Phase I, first-in-human study of MSC-1 (AZD0171), a humanized anti-leukemia inhibitory factor monoclonal antibody, for advanced solid tumors

Borazanci, Erkut; Schram, Alison M.; Garralda, E.; Braña, Irene; Villar, M. Vieito; Spreafico, Anna; Oliva, Marc; Lakhani, Nehal; Hoffman, Kimberly; Hallett, Robin; Maetzel, D.; Hua, Fei; Hilbert, James; Giblin, Patricia; Anido, Judit; Kelly, A.; Vickers, P.J.; Wasserman, Robert; Seoane, Joan; Siu, L.; Hyman, David M.; Hoff, D.V.; Tabernero, Josep

doi:10.1016/j.esmoop.2022.100530

Cited by 17 publications

(7 citation statements)

References 31 publications

(59 reference statements)

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“…Interestingly, MSC-1 (a humanized monoclonal antibody that binds to LIF) treatment drove TAMs to obtain antitumor and proinflammatory function in syngeneic colon cancer mouse models 56 . Moreover, phase I clinical trial of MSC-1 for advanced solid tumors showed that the treatment increased M1:M2 ratio and decreased levels of STAT3 phosphorylation 57 . Our studies using EC359 also demonstrated the beneficial effect of blocking LIF signaling in modulating TME including enhanced recruitment of cytotoxic T cells and increased M1:M2 ratio.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of the LIF/LIFR autocrine loop reveals vulnerability of ovarian cancer cells to ferroptosis

Ebrahimi,

Viswanadhapalli,

Pratap

et al. 2024

npj Precis. Onc.

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Of all gynecologic cancers, epithelial-ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard surgical and cytotoxic therapy experience disease recurrence. The precise mechanism by which leukemia inhibitory factor (LIF) and its receptor (LIFR) contribute to the progression of OCa remains unknown. Analysis of cancer databases revealed that elevated expression of LIF or LIFR was associated with poor progression-free survival of OCa patients and a predictor of poor response to chemotherapy. Using multiple primary and established OCa cell lines or tissues that represent five subtypes of epithelial-OCa, we demonstrated that LIF/LIFR autocrine signaling is active in OCa. Moreover, treatment with LIFR inhibitor, EC359 significantly reduced OCa cell viability and cell survival with an IC50 ranging from 5-50 nM. Furthermore, EC359 diminished the stemness of OCa cells. Mechanistic studies using RNA-seq and rescue experiments unveiled that EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system. Using multiple in vitro, ex vivo and in vivo models including cell-based xenografts, patient-derived explants, organoids, and xenograft tumors, we demonstrated that EC359 dramatically reduced the growth and progression of OCa. Additionally, EC359 therapy considerably improved tumor immunogenicity by robust CD45+ leukocyte tumor infiltration and polarizing tumor-associated macrophages (TAMs) toward M1 phenotype while showing no impact on normal T-, B-, and other immune cells. Collectively, our findings indicate that the LIF/LIFR autocrine loop plays an essential role in OCa progression and that EC359 could be a promising therapeutic agent for OCa.

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Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of the LIF/LIFR autocrine loop reveals vulnerability of ovarian cancer cells to ferroptosis

Ebrahimi,

Viswanadhapalli,

Pratap

et al. 2024

npj Precis. Onc.

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“…The most common treatment-related adverse events are fatigue and nausea. 95 It is possible that MSC-1 is a therapeutic candidate for CKD patients. Besides, a couple of small molecules targeting LIF/LIFR axis including EC330, EC357, EC363 have been developed (US patent 10,053,485).…”

Section: Discussionmentioning

confidence: 99%

Leukemia inhibitory factor is a therapeutic target for renal interstitial fibrosis

Xu¹,

Yang²,

Chen³

et al. 2022

eBioMedicine

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“…In a phase 1 trial, a slight prolonged progression-free survival was observed along with an M2 to M1 macrophage shift. Although ani-tumor activity was relatively small, the TME modulation observed in patients with previously treated PDAC was promising, prompting a further phase 2 clinical trial [61].…”

Section: Future Prospectsmentioning

confidence: 99%

Modulation of the Tumor Stroma and Associated Novel Nanoparticle Strategies to Enhance Tumor Targeting

Haze,

Sier,

Vahrmeijer

et al. 2024

Surgeries

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Growth of malignant cells in solid tumors induces changes to the tumor microenvironment (TME). These changes result in promotion of tumor growth, invasion, and metastasis, but also in tumor resistance to drugs and radiotherapy. The enhanced permeability and retention (EPR) effect in neo-angiogenic tumor tissue enables the transport of therapeutic molecules from the circulation into the tumor, but studies show that further diffusion of these agents is often not sufficient for efficient tumor eradication. Despite the hyperpermeable vasculature facilitating the delivery of drugs and tracers, the high density of stromal cells and matrix proteins, in combination with the elevated interstitial fluid pressure in the microenvironment of solid tumors, presents a barrier which limits the delivery of compounds to the core of the tumor. Reversing the cancer-cell-induced changes to the microenvironment as well as novel nanoparticle strategies to circumvent tumor-induced stromal changes have therefore been suggested as potential methods to improve the delivery of therapeutic molecules and drug efficacy. Strategies to modulate the TME, i.e., normalization of tumor vasculature and depletion of excessive stromal proteins and cells, show promising results in enhancing delivery of therapeutic compounds. Modulation of the TME may therefore enhance the efficacy of current cancer treatments and facilitate the development of novel treatment methods as an alternative for invasive resection procedures.

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Phase I, first-in-human study of MSC-1 (AZD0171), a humanized anti-leukemia inhibitory factor monoclonal antibody, for advanced solid tumors

Cited by 17 publications

References 31 publications

Pharmacological inhibition of the LIF/LIFR autocrine loop reveals vulnerability of ovarian cancer cells to ferroptosis

Pharmacological inhibition of the LIF/LIFR autocrine loop reveals vulnerability of ovarian cancer cells to ferroptosis

Leukemia inhibitory factor is a therapeutic target for renal interstitial fibrosis

Modulation of the Tumor Stroma and Associated Novel Nanoparticle Strategies to Enhance Tumor Targeting

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