Chat GPT Q&A, page-409

feel free to post your thoughts Dr B

Theremay be a compelling connectionbetweenVEGF,FTO inhibition, and theanti-cancer activity of RC220 (Bisantrene)—though it'sindirect, mechanistically complex, and context-dependent.

Here’s a breakdown of how they might relate, based on known biology and RC220’s emerging mechanisms:

1.FTO inhibition → m6A RNA methylation → Suppression of oncogenes including VEGF

• FTO (Fat Mass and Obesity-associated protein)is anm6A RNA demethylase.

• In many cancers,FTO overexpressionleads to thestabilization of oncogenic transcriptsby demethylating m6A-modified mRNAs.

• One such transcript isVEGFA mRNA.

✅Evidence:

• Studies have shown thatFTO inhibition increases m6A levels on VEGFA mRNA, leading toreduced stability and translation, and thuslower VEGF proteinlevels.

• Result:Reduced angiogenesis, limiting tumour vascularization and growth.

“FTO promotes angiogenesis by stabilizing VEGFA mRNA in certain cancers. Its inhibition reduces VEGF levels and tumor angiogenesis.” —Cell Reports, 2019; Nature Communications, 2020

2.RC220 as an FTO inhibitor → Anti-angiogenic potential via VEGF downregulation

• RC220 has been shown to be apotent FTO inhibitorin Race Oncology's studies.

• Thus, RC220 may indirectlydownregulate VEGF, contributing to:

  • Tumour growth suppression

  • Inhibition of metastasis

  • Reduced tumour hypoxia-induced resistance

Implication: RC220 may not just be cytotoxic—it maystarve tumours by suppressing blood vessel formationvia VEGF downregulation.

3.Cancer contexts where FTO and VEGF co-drive pathology

• AML,glioblastoma,lung cancer, and somemelanomasare examples where:

  • FTO is highly expressed

  • VEGF is critical to tumor survival

• In these,RC220 may exert dual benefit:

  • Induce apoptosis/cell cycle arrest

  • Reduce VEGF-driven angiogenesis

4.Senescence, VEGF, and inflammation(RC220 and vascular protection)

• VEGF is often secreted bysenescent and inflamed cells(via theSASP– senescence-associated secretory phenotype).

• If RC220modulates senescence, it may also reduce pathologicalVEGF expressionfromnon-cancerous cells, limitingoff-target pro-tumour inflammationandcardiovascular damage.

Summary Table

	Pathway	RC220 Role	VEGF Impact	Anti-Cancer Benefit
1	FTO–VEGF axis	Inhibits FTO	↓ VEGF mRNA stability	↓ Angiogenesis
2	Tumour vasculature	May suppress via VEGF modulation	↓ Blood vessel formation	↓ Growth, metastasis
3	Senescence modulation	Alters SASP profile	↓ Paracrine VEGF from stromal cells	↓ Tumour-supportive microenvironment
4	Immunomodulation	VEGF suppresses immune cell infiltration	↓ VEGF may enhance M1 macrophage response	↑ Anti-tumour immunity

Final Thoughts

WhileVEGF is not RC220's primary target, itsFTO inhibitionmay meaningfullydownregulate VEGFandenhance anti-cancer efficacyby:

• Suppressing angiogenesis

• Normalizing tumour vasculature

• Reducing senescence-associated inflammation

• Possibly improving immune infiltration

Let me know if you’d like a schematic to illustrate this cascade or references from recent VEGF–FTO studies

DYOR might be a hallucination.