Targeting leukemia inhibitory factor in pancreatic adenocarcinoma

ABSTRACT

Introduction

The Leukemia Inhibitory Factor (LIF) is a member of the interleukin-6 (IL-6) cytokine family. Known to induce differentiation of myeloid leukemia cells, evidence has accumulated supporting its role in cancer evolution through regulating cell differentiation, renewal, and survival. LIF has recently emerged as a biomarker and therapeutic target for pancreatic ductal adenocarcinoma (PDAC). The first in-human clinical trial has shown promising safety profile and has suggested a potential role for LIF inhibitor in combination regimen.

Areas covered

Herein, we summarize, discuss, and give an expert opinion on the role of LIF in PDAC promotion, and its potential role as a biomarker and target of anti-cancer therapy. We conducted an exhaustive PubMed search for English-language articles published from 1 January 1970, to 1 August 2022.

Expert opinion

PDAC carries a devastating prognosis for patients, highlighting the need for advancing drug development. The results of the phase 1 trial with MSC-1 demonstrated tolerability and safety but modest efficacy. Future research should focus on investigating LIF targets in combination with current standard-of-care chemotherapy, and immunotherapy can be a promising approach. Further, larger multicenter clinical trials are needed to define the use of LIF as a new biomarker in PDAC patients.

KEYWORDS:

• Leukemia inhibitory factor
• pancreatic ductal adenocarcinoma
• therapeutic target
• biomarker
• MSC-1
• EC359
• tumor microencironment

Article highlights

• LIF is secreted by pancreatic stellar cells (PSCs) and acts as an autocrine to activate PSCs, therefore triggering and maintaining the development of the dense and complex desmoplastic tumor microenvironment (TMN) in PDAC.

• Current clinical and preclinical data suggests that serum LIF is a promising biomarker to modulate pancreatic ductal adenocarcinoma (PDAC) diagnosis, disease progression, and prognosis; LIF exhibits superior sensitivity and specificity than other conventional biomarkers for PDAC, CA19-9, and CEA.

• MSC-1, a humanized immunoglobulin G monoclonal antibody, is a potent and specific LIF antagonist. The results of the phase 1 trial with MSC-1 demonstrated tolerability and safety but modest efficacy.

• EC359, a small-molecule LIFR inhibitor, alone and in combination with gemcitabine, efficiently reduced the expression of activated stromal markers in a novel cell line-derived 3D organoid model containing murine PDAC and PSCs.

• Studying LIF targets in combination with chemotherapies and immunotherapies can be a promising approach.

Declaration of interest

HM Babiker is a Paul Calabresi Scholar at the Mayo Clinic Cancer Center and acknowledges the K-12 grant Program, K12CA090628. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.