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dng050
(@dng050)
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07/06/2020 6:54 pm  

Dear all,

My brother (32) has recently been diagnosed with stage IV NSCLC. Nedless to say, we are devastated by this. There has not been one day for four weeks that I have not wept for my brother, while trying to figure out how to save him.

My current dilemma is that he has responded well on crizotinib. This is a TKI targeting the mutation which my brother has (ROS1). The problem with this TKI (and other TKIs) is that they eventually most probably will be ineffective due to drug resistance in the cancer. This might take months or a couple of years. So I was thinking that our strategy should be to BLOCK the metabolic pathways of the cancer while the TKI is working. The dilemma is that I am afraid that this approach might hasten the drug resistance.

From what I can understand from research, it seems that drug resistance develops by the cancer activating other signaling pathways [example]. So my theory is that if I block some pathways of the cancer, it might reroute to other pathways and thereby render crizotinib ineffective. So I am hesistant about starting my brother on the COC protocol (metformin, atorvastatin, mebendazole, and doxycycline) and other repurposed drugs (like dipyridamole, hydroxychloroquine and LDN).

On the other hand, if we just still and wait, I am afraid we risk brain metastates and other types of metastases and that we will not have sufficent time when the drug resistance has developed. 

So do you think we should go ALL IN now? Or should we wait to mount the attack on the cancer when crizotinib has failed? (I have a slight hope that my brother, like some of the exceptions I have seen, can last beyond five years++ on crizotinib).

Kind regards,
Nguyen


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johan
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07/06/2020 8:45 pm  

Hi Nguyen, I'm very sorry to hear about your brother. Earlier today I've posted about a clinical trial (NSCLC) here:

https://www.cancertreatmentsresearch.com/shutting-down-the-power-house-of-cancer-a-strategy-to-fight-cancer/#comment-10918

As far as I know results aren't available yet, the study ends this month, but you might want to contact the investigators (contact info at above link)

 

Best regards

 

Johan

 


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asafsh
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07/06/2020 9:33 pm  

Hi Nguyen, really sorry for this. 

Achievable complete remission of advanced non-small-cell lung cancer: Case report and review of the literature
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068813/
Bronchial artery infusion (BAI) is a manageable and effective method for treating advanced NSCLC. Outcome is good by BAI due to its repeatability and low toxicity. Icotinib hydrochloride is a newly developed and highly specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and has been safely and efficiently used to treat advanced NSCLC. We herein report a 73-year-old patient with chronic cough, who was diagnosed with advanced NSCLC with the EGFR mutation of L858R substitution in exon 21, and treated with the combination of oral icotinib and BAI chemotherapy as the first-line therapy, which resulted in a satisfactory clinical outcome. Complete remission of advanced NSCLC can be achieved using the
combination of oral icotinib and BAI chemotherapy.

there should be more articles describing complete NSCLC remission.

But before starting to try any kind of treatment it is good to build a strategy of what can be tried and in what sequence.
In my case if i knew all what i know right now, i had to take different route and strategy instead of i am doing and with much less complication. For example - i lately learned info about maximum life time cumulative dose of chemo drugs that limits their continuous administration.

So, imho better to find someone who has a good experience in both clinical and integrative oncology, and discuss all choices before going further. May be someone here can recommend you one.

Of course, finding right person is extremely difficult. 

All the best and good luck!


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dng050
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08/06/2020 8:05 pm  

I e-mailed prof. Jürgen Wolf about my question regarding whether repurposed drugs might hasten drug resistance of crizotinib. This is his reply:

good to hear that crizotinib is active and well tolerated. My advice is just to go on with crizotinib and to hope that resistance will develop late. Unfortunately, we can not predict, when this will happen.

But there is no evidence that adding re-purposed drugs will delay occurrence of resistance. Definitely not for the regimens mentioned in your mail. There is indeed new trial data from EGFR-mutated NSCLC that initially combining TKIs with standard chemotherapy will prolong disease control significantly. But no data so far for ROS1. Thus, there is a high probability that you will suffer from side effects without having any benefit but potentially increasing the risk that the tolerability of crizotinib will decrease !

Also, there is no evidence for brain mets activity of such a combination !

I hope very much, that crizotinib will be active for a long time in your case. But if you will suffer from relapse, then in my opinion it is important to do a rebiopsy and to look for resistance mutations in order to select the optimal treatment sequence.

So in the professor's opinion, there are no evidence that the drugs might hasten resistance when taken with the TKI. But I noticed his advice about possibly aggravating side effects and make my brother less tolerable towards crizotinib.

Based on the opinion of prof. Wolf, we should wait with the COC protocol. But it is so difficult to sit still and wait for the resistance to develop!

