LIF

Detailed Information

In 1987, Donald Metcalf's laboratory at the Walter and Eliza Hall Institute (WEHI), Royal Melbourne Hospital, Australia, isolated a protein from mouse Krebs sarcoma cell culture medium that could induce differentiation of mouse M1 myeloid leukemia cells. Because this protein demonstrated inhibitory effects on M1 myeloid leukemia cell proliferation, it was named Leukemia Inhibitory Factor.

Leukemia Inhibitory Factor (LIF) is an immunosuppressive cytokine associated with tumor growth and metastasis. LIF can be expressed in various cells, including activated T cells, monocytes, glial cells, liver fibroblasts, bone marrow stromal cells, embryonic stem cells, thymic epithelial cells, and many others. It is an IL6-class cytokine that affects cell growth by inhibiting differentiation. LIF promotes an immunosuppressive tumor microenvironment and impedes the recruitment of cytotoxic CD8+ T cells. LIF overexpression is associated with poor prognosis and chemotherapy resistance in multiple tumor types, including pancreatic ductal adenocarcinoma (PDAC).

Figure 1. LIF/LIFR oncogenic signaling network. (Viswanadhapalli S, et al., 2021)

LIF can phosphorylate STAT3 through several reactions. The phosphorylated STAT3 then forms dimers, translocates to the nucleus, and activates target gene transcription. The LIF-JAK/STAT3 pathway is recognized in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), ovarian cancer, and non-small cell lung cancer (NSCLC). Additionally, LIF has been shown to activate other signaling pathways such as YAP/TEAD and AKT/mTOR.

In recent years, multiple studies have shown that LIF is a promising new biomarker and therapeutic target for cancer. In 2019, Nature published a landmark original paper titled "Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring." Researchers discovered a key factor—Leukemia Inhibitory Factor (LIF)—that mediates signaling between pancreatic cancer cells and stellate cells, revealing LIF's important biological function in pancreatic tumor development and highlighting its promising prospects as an effective therapeutic target and tumor diagnostic marker. In 2021, A. Italiano's team from the University of Bordeaux Medical School published important findings in Annals of Oncology, discovering that LIF in the blood is a novel biomarker associated with immunotherapy efficacy. Moreover, LIF may be a key factor in cancer resistance to immunotherapy, suggesting that combining LIF inhibitors with immune checkpoint blockers (ICBs) could enhance cancer treatment efficacy.

The Treatment Dilemma of Pancreatic Cancer

Pancreatic cancer is a highly malignant digestive tract tumor that is difficult to diagnose and treat. Approximately 90% are ductal adenocarcinomas (PDAC) originating from ductal epithelium, dubbed the "king of cancers" due to its lowest survival rate and extremely short survival period. The median survival time without any treatment is only about 4 months, with nearly three-quarters of patients dying within one year of diagnosis. The prognosis is extremely poor, with high rates of postoperative recurrence and metastasis, and an overall 5-year survival rate of less than 8%. Low diagnostic rates and strong drug resistance make it one of the malignant tumors with the worst prognosis.

Early pancreatic cancer lacks specific symptoms and is usually diagnosed at an advanced stage when metastasis has already occurred. Additionally, advanced pancreatic cancer exhibits strong resistance to chemotherapy drugs and is insensitive to radiation therapy. To date, treatment outcomes for pancreatic cancer have been disappointing. Therefore, developing effective targeted drugs and highly sensitive biomarkers for early detection is considered a potentially effective approach to conquering this malignant tumor and has become the focus of scientists in the field.

With the revelation of LIF's important biological function in pancreatic tumors and its feasibility as a therapeutic target, pancreatic cancer patients may hopefully emerge from the predicament of low survival rates and welcome a new dawn of life.

LIF-Targeted Drug Development: Only Two Products in Clinical Stages Globally

After discovering LIF's key role in pancreatic cancer cell communication, in January 2020, the first anti-LIF antibody (MSC-1) developed by Canadian biopharmaceutical company Northern Biologics was approved for Phase I clinical trials in pancreatic cancer. In August 2021, global pharmaceutical leader AstraZeneca acquired MSC-1 and launched a Phase II clinical trial of AZD0171 (MSC-1) in combination with anti-PD-L1 monoclonal antibody durvalumab and chemotherapy (gemcitabine and nab-paclitaxel) as first-line treatment for pancreatic ductal adenocarcinoma (PDAC). Currently, no immunotherapy has been approved for PDAC globally. This study is an open-label, single-arm, multi-center Phase II study that plans to enroll 115 subjects and is expected to conclude in November 2023.

At the 2022 American Association for Cancer Research (AACR) Annual Meeting, AstraZeneca announced the latest research results for the humanized monoclonal antibody AZD0171, which specifically binds to LIF and blocks downstream signaling. In a Phase I dose-escalation study (NCT03490669), AZD0171 monotherapy demonstrated manageable safety and prevented cancer progression in 34.2% of patients with advanced solid tumors. According to preclinical data, AZD0171 may stimulate anti-tumor immune responses, and when used in combination with the PD-L1 inhibitor durvalumab, it can prolong this response and overcome peripheral tolerance in patients with metastatic PDAC.

According to Jacobio's website, LIF is an attractive target for treating KRAS-driven tumors (such as pancreatic cancer and colorectal cancer). Research indicates that 90% of pancreatic ductal adenocarcinoma (PDAC) patients carry KRAS mutations, have a poor prognosis, and are unresponsive to targeted therapy. In PDAC, the oncogene KRAS specifically induces LIF expression through the MEK/ERK cascade, and LIF, through autocrine action, further promotes the carcinogenic ability of KRAS-mutated tumors and enhances PDAC's resistance to chemotherapeutic drugs. In other words, inhibiting LIF is an important potential approach for treating KRAS-mutated pancreatic cancer. Jacobio has multiple research projects on the KRAS signaling pathway, including SHP2 inhibitors (JAB-3312 and JAB-3068), KRAS G12C inhibitor glesatinib (JAB-21822), and KRAS multi-inhibitor (JAB-23400), which could potentially explore more treatment options through internal combination therapy in the future.

Conclusion

From 2013 to 2022, in just a few short years, LIF has progressed from initial blind screening to Phase II clinical trials. Anti-LIF antibody therapy can also be combined with other treatment methods, such as immunotherapy, for treating pancreatic cancer. We look forward to more pharmaceutical companies entering the field to develop LIF-targeted therapies, bringing new hope for treating pancreatic cancer, the "king of cancers."