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, 55,300 new cases are expected in 2016. 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. Gemcitabine (GEM), first line therapy for advanced PC, is only modestly effective with a median survival of about 6 months in randomized clinical trials, The combination of GEM with different anticancer agents does not show significant survival advantage as compared with GEM alone. These 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. Triggering receptor expressed on myeloid cells (TREM-1), an inflammation amplifier, plays a role in PC progression. Expression of TREM-1 on tumor-associated macrophages (TAMs), is upregulated in patients with PC and correlates to disease severity. Recently, we demonstrated that a first-in-class TREM-1 inhibitory peptide GF9 in free form and bound to macrophage-targeted lipopeptide complexes that mimic human high density lipoproteins (GF9-HDL) inhibits tumor growth in animal models of PC. We also showed that blockade of TREM-1 inhibits release of cytokines and M-CSF in these animal models. The main hypothesis of this project is that a combination therapy that includes TREM-1 inhibitors and anticancer agents and targets cancer-related inflammation and tumor cells directly can synergistically improve survival of PC patients. We also hypothesize that this effect will be especially pronounced in PC patients with high intratumoral macrophage infiltration. Our preliminary studies strongly support this hypothesis. The long-term objective of the proposed project is to develop a novel combinatorial approach to efficiently target PC. The major goal of the Phase I study is to demonstrate that specific inactivation of TREM-1 with first-in-class inhibitory peptides in combination with GEM or nanoparticle albumin (nab)- bound paclitaxel (nab-PTX), another promising agent that directly targets cancer cells and is widely approved for the treatment of metastatic breast cancer (BC), synergistically suppresses PC tumor progression in animal model system and improves survival. Phase I specific aims are to: 1) evaluate effects and mechanisms of GF9-GEM and GF9-nab-PTX combinations in vitro, and 2) test GF9-GEM and GF9- nab-PTX combinations in two xenograft mouse models of PC. Non-toxic peptide GF9, which employs novel, ligand-independent mechanisms of TREM-1 inhibition, is anticipated to have less severe side effects. In order to increase peptide solubility, bioavailability and targeting to TAMs, we will utilize SignaBlok's proprietary HDL-based nanosystem for macrophage-targeted delivery of water insoluble and poorly water soluble drugs. We will use in vitro macrophage uptake assay to elucidate the molecular mechanisms of a putative receptor-mediated process of targeted delivery of GF9 to macrophages. We will optimize GF9 formulations based upon their stability, GF9 content, and macrophage uptake in vitro. We will use an in vitro cytotoxicity assay and immunoblot analysis to test proliferation of BxPC-3 and AsPC-1 cells as well as expression of phospho-stathmin and alpha-tubulin in the presence of GEM, nab-PTX or their combinations with GF9 formulations. We will use BxPC-3 and AsPC-1 mouse xenograft models to test the ability of GF9- GEM and GF9-nab-PTX combinations to synergistically inhibit tumor progression and promote survival as compared with GF9, GEM, and nab-PTX alone. Free GF9 and GF9-HDL will be tested. Comprehensive histology and immunohistochemistry studies will be performed to analyze angiogenesis, intratumoral macrophage infiltration, and potential non-specific toxicity for organ/tissues. It is anticipated that the proposed research will identify a novel anticancer combination approach that will set the stage for the development of new targeted combination therapies of PC, thereby leading to a higher survival rate of the patients. If successful, the Phase I will be followed in the 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. Final product will be the stable TREM-1- targeted lipopeptide formulation that can be used in combination therapies of PC patients to prolong their survival. Importantly, our recent data demonstrate that blockade of TREM-1 suppresses in vivo progression of not only PC but also non-small cell lung cancer (NSCLC). Thus, successful completion of Phase I will provide the proof of concept of the hypothesis that might be applicable to a variety of inflammation- associated tumors such as NSCLC, BC, colon cancer, and others.
Public Health Relevance Statement: Project Narrative 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 therapeutic combinations that could substantially improve treatment of this type of cancer, thereby leading to a higher survival rate of the patients.
Project Terms: absorption; Adenocarcinoma; Adverse effects; Albumins; alpha Tubulin; American Cancer Society; Amplifiers; angiogenesis; Animal Model; Animal Testing; Animals; anti-cancer therapeutic; anticancer activity; Antineoplastic Agents; Apolipoprotein A-I; base; Biological; Biological Assay; Biological Availability; Biological Models; cancer cell; Cancer Etiology; Cancer Patient; cancer therapy; cancer type; Cells; Cessation of life; Chemistry; chemotherapy; Colon Carcinoma; combinatorial; Combined Modality Therapy; comparative; Comparative Study; Complex; Controlled Study; cytokine; cytotoxicity; Data; Development; Dose; drug candidate; Drug Combinations; drug development; Evaluation; Excretory function; Female; Formulation; Future; gemcitabine; Goals; Half-Life; High Density Lipoproteins; Histology; Human; Immunoblot Analysis; Immunohistochemistry; Immunotherapy; improved; In Vitro; in vivo; Infiltration; Inflammation; inhibitor/antagonist; Interleukin-6; Investigational New Drug Application; lead series; Lesion; Ligands; macrophage; Macrophage Colony-Stimulating Factor; malignant breast neoplasm; Malignant neoplasm of pancreas; Malignant Neoplasms; Mediating; Metabolism; Metastatic breast cancer; Molecular; mouse model; Mus; Myeloid Cells; nanoparticle; nanosystems; Neoplasm Metastasis; neoplastic cell; Non-Small-Cell Lung Carcinoma; novel; Nude Mice; oncology; Operative Surgical Procedures; Organ; Oxides; Paclitaxel; Pancreas; Pancreatic carcinoma; Patients; peptide I; Peptides; Pharmaceutical Preparations; Pharmacology; Phase; phase 1 study; Plasma; Play; Process; Radiation therapy; Randomized Clinical Trials; receptor; reduce symptoms; Regimen; Research; Risk; Role; Severity of illness; sex; Site; Solubility; stathmin; Supervision; Survival Analysis; Survival Rate; targeted delivery; Testing; Tissues; Toxic effect; Toxicology; tumor; tumor growth; tumor progression; Tumor Promotion; United States; United States Food and Drug Administration; uptake; Water; Work; Xenograft Model; Xenograft procedure
