hope for those with brain mets
 

PUBLIC RELEASE: 11-JUN-2018
A new therapy proves effective against brain metastasis
Silibinin reduces brain metastasis in mice and patients, according to a study led by researchers at the CNIO. This proof of concept opens up a new path for treating these secondary tumors in the brain

CENTRO NACIONAL DE INVESTIGACIONES ONCOLÓGICAS (CNIO)


A study published in Nature Medicine by a team led by Manuel Valiente, head of the Brain Metastasis Group at the Spanish National Cancer Research Centre (CNIO), shows that the administration of silibinin in patients with brain metastasis reduces lesions without causing any adverse effects. This preliminary trial provides proof of concept that this compound could be a new effective and safe alternative to treat brain metastasis.

"We have demonstrated, taking into account all the considerations relevant to a compassionate use trial such as ours, that we can successfully treat brain metastasis", highlights Valiente. "This treatment could also be valid for any type of brain metastasis, regardless of the primary tumour that generated it", he added.

One of the biggest challenges in oncology is brain metastasis. It is estimated that between 10% and 40% of primary tumours generate metastasis in the brain, a situation that worsens patient prognosis considerably. Few advances have been made in terms of treatment; currently, brain metastasis is still being treated with surgery and/or radiotherapy. In recent years, some alternatives have appeared in terms of targeted therapies or immunotherapy, but the percentage of patients who might benefit from these therapies is just 20% in the best-case scenario.

The tumour microenvironment as a critical factor in metastasis

The role of the cellular context (microenvironment) in which a tumour develops is becoming increasingly important, not only with a view to understanding how cancer cells grow but also so we can know how to attack them. In the brain, an inhospitable environment for any element that is foreign to it, the role of the microenvironment is as relevant as it is unknown.

Valiente and his group have been studying this aspect for years, focusing in particular on two elements. On the one hand, on a population of cells known as astrocytes, which respond to damage by entering into a reactive state and which are associated with metastasis. And on the other, on the STAT3 gene, which has already been proved to be involved with brain metastasis. As shown in this research, the activation of STAT3 is significant in a subpopulation of reactive astrocytes that are key to establishing a pro-metastatic environment.

When this gene is eliminated from the reactive astrocytes, the viability of brain metastasis is compromised. With this information on the table, Valiente's research group used a novel drug screening strategy developed by them called METPlatform. This tool is capable of analysing the relationship between hundreds of compounds and the metastatic cells found in the target organ simultaneously; in this case in the brain.

"This strategy allows us to assess experimental drugs as well as those that are already in use for other types of pathologies that might or might not be linked to cancer. We believe that by using METPlatform we can be more efficient in developing new therapeutic options, since we can study the metastatic cell growing in the organ being colonised", explained Valiente.

One of the compounds tested in this preparation was silibinin, whose anti-tumour potential had previously been established by Joaquim Bosch, Head of the Lung Cancer Unit at Catalonia's Cancer Institute (ICO) in Girona, and co-author of this study. "In 2016, we reported positive brain responses in two patients with no other treatment options who received silibinin, but we did not know how it worked. Thanks to this research, led by Valiente's group, we now understand how it acts at the level of the brain", said Bosch.

A new therapeutic concept with encouraging results

Following the good results obtained by blocking STAT3 with silibinin in mice, the authors established a cohort of 18 patients with lung cancer and brain metastasis for whom compassionate use to this drug was granted in combination with standard treatment. 75% of the patients reacted positively at the level of brain metastasis. Three patients (20%) displayed a total response, and 10 (55%) a partial response. Average survival rate was 15.5 months, whereas in the control group (composed of patients treated for this disease in the same institution during 2015-2016) it was four months.

"Our treatment mainly targets the brain environment that has been altered by metastasis. This is a new therapeutic concept", said Valiente. "We are also attacking an alteration that is only seen when there is brain metastasis, and which is necessary for its viability", he added.

"We have explored whether therapies targeting organ-specific survival mechanisms could be a novel approach to treat brain metastasis", explains Neibla Priego, first author of the study.

