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Fibroblast Growth Factor Receptor Functions in Glioblastoma

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(@manuone)
Joined: 6 years ago
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678715/

https://eprints.ucm.es/45017/

http://digital.csic.es/bitstream/10261/116805/1/J.%20of%20Translational%20Medicine_G.%20Gim%C3%A9nez%20Gallego_2015.pdf

I think that the inhibition of fibroblast growth facotr can be an important target.
It seems directly related to inflammation through COX and angiogenesis.
They identify the drug Calcium Dobesilate ((2,5-dihydroxyphenyl sulfonate, DHPS) as a potent FGF inhibitor.
It is marketed as Doxium used for diabetic retinopathy, it seems a reasonably safe drug with few side effects. Reading the pharmacological properties of calcium dobesilate they say that it does not cross the BBB in rodents but they cannot affirm it in humans? I do not understand this, in the thesis that I enclose above the well detailed study in rodents is performed with oral intake.
The following investigations improve the effect of dobesilate by acetylation becoming DAPS but unfortunately it is no longer an accessible drug

 

I would appreciate your opinions!

 

Kind regards


   
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(@manuone)
Joined: 6 years ago
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I still share information about FGF inhibition ? 


   
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(@j)
Joined: 6 years ago
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@manuone

Hi Manuel! 

This study identifies how cancer cells may develop resistance to FGFR inhibitors

"Examining other molecules in the FGFR pathway, the researchers found that a regulatory protein called Akt remained highly active, even during FGFR inhibition. Akt, a key regulator of cell biology, is directly involved in cell proliferation, cell survival and cell growth.

Furthermore, they found that by inhibiting Akt they could significantly slow cell proliferation, cell migration and cell invasion in the lung cancer and bladder cancer cells."

https://www.sciencedaily.com/releases/2017/03/170302115807.htm


   
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(@manuone)
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@johan

Thanks for the reply Johan!
As with any treatment, cancer cells look for escape alternatives ... maybe this happens less in a broader therapy like ours ...
I find it an interesting therapy because in vitro and rodents dobesilate seems to be a good antiangiogenic drug without side effects like other anti VEGFs like bevacizumab .....
The only thing that worries me is if any anti angiogenic therapy working on the tumor vasculature would produce the famous rebound effect that Avastin produces, eventually returning more aggressive tumors.

Kind regards


   
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(@j)
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@manuone

"at least one RTK was found altered in 67.3% of GBM overall: EGFR (57.4%), PDGFRA (13.1%), MET (1.6%), and FGFR2/3 (3.2%)."

https://www.sciencedirect.com/science/article/pii/S0092867413012087

 

 


   
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(@manuone)
Joined: 6 years ago
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@johan

Thanks a lot Johan!
I will read the study in detail although it seems focused on genetic mutations, it is something that I never liked especially given the capacity of gbm mutation. The primary tumor 4 years ago was mutated in PTEN ..... I always thought of mTOR inhibitors like everolimus but they didn't seem safe or effective in their condition.
Regarding the inhibition of FGF I find it interesting especially because it is an accessible, cheap drug and apparently of few side effects and interactions with other drugs.


   
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(@ovidiu)
Joined: 8 years ago
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@manuone

Dobesilate has poor biovailability at commonly used doses, and may prove too hepato-toxic at higher doses.

However, if it reaches the tumor, it appears to be effective, especially against cancers strongly overexpressing bFGF. It is also a VEGF inhibitor.

Dramatic response to inhaled dobesilate in a patient with lung squamous cell cancer. PMID: 22952275 

Calcium Dobesilate Restores Autophagy by Inhibiting the VEGF/PI3K/AKT/mTOR Signaling Pathway. PMID: 31447680


   
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(@manuone)
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@ovidiu

Hi ovidiu!

A pleasure to read you again! I was discussing that topic with one of the researchers but I still didn't get an answer.
I certainly considered 1500mg in small alternate weeks cycles to avoid possible liver toxicity.
The increase in ALT I saw was a possible side effect, my mother has hepatitis C and I must be cautious.


   
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(@j)
Joined: 6 years ago
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@manuone

Fucoxanthin, ginger(zerumbone) and ursolic acid have shown FGF inhibition potential.

 


   
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(@manuone)
Joined: 6 years ago
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@johan

Thank you for your valuable comments! I am especially interested in calcium dobesilate because it is also shown as an antiangiogenic and COX 2 inhibitor. The problem is that I am not sure if it is well absorbed as ovidiu said.  I read it seems well absorbed but I have doubts about whether it crosses the BBB. Regardless of this I believe that the systematic action in the organism on the tumor vasculature is through blood circulation.


   
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(@j)
Joined: 6 years ago
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@manuone

In this product http://www.canixalife.com/our_product.php?id=64 it says Lignocaine crosses BBB but don't mention it for Calcium Dobesilate.

Phenethyl Isothiocyanate (crosses BBB) might interest you, it's anti-angiogenic( through VEGF suppression)

https://www.ncbi.nlm.nih.gov/pubmed/30201893

Saludos!

 

 


   
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(@ovidiu)
Joined: 8 years ago
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@manuone

I'm sorry, I must have mis-remembered about the biovailability of Calcium Dobesilate, from 7 years ago. It appears that it's orally well absorbed, but slowly. And unfortunately, it does not cross the BBB. This article should be useful, you can find it as PDF on Semanticscholar (but it's not on Pubmed):

Calcium Dobesilate in Prevention and Treatment of Diabetic Retinopathy


   
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(@manuone)
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I understand that for the antiangiogenic effect it is not necessary to cross the BBB since it is through the circulatory system ..... this is correct ?.
Thanks Johan and ovidiu for your help 🙂


   
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(@ovidiu)
Joined: 8 years ago
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@manuone

AFAIK in order to be effective against brain cancer, a drug must be able to cross the BBB.

While looking into anti-angiogenic therapy for GBM, I found a couple of articles which may sometime be useful:

4-Hydroxy-7-oxo-5-heptenoic acid lactone is a potent inducer of brain cancer cell invasiveness that may contribute to the failure of anti-angiogenic therapies. PMID: 31715381 

SNAP reverses temozolomide resistance in human glioblastoma multiforme cells through down-regulation of MGMT. PMID: 31725331 


   
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(@ovidiu)
Joined: 8 years ago
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@manuone

About the BBB and GBM, this article may explain better, that while the BBB can be disrupted in GBM, there always are regions of the tumor with an intact BBB.

Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data. PMID: 29016900 

Drugs that easily penetrate the BBB are anti-psychotics, and many of them have anti-cancer properties. However, the side effects limits their usefulness against cancer. There is a newer one which may be more appropriate, Brexpiprazole.

In vitro and in vivo anti-tumor effects of brexpiprazole, a newly-developed serotonin-dopamine activity modulator with an improved safety profile. PMID: 31191825 

Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction. PMID: 31284441


   
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