A few days ago I was responding to a kind request to help with some ideas for a young girl dealing with a benign but fast growing neurofibromatosis type 1 (NF1). There are some tumors of about 1 cm located in difficult areas making it impossible to removed them surgically, and are life-threatening. Below is my response to that request. I thought is good to share it here, as we never addressed this subject “cancertreatmentsresearch.com” and it may help other people too. If you have comments, remarks, regarding the content below or other ideas for treatments relevant to neurofibromatosis type 1 (NF1) patients please write a comment below.
Selumetinib seems to be an option that has been granted in 2019 breakthrough designation by FDA, based on the following results https://www.nejm.org/doi/full/10.1056/NEJMoa1605943 blocking MAPK/ERK pathway.
Update April 2020: the patient is on Selumetinib and she is doing very well.
Assuming this is not a glucose avid tumor, but its growing fast, the tumor must use respiration in order to produce the required energy. On this line:
– Glutamine and fatty acids will be in this case critical nutrients for driving cancer cell proliferation. Indeed, it has been showed that NF1 associated tumors can be targeted via glutamine depletion and glutaminase inhibition (Ref.). Deplition of Glutamine can be done with Phenyl Butyrate, and FDA approved drug. Avoiding foods (like red meat) containing large amounts of glutamine may also help. I just checked and see if this idea has been applied before and it seems where was some phase 1 clinical trial on Phenyl Butyrate in children with NF1-related plexiform neurofibromas https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764415/ but there was no follow up, probably due to the financial limitations. EGCG and Curcumin supplements may help here too.
– Another way to make use of the fact that the tumors may use mainly oxidation is to use mitohocondria inhibitors such as Metformin, or other mito inhibitors that I listed here https://www.cancertreatmentsresearch.com/a-list-of-mitochondria-inhibitors/
– Given that these tumors rely on mitochondrial energy production, another approach could be to consider inducing catastrophic oxidative stress combining e.g. mTOR inhibitors (such as Metformin – indirectmTOR inhibitor) with HDAC inhibitors (such as Valproic Acid) with thioredoxin reductase inhibitors (such as Auranofin). Here is a paper from Harvard discussing this approach https://cancerdiscovery.aacrjournals.org/content/candisc/early/2017/09/29/2159-8290.CD-17-0177.full.pdf Here is another reference discussing a similar approach in (malignant) NF1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233475/
– Also because the tumors rely on mitochondrial energy production, access to oxygen is very important for their growth. This is why they should be sensitive to angiogenesis inhibitors. Thalidomide is an angiogenesis inhibitor https://www.cancertreatmentsresearch.com/thalidomide-once-alleviate-morning-sickness-in-pregnant-women/ Celecoxib is another one that targets angiogenesis. Mebendazole could also be useful here. Here is a longer list of angiogenesis inhibitors https://www.cancertreatmentsresearch.com/category/angiogenesis-inhibitors/
Furthermore, it is known that Ras, angiogenesis, COX-2 could be good targets in NF1. https://app.dimensions.ai/details/grant/grant.5477844 The development of NF1-associated tumors is largely explained by the underlying defect of the NF1 gene which results in activation of the RAS proto-oncogene- a key mechanism of tumorigenesis.
– Drugs to target Ras:
Mevalonate is also an essential precursor for producing isoprenoids such as farnesylpyrophosphate and geranylgeranylpyrophosphate. These isoprenoids are especially important for anchoring small GTPases to the membrane before they function; e.g., Ras GTPases modulate proliferation and apoptosis, Rho GTPases control cytoskeleton formation, and Rab GTPases are essential for intracellular vesicle trafficking. Inactivation of these small GTPases alters cellular functions. (Ref.) inhibiting Mevalonate pathway:
- Statin (Atorvastatin or Pitavastatin) to inhibit mevalonate
- Dipyridamole to maintain effectiveness of statins
- Vitamin E to maintain effectiveness of statins
- HCA supplement may also help here to reduce input on mevalonate pathway
- Bisphosponates (e.g. zoledronic acid) will also inhibit mevalonate pathway and as a result Ras (Ref.)
Geranylgeraniol addition via food could be fine since the goal here is to inhibit Ras and not Rho. This could reduce the chance of side effects from Statins. Flaxseed oil contains good amounts of Geranylgeraniol.
Note: Such approach to target mevalonate has been proposed in the past although a little different https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3768167/ Indeed, pilot studies concerning the use of drugs—such as the protein farnesyltransferase inhibitor tipifarnib are underway https://pubs.rsna.org/doi/full/10.1148/radiol.2503080700#R21
– Drugs to target COX2
Other targets in neurofibromatosis type 1 (NF1) is neurofibroma, are Schwann cells, fibroblasts, mast cells, neuritis, and collagen. https://pubs.rsna.org/doi/full/10.1148/radiol.2503080700
– To target Mast Cells
- Histamine inhibitors such as Ketotifen: Ketotifen suppression of NF1 neurofibroma growth over 30 years https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.a.37045
- Quercetin, a natural substance found as supplement online (Ref.1, Ref.2)
– To target fibroblasts
- Tranilast (also addressing mast cells) or NSAIDs. Indeed, here are publication indicating Transilast may help: Tranilast, an anti-allergic drug, down-regulates the growth of cultured neurofibroma cells derived from neurofibromatosis type 1 https://www.ncbi.nlm.nih.gov/pubmed/19282654 Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells https://www.ncbi.nlm.nih.gov/pubmed/29666462
- CAPE that can be found in high amounts in the Propolis from Manuka has also be found to stop the growth of NF1 tumors:
- CAPE (caffeic acid phenethyl ester)-based propolis extract (Bio 30) suppresses the growth of human neurofibromatosis (NF) tumor xenografts in mice. https://www.ncbi.nlm.nih.gov/pubmed/18726924
- Effective neurofibromatosis therapeutics blocking the oncogenic kinase PAK1 https://pdfs.semanticscholar.org/2c2e/3056a110ce96d217c71e9418cd828865c811.pdf
- Strong antioxidants such as NAC (supplements found online) may help NF1 patients (although may not help the direct fight against the tumors):
- Nf1 Loss and Ras Hyperactivation in Oligodendrocytes Induce NOS-Driven Defects in Myelin and Vasculature https://www.sciencedirect.com/science/article/pii/S221112471300435X
- A women giving NAC supplements to her 9-year boy suffering from NF and she sees important benefits https://nfwithkerry.wordpress.com/2018/05/02/nac-n-acetyl-cysteine-for-nf/
Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827037/
Dietary intervention rescues myopathy associated with neurofibromatosis type 1. https://www.ncbi.nlm.nih.gov/pubmed/29228356
Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1. https://www.ncbi.nlm.nih.gov/pubmed/28099845/
In conclusion, there are several drugs and supplements that are easily accessible and could be add value in the treatment strategy against NF1. Using the above information, I would create a cocktail of drugs and supplements to increase the chance of success.
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