In spite of the positive results achieved, further trials must be conducted with this compound before it can be incorporated into clinical practice. Researchers have been trying to launch such trials for months, but so far they have not been able to secure the funding they need in order to do so. "This present research describes the first targeted therapy for brain metastasis that acts by attacking its tumour microenvironment. However, more data are needed before it can be incorporated into clinical practice. The 18 patients treated so far indicate that it would be feasible to administer this treatment and that it could be very relevant at a clinical level. Clinical trials, with silibinin or with drugs that act against this target, are crucial if we wish to make this new therapeutic option available to patients", concluded Bosch, head of the clinical study, and Valiente, research director.

Patients with brain metastasis have traditionally been excluded from clinical trials because of their poor prognosis. "It now appears that there is a move towards not excluding them given their growing importance in clinical practice. In this regard, we hope that with METPlatform we will be able to help build confidence so that new drugs can be evaluated on these patients", adds Valiente.

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A new therapy proves effective against brain metastasis
CENTRO NACIONAL DE INVESTIGACIONES ONCOLÓGICAS (CNIO)
JOURNAL
Nature Medicine
FUNDER
Spanish Ministry of Economy, Industry and Competitiveness, Melanoma Research Alliance, Spanish Association Against Cancer, Spanish Society of Medical Oncology, Pfizer, Meda Pharma, Armangué Family, ''la Caixa'' Foundation, Fulbright Program
KEYWORDS


ORIGINAL SOURCE

https://www.cnio.es/ing/publicacione...ain-metastasis
RELATED JOURNAL ARTICLE

http://dx.doi.org/10.1038/s41591-018-0044-4

Re: hope for those with brain mets
 

Silibinin is found in milk thistle. I thought so but checked it out to be sure. It seems you can purchase Silibinin at Amazon. Interesting. I think drugs like Jakafi (Ruxolotinib) and Xeljanz (Tofacitinib block stat 3 and these two drugs are associated with low neutrophil and low platelet counts and need careful monitoring. Milk thistle is relatively safe and of course sold OTC

Paul

Re: hope for those with brain mets
 

Hello Donocco,
Do you think taking Milk Thistle as a preventative measure is worthwhile?

Re: hope for those with brain mets
 

Unclaimed

Id have to research this a bit but it might be. You have to speak with the oncologist first, but it might be an option. When I mentioned about Amazon selling the Silbininin I wasnt conciously telling people to buy it and take it. It might have sounded that way. I just found it interesting that the article neglected to mention exactly what silbinin is. To me it sounded like a drug in the pipeline like ONT-380 without the code designation. Im curious, did anyone on the board link Silbinin with Milk thistle?

I have no idea how effective Silbiniin is against preventing brain mets and will research this. But lets make believe its 100% effective. This is all fantasy now. Despite its "effectiveness" no drug company is going to research this as the product cant be pattened (spelling?)

Legally and morally the only thing I can tell you is to discuss this with your oncologist

Hope this answers your question, at least somewhat. Since we are talking about an OTC product the ultimate decision is up to the patient. If you are interested discuss this with the doctor.I will do some research on it. Its an interesting topic and brain mets are the most dreaded mets of many cancers

Paul

Re: hope for those with brain mets
 

One thing I didnt mention. There are a lot of possible drug interactions between Herbs and medicines. Im sure you have heard of Ginko Biloba. It turns out that this herb activates the enzyme (enzyme induction) Cyp2C19 and can lead to subtherapeutic levels of phenobarbital
and I think Valproate, two anti-siezure drugs. There were reports of nursing home patients with seizures well controlled by anti-convulsant drugs who developed siezures after many years of seizure control within 14 days after starting Ginko for dementia symptoms. Their phenobarbital levels were subtherapeutic due to the enzyme induction due to the Ginko. Im curious what drugs fi any interact with Milk thistle

Re: hope for those with brain mets
 

Hello Donocco,
Thank you for responding! I didn't think you were advocating or advising for the use of milk thistle. I thought it might be possible for something that may impact already present mets, to possibility deter them. Maybe?? I am very new to all of this, just began treatment in February, and I was already Stage 4. Just had a PET scan that came back NEAD so my oncologist is giving me a break from Capecitabine. I thought I could take the milk thistle during the time I'm off chemo as a safeguard, so to speak. I'm still on H&P. Brain mets arr indeed a constant source of anxiety and any possibility, especially an organic product, to thwart them is welcomed. Thank you again!!
Ana

Re: hope for those with brain mets
 

Ana,

I scanned your history and didn't notice if you were hormone positive. But, if you're ER positive milk thistle should be avoided. Otherwise, like Paul said, just confirm with your oncologist that it's okay to take.

