Midkine as a therapeutic node in NF1-driven neuro‑oncology: Biology, biomarkers, and translational strategies

Area of Science:

• Neuro-oncology
• Cancer Biology
• Molecular Signaling

Background:

• Neurofibromatosis type 1 (NF1) disrupts RAS signaling, creating a pro-tumorigenic environment.
• This dysregulation contributes to optic pathway glioma (OPG) and malignant peripheral nerve sheath tumors (MPNST).
• Midkine (MDK), a growth factor re-expressed in cancers, promotes tumor progression and immune evasion.

Purpose of the Study:

• To explore the role of Midkine (MDK) as a biomarker and therapeutic target in NF1-associated neuro-oncology.
• To review mechanistic and translational evidence for MDK inhibitors in NF1 tumors.
• To propose combination strategies for MDK-targeted therapies.

Main Methods:

• Review of mechanistic and translational studies on MDK signaling in NF1.
• Analysis of MDK's engagement with receptor complexes (LRP1, PTPRZ1, ALK).
• Evaluation of MDK's impact on ERK, AKT, STAT signaling, angiogenesis, and immunosuppression.

Main Results:

• MDK amplifies oncogenic signaling pathways (ERK, AKT, STAT) in NF1 tumors.
• MDK promotes the formation of angiogenic and immunosuppressive tumor microenvironments.
• MDK is consistently re-expressed in NF1 malignancies and correlates with glioma grade.

Conclusions:

• The MDK axis represents a significant biomarker and therapeutic target for NF1-altered tumors.
• Combination therapies involving MDK inhibitors with MEK, SHP2, or immune checkpoint inhibitors show promise.
• Serum MDK and phospho-signaling can serve as pharmacodynamic markers for treatment efficacy.