# First-in-class TREM-1 inhibitors in combination therapy for pancreatic cancer

> **NIH NIH R44** · SIGNABLOK, INC. · 2020 · $1,198,246

## Abstract

Project Summary/Abstract
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
S...

## Key facts

- **NIH application ID:** 10024061
- **Project number:** 5R44CA217400-03
- **Recipient organization:** SIGNABLOK, INC.
- **Principal Investigator:** Alexander B Sigalov
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,198,246
- **Award type:** 5
- **Project period:** 2017-09-21 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10024061

## Citation

> US National Institutes of Health, RePORTER application 10024061, First-in-class TREM-1 inhibitors in combination therapy for pancreatic cancer (5R44CA217400-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10024061. Licensed CC0.

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