Everolimus inhibits angiogenesis and lymphangiogenesis in TP53 mutant HNSCC via STAT3/HIF-1α/VEGF pathway (Head and neck squamous cell carcinoma “significantly inhibited”)

Medical Xpress / Impact Journals LLC / Oncotarget ^ | Feb. 9, 2023 | Md Maksudul Alam et al

[ConservativeMind]

TP53 mutant head and neck squamous cell carcinoma (HNSCC) patients exhibit poor clinical outcomes with 50–60% recurrence rates in advanced stage patients. In a recent phase II clinical trial, adjuvant therapy with everolimus (mTOR inhibitor) significantly increased 2-year progression-free survival in p53 mutated patients. TP53-driven mTOR activation in solid malignancies causes upregulation of HIF-1α and its target, downstream effector VEGF, by activating STAT3 cell signaling pathway.

In this recent study, Md Maksudul Alam investigated the effects of everolimus on the STAT3/HIF-1α/VEGF pathway in TP53 mutant cell lines and xenograft models.

"The role of mTOR inhibitors (mTORi) as potent growth inhibitory and antiangiogenic/anti-lymphangiogenic agents in HNSCC is well established," the paper explains. "Moreover, mTORi significantly suppressed baseline invasiveness of endothelial and HNSCC tumor cells. However, the underlying molecular mechanisms for mutant p53 protein-mediated activation of the mTOR pathway which drive the oncologic processes in HNSCC are yet to be elucidated."

Treatment with everolimus significantly inhibited cell growth in vitro and effectively reduced the growth of TP53 mutant xenografts in a minimal residual disease (MRD) model in nude mice. Everolimus treatment was associated with significant downregulation of STAT3/HIF-1α/VEGF pathway in both models.

Further, treatment with everolimus was associated with attenuation in tumor angiogenesis and lymphangiogenesis as indicated by decreased microvessel density of vascular and lymphatic vessels in HN31 and FaDu xenografts. Everolimus downregulated the STAT3/HIF-1α/VEGF pathway to inhibit growth and in vitro tube formation of HMEC-1 (endothelial) and HMEC-1A (lymphatic endothelial) cell lines.

[ConservativeMind]

Everolimus is an inexpensive cancer drug and appears to cost under $260 at multiple pharmacies in my area.

[ConservativeMind]

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[HollyB]

A friend of mine’s husband just passed from this. Of all the cancer’s I’ve come across, it was the most resistant I’ve seen. It started as a stage 1. And it kept coming back. Till it was everywhere.

[ConservativeMind]

A truly sad and scary thing to hear.

I am saddened for the man and his family.

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Your prayers would mean a lot. It happened a week ago and left behind his wife of over 20 years and 3 children under 18.