Carcinoma of the pancreas, or pancreatic cancer (PC), is the third leading cause of cancer-related death in the US. Despite recent advances in the current treatments that include surgery, radiation therapy, chemo- and immunotherapy, the 5-year survival rate is as low as 9%. The long-term goal of this project is to develop a first-in-class, efficient and well tolerable therapy for PC to be used standalone or with standard chemo- and/or immune checkpoint blockade (ICB) treatments as induction and/or maintenance therapy. In PC patients, overexpression of TREM-1 correlates with poor survival, implicating TREM-1 as a new target. Current TREM-1 blockers all attempt to block binding of uncertain ligand(s) to TREM-1. To reduce risk of failure in the clinic, we developed a ligand-independent TREM-1 inhibitory peptide GF9 that can be formulated into macrophage-specific lipopeptide complexes (LPC) to improve its half-life and targeting. In Phase I, we showed that: 1) In suppressing tumor growth and improving survival, TREM-1 blockade using GF9-LPC in PC xenografts is as effective as a standard chemo: gemcitabine (GEM)+nab-paclitaxel (PTX) combo, and 2) addition of GF9-LPC to GEM+nab-PTX sensitizes the tumor to chemo and triples survival rate of mice. Mechanistically, in PC xenografts, GF9-LPC reduces tumor-associated macrophage (TAM) infiltration and serum level of CSF1. As shown by others, in mice with hepatocellular carcinoma, blocking TREM-1+ TAMs by GF9 reverses immunosuppression and overcomes anti-PDL1 resistance. The goal of this project is to further develop GF9 therapy for PC to be used as an induction/maintenance therapy alone or with first-line standard chemo treatments (GEM+nab-PTX) and/or ICB (anti-PD1/PDL1). Phase II aims are to: 1) generate and test rationally designed manufacturing friendly GF9 sequence- based formulations with favorable pharmacokinetic profile and high efficacy in vivo and select the lead (sub-aim ? develop an assay to analyze GF9 in blood in PK studies), 2) test the lead in combination with GEM+nab-PTX in xenograft and syngeneic mouse models of PC, 3) test the lead in combination with anti- PD1/PDL1 in syngeneic mouse models of PC, and 4) test the lead in the non-clinical toxicology studies. Histology/IHC studies will be performed to analyze intratumoral macrophage infiltration as well as angiogenesis, tumor cell proliferation and death. Cytokines including CSF-1 will be analyzed. Follow-up Phase IIb will include other administration and combination (eg, radiation+GF9; anti-CSF-1R+ GF9) regimen, TOX, ADME, CMC and other IND-enabling studies. Final manufacturing friendly product will represent safe and stable PC therapy. Its anticipated safety is supported by good tolerability of SignaBlok's GF9 sequence-based formulations by long term-treated healthy, cancer and arthritic mice. Prototypes of SignaBlok's LPC were safe and well tolerated in clinical trials. TREM-1 blockade using peptide LR12 by SignaBlok's top competitor (Inotrem, France) was safe and well tolerated in healthy and septic subjects.

Public Health Relevance

Pancreatic cancer is the third leading cause of cancer-related death in the United States, and the 5-year survival rate is less than 9%. 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, first-in-class therapeutic combinations that could substantially improve treatment of this type of cancer, thereby leading to a higher survival rate of the patients and higher quality of their life.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44CA217400-02
Application #
9902597
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Weber, Patricia A
Project Start
2017-09-21
Project End
2021-08-31
Budget Start
2019-09-25
Budget End
2020-08-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Signablok, Inc.
Department
Type
DUNS #
962285263
City
Worcester
State
MA
Country
United States
Zip Code
01604