Nguyen


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johan
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08/06/2020 11:15 pm  
Posted by: @dng050

Based on the opinion of prof. Wolf, we should wait with the COC protocol. But it is so difficult to sit still and wait for the resistance to develop!

Nguyen

You can always stop any additional treatment as soon as side effects appear. Much depends on how your brother is feeling. If he's feeling well you have a window of opportunity. Time is on your side, it's been only a month, so you do have time to consider various complementary treatment option and combinations. 

"Chidamide increases the sensitivity of non-small cell lung cancer to crizotinib by decreasing c-MET mRNA methylation:" https://www.biorxiv.org/content/10.1101/2020.03.28.012971v1.full

 


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johan
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08/06/2020 11:40 pm  

CURCUMIN

"combined Treatment of Curcumin and Small Molecule Inhibitors Suppresses Proliferation of A549 and H1299 Human Non-Small-Cell Lung Cancer Cells" : https://pubmed.ncbi.nlm.nih.gov/21567511/

"Cytotoxicity of curcumin derivatives in ALK positive non-small cell lung cancer" (ALK is related to ROS1): https://www.sciencedirect.com/science/article/abs/pii/S0014299919307010?via%3Dihub Retained cytotoxic potency of the curcumin derivatives in crizotinib resistant cells indicated that mechanisms of resistance to the two drug types are independent, with resistance to ALK inhibitors not necessarily causing cross-resistance to curcumin derivatives.

Curcumin is an HDAC inhibitor so might fit into the current treatment.

 


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Deborah Dubnow
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09/06/2020 3:31 am  

I am trying to find out if fenbendazole also eradicates NSCLC EGFR Mutation.  I know of it putting people into remission that have more of the TP53 mutation but want to know about the EGFR with deletions.  And, is there anything else in conjunction that can attack the specific mutation?


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johan
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09/06/2020 5:26 am  

Hi Deborah,

here's a link to more information on fenbendazole:

https://www.cancertreatmentsresearch.com/fenbendazole

Also, this comment by Daniel has more information related to your question on fenben&egfr:

https://www.cancertreatmentsresearch.com/fenbendazole/#comment-10846

I also wanted to share this study:

Honokiol suppresses lung tumorigenesis by targeting EGFR and its downstream effectors:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295387/

and a few ideas:

Targeting galectin-3 could have a synergistic effect on EGFR targeted therapy

https://pdfs.semanticscholar.org/259e/c3852da519df80ce25086599421411d5d18c.pdf

Modified citrus pectin inhibits galectin-3 function to reduce atherosclerotic lesions in apoE-deficient mice

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482107/

 


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dng050
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10/06/2020 1:50 pm  

Thank you, Johan and asafsh, for your kind help.

My brother recently took a blood test showing that his ALT was 114 (normal range up to 70), which was an elevation from last time he took a blood test (about 80, three weeks apart). The trend was that ALT was in fact decreasing, but after starting on mebendazole the ALT rose again. So my brother has, per the advice of the doctor from COC, stopped taking mebendazole (100 mg/daily) for now. We have not started on metformin or doxycycline since we want to wait and see how ALT develops (and to work on a strategy for treatment).

I am taking a look into diet and supplements to battle the cancer. However, I have learned that most of the best supplements and food like turmeric (curcumin), green tea (EGCG) and tofu (genistein) are CYP3A4 inhibitors. In the pamphlet of Xalkori (crizotinib), it is advised to "Avoid concomitant use of strong CYP3A inhibitors" (reference).

I saw that Daniel says that I should watch out for inducers (comment), but that inhibitors could be fine as long as the supplement is introduced slowly. But I am not sure whether this nevertheless will pose a risk of increasing crizotinib. Also, it is the psychological barrier which makes it difficult to do something against the recommendation in the drug pamphlet. On the other hand, we have read so much positive on the mentioned supplements that it is a shame not to utilise them!

Do you have any opinion on this issue?


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asafsh
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10/06/2020 4:35 pm  

@dng050, Daniel may answer this precisely.

from what i know, you shouldn't try to add something on top of current treatment :

  • before your current treatment is found inefficient
  • if there is no evidence in scientific literature indicating synergistic or additive effect of co-administration of drugs and supplements. that is because of mechanism of actions of drugs might not be described or explored fully. (e.g. for some drugs you may find statement on drug leaflet that mechanism of actions is not fully understood yet.)
  •  therapy is daily metronomic, so you don't have resting period between drug administrations free of drug influence so another one can be tried. also, note that another drug could influence mutation and can lead to tumor resistance. So subject has to be properly researched.
  • interference in drug metabolism

You may order drug combination tests against biopsy samples if there is a lab around for personalized drug testing and offer such service to outside. That could be expensive.