Re: hope for those with brain mets
 

I just saw that myself about possible estrogen action. I wasnt gpong to anwer until I did some research. Its all confusing because it seems milk thistle is a weak estrogen which could actually be beneficial by blocking the effect of stronger estrogensBut so is Genistein found in soy very weak but this "weak estrogen can stimulate breast cancer growth in rats.
If it really does have a preventive action against brain mets the benefits might well outway the risks but I would hesitate to confirm this based on one study. Talk with the oncologist first. Herbs are complex because they contain many chemical constituants

Re: hope for those with brain mets
 

I couple of points. My tumor was er/pr negative. My cancer blazed into my liver big time soon after finishing radiation and first line treatments.

A friend who had gone through alcoholism mentioned that milk thistle is good for liver cleansing. I began taking it in 2002. I have continued to take it pretty regularly since that time.

My brain mets appeared at a time that I knew my liver has nearly regenerated after mets treatment. I let the Milk Thistle drop.

Later I realized that I feel better when I take the Milk Thistle (almost always used Jarrow 150 milligrams, one cap/day), so have taken it all these years.

This is the first I have heard that Silibinin could have any effect against brain mets. Such a coincidence that I never had any mets come back in brain or anyplace. My supplements, olive oil and good diet may well have contributed.

Re: hope for those with brain mets
 

This is a great thread. Can't wait to look into the milk thistle...
Thanks friends,
Flori

Re: hope for those with brain mets
 

Ill do some research on the estrogenic effects of Milk thistle and try to determine how clinically significant these effects are. If you are on estrogenic blocking drugs like Tamoxifen, Evista or Faslodex these possible effects are likely to be minimized. Cant say for sure.

Aromatase Inhibitors prevent Estrogen formation but don't block estrogen action so AIs probably wouldnt be protective. Its all kind of up in the air.

Paul

Re: hope for those with brain mets
 

Paul,

I don't know what you will find but I can say this - my tumor was so low ER positive that a few years ago it would've been treated as ER negative. But I was told that even a 1% ER positive tumor results in a recommendation of an AI now, so I was put on an AI. My liver enzymes numbers went through the roof on the AI and I asked about taking milk thistle to help with the liver enzymes and was told in no uncertain terms that I could not take it, even while on the AI and even with a very low ER positive tumor. Different doctors or studies may show something different but that is what I was told about it.

Re: hope for those with brain mets
 

I did some quick research and even Dr Andrew Weil cautions against ER positive patients taking milk thistle. Other reports mention experiments with female mice given very high doses of milk thistle extract (2700mg/kg) way above what a human would take and the effects on prevention of breast cancer and apoptosis of breast cancer cells were postitive not negative.

You can avoid (apparently) the estrogenic effects of milk thistle by purchasing milk thistle seed extract rather than the plant.This assumes the plant is really harmful. Go to Amazon and type in milk thistle seed extract. Ill do some more research as it keeps my retired mind active.

Paul

Re: hope for those with brain mets
 

Lucy

Because of the possible protective effect of milk Thistle against brain m ets this might prove to be an extensive topic. AIs have no antiestrogenic blocking effects at the receptor. They prevent estrogen formation from a weak androgen called androstenedione. I wonder what the doctor would have said if you were on an estrogen receptor blocking drug like Tamoxifen or Faslodex. Possibly the same thing. You have to follow the doctors orders. Unfortunately so much of this info is up in the air. Some of the reports contradict the others.

Re: hope for those with brain mets
 

Hi Lucy,
My biopsy report says I am estrogen and progesterone receptor negative. I bought Milk Thistle Extract from the Vitamin Shoppe. I hate to swallow pills, so I'll only take it once a day (says you can take three times daily). Once the oncologist makes me go back on the Capecitabine ( eight pills a day...blah 🤢) I probably won't take it anymore. I thought I'd give it a try while I was on a chemo break.
Hope things are going well for you!!

Re: hope for those with brain mets
 

Thanks for this post. Excellent information. I had a brain met in 2008 and have never had another. Not sure why.

Re: hope for those with brain mets
 

Interesting further info from Donocco.

The Jarrow Milk Thistle I take is SEED extract.

Re: hope for those with brain mets
 

Very interesting thread! And Paul? Can I just say that you ROCK!!! Thanks for saving your retired brain for us!