprietary nanosystem for macrophage-targeted delivery of water insoluble and poorly water soluble drugs. We will use a BxPC-3 xenograft mouse model of PC to test the ability of the peptides in free and particulate forms to inhibit cancer progression and promote survival. It is anticipated that the proposed research will identify novel anticancer lead compounds that will set the stage for the development of new targeted therapies of PC, thereby leading to a higher survival rate of the patients. If successful, the Phase I will be followed in te Phase II by toxicology, absorption/ disposition/ metabolism/ excretion (ADME), pharmacology and chemistry/ manufacturing/ control (CMC) studies, filing an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) and subsequent evaluation in humans. Importantly, TREM-1 may play a role in the progression of not only PC but also other tumors. Thus, successful completion of Phase I will provide the proof of concept of the hypothesis that might be applicable to a variety of tumors.
Pancreatic cancer is the fourth leading cause of cancer-related death in the United States, and the 5-year survival rate is less than 4%. Current treatments are substantially ineffective and only slightly prolong survival or relieve symptoms in the cancer patients. The proposed research is expected to result in the development of novel anticancer therapeutics that could substantially improve treatment of this type of cancer, thereby leading to a higher survival rate of the patients.
| Shen, Zu T; Sigalov, Alexander B (2017) Novel TREM-1 Inhibitors Attenuate Tumor Growth and Prolong Survival in Experimental Pancreatic Cancer. Mol Pharm 14:4572-4582 |