Also, some labs may do genetic test for particular tumor samples and find therapeutic targets matched to available drugs.I know only one in USA that may require tissue biopsy samples to make test against, though can't recommend it to you as i don't have an experience with them. 

Good luck

 


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johan
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10/06/2020 6:34 pm  
Posted by: @dng050

I am taking a look into diet and supplements to battle the cancer. However, I have learned that most of the best supplements and food like turmeric (curcumin), green tea (EGCG) and tofu (genistein) are CYP3A4 inhibitors. In the pamphlet of Xalkori (crizotinib), it is advised to "Avoid concomitant use of strong CYP3A inhibitors" (reference).

I saw that Daniel says that I should watch out for inducers (comment), but that inhibitors could be fine as long as the supplement is introduced slowly. But I am not sure whether this nevertheless will pose a risk of increasing crizotinib. Also, it is the psychological barrier which makes it difficult to do something against the recommendation in the drug pamphlet. On the other hand, we have read so much positive on the mentioned supplements that it is a shame not to utilise them!

Do you have any opinion on this issue?

Hi Nguyen, I fully understand your hesitation and it's very important to check for interactions. In the case of Curcumin, and considering it's poor pharmacokinetic profile, I don't think there's cause for concern. You might want to consider intermittent supplementation to further reduce the possibility of negative interactions.


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johan
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10/06/2020 8:08 pm  

https://www.ernaehrungs-umschau.de/fileadmin/Ernaehrungs-Umschau/pdfs/pdf_2015/11_15/EU11_2015_Special_Kocher_Eng.pdf

"Cell culture and animal studies have shown that native curcumin can affect xenobiotic metabolizing enzymes. There are also effects on the pharmacokinetics of active substances in animal studies and in men. On the other hand, it has not been shown that curcumin has any adverse effects on the pharmacological activity of other drugs. However, it must be emphasized that these studies are preliminary rather than conclusive and must be supported by larger scale investigations. It has also not been investigated whether the formulations with better bioavailability can influence the pharmacokinetics of other drugs"


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johan
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10/06/2020 8:34 pm  

https://www.thelancet.com/article/S2352-3964(19)30159-8/fulltext

"Cyclosporine A sensitizes lung cancer cells to crizotinib through inhibition of the Ca2+/calcineurin/Erk pathway"


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dng050
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16/06/2020 11:17 am  

Crizotinib, the TKI which my brother is taking, has poor CNS protection. So I have tried to find supplements to counter possible metastasis. It seems from my research that modified citrus pectin (MCP) has great potential to prevent metastatis:

1. Modified citrus pectin anti-metastatic properties: one bullet, multiple targets (link)
2. Modified Citrus Pectin Fights Cancer Metastases • Moss Reports (link)

Thinking about taking the MCP from Pectasol-C, 5 g three times a day. 


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johan
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16/06/2020 6:35 pm  
Posted by: @dng050

Crizotinib, the TKI which my brother is taking, has poor CNS protection. So I have tried to find supplements to counter possible metastasis. It seems from my research that modified citrus pectin (MCP) has great potential to prevent metastatis:

1. Modified citrus pectin anti-metastatic properties: one bullet, multiple targets (link)
2. Modified Citrus Pectin Fights Cancer Metastases • Moss Reports (link)

Thinking about taking the MCP from Pectasol-C, 5 g three times a day. 

I believe that's a good choice, and an adequate dose. You might want to look into combining this with IP6(+Inositol), there's a supplement that combines both IP6 Gold. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882699/

 


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johan
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Daniel
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17/06/2020 2:17 am  

@dng050

Hi,

I think one of the best against mets is Cimetidine, but you need to check the interaction with the current drugs. With my wife we used this for 3 years (next to others) and we kept away metastasis from a very aggressive cancer. Second, use good anti-inflammatory supplements and drugs.

Kind regards,
Daniel

 


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dng050
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19/06/2020 8:25 pm  

Thank you, @johan and @Daniel, for the valuable suggestions. 

Now to the task to find a way to source Cimetidine, as it is not OTC medicine here in Norway. 

Best regards,
Nguyen


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dng050
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22/06/2020 7:45 pm  

The main problem with targeted treatments is the almost certain drug resistance which the cancer develops. If we had only a way to prevent such a resistance, we could make my brother's disease a chronic one...

Article: Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours

"We report here testing of this Multiple Low Dose (MLD) therapy model in EGFR mutant NSCLC. We show that as little as 20% of the individual effective drug doses is sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF + MEK + ERK) or 4D (EGFR + RAF + MEK + ERK) inhibitor combinations. Importantly, EGFR mutant NSCLC cells treated with MLD therapy do not develop resistance."


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johan
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22/06/2020 10:30 pm  

@dng050

Interesting study, and confirms why a multi-drug combination is an important strategy to fight cancer.

 


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johan
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23/06/2020 12:01 am  

@dng050

For patients with lung cancer who are receiving chemoradiation or taking painkillers that are easily drug-resistant, ginsenosides can be used to reduce drug resistance.

https://redsenolhealth.com/appd-as-a-potential-adjuvant-to-chemotherapy-in-reversing-multidrug-resistance/


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Jcancom
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23/06/2020 12:10 am  

dng050, I hope that this citation is of help. The article shows that metabolic treatment can have quite strong  effects in cancer. Many people were quite astonished when these results first were announced at how effective these seemingly weak treatments could be when combined together.

https://chemothermia.com/wp-content/uploads/2019/04/feasibility-study-metabolically-supported-chemotherapy.pdf


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Jcancom
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23/06/2020 12:11 am  

@dng050

Wanted to get your attention. See my post above.


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johan
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dng050
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23/06/2020 2:35 pm  

@johan 
Yes, I agree. Everything I have read points in the direction that this disease must be treated with a multifaceted approach to have hope of being succesful, since it is a complex disease.
I am always on the look for good supplements to add to my brother's growing list, so thank you for the suggestions. The ginsenosides, in particular, seem very interesting.

@jcancom
The article is of help, Jcancom. Fortunately. my brother is stable now on his TKI - while I am devising a plan to attack the disease. I am thinking of an approach just like the one mentioned in the article you linked to. Besides IVC, hyperhermia, etc., I think I will also add various repurposed drugs.

-----

My brother just got his blood work, which shows a reduction of hemoglobin from about 16 down to 11 in just four weeks. So he is mild anemic. I am a little bit worried now, awaiting for suggestions from the oncologist on how to handle this. My brother's B12 vitamin is normal, but we have not checked his ferritin yet. He has been taking calcium for some time now, and I wonder if this might be the cause. Anyway, I am now looking for supplements to counter further drop of Hb.

Best regards,
Nguyen
 
 


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Jcancom
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23/06/2020 9:13 pm  

@dng050

https://www.drzinx.com/iron-man-molecule

Best Wishes


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Jcancom
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23/06/2020 11:07 pm  

@Manuone

Manuone, there are some exciting ones out there! A 4aa peptide targeted to GBM?

https://pubmed.ncbi.nlm.nih.gov/32510090/


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Jcancom
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23/06/2020 11:20 pm  

hmm, Johan has arrived on thread. Here's some interesting research for betulinic acid that he has mentioned previously.

"...we demonstrated that the downregulation of Caveolin-1 (Cav-1) usually occurred in BCSCs and was associated with a metabolic switch from mitochondrial respiration to aerobic glycolysis."

Yet, Betulinic Acid suppresses glycolysis and upregulates Cav-1.

https://pubmed.ncbi.nlm.nih.gov/32528105/

https://pubmed.ncbi.nlm.nih.gov/30684465/


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johan
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24/06/2020 12:01 am  
Posted by: @jcancom

hmm, Johan has arrived on thread. Here's some interesting research for betulinic acid that he has mentioned previously.

"...we demonstrated that the downregulation of Caveolin-1 (Cav-1) usually occurred in BCSCs and was associated with a metabolic switch from mitochondrial respiration to aerobic glycolysis."

Yet, Betulinic Acid suppresses glycolysis and upregulates Cav-1.

https://pubmed.ncbi.nlm.nih.gov/32528105/

https://pubmed.ncbi.nlm.nih.gov/30684465/

Hi J, I think you're referring to the cocktail liposome therapy I posted in the lung cancer forum, right? 


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Jcancom
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24/06/2020 1:00 am  
The below is your comment from Jess' thread.
 
Thank you for this liposome cocktail citation.
Quite remarkable. The 4 natural products in the liposomal cocktail was
almost as effective as cisplatin in lung cancer.
 
This might be a reasonably applicable suggestion for dng050.
 
After you have been on forum awhile you start to see the same chemicals
endlessly being recombined: curcumin, honokiol, quercetin ... .
Update the formulation and things start to look quite interesting.
Helping those on forum to access these easier formulations using liposomes would
be a big step forward.
 

I’d start hitting the damned thing with a different chemo, and a combo of supplements:
Vitamin D3
Liposomal Curcumin + Berberine
Honokiol + Magnolol
Luteolin
Betulinic acid + Delphinidin
Citric acid
Sodium selenite
Resolvins(EPA, DHA and DPA)
Royal Jelly(has Phenylbutyrate) + Melatonin    ....


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