glioblastoma multiforme

Markedly divergent effects of Ouabain on a Temozolomide-resistant (T98G) vs. a Temozolomide-sensitive (LN229) Glioblastoma cell line

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Abstract

Background

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor prognosis. GMB are highly recurrent mainly because of radio- and chemoresistance. Radiotherapy with Temozolomide (TMZ) is until today the golden standard adjuvant therapy, however, the optimal treatment of recurrent glioblastoma remains controversial. Ouabain belongs to the Cardiotonic Steroids (CTS) the natural ligands of the Na/K-ATPase (NKA). It is established that the NKA represents a signal transducer with either stimulating or inhibiting cell growth, apoptosis, migration and angiogenesis. Over the last decade evidence grew that CTS have anti-tumor properties especially in GBM.

Discussion

The results show that with regard to cell migration as well as plasma cell membrane depolarization Ouabain indeed has different effects on the two GBM cell lines, the TMZ-sensitive LN229 and the TMZ-resistant T98G cell line, similar to the results found by the group of Chen and coworkers with respect to apoptosis [46]. The authors showed that in T98G cells apoptosis was induced at significantly lower Ouabain concentrations (0.1 μM) as compared to LN229 cells (> 1 µM). However, in our setting, LN229 cells did not show any reaction to Ouabain neither in the migration assay nor in the cell membrane potential assay, even at higher concentrations (> 10 µM). For this discrepancy we do not have a plausible explanation and further studies are needed.

In contrast, the TMZ-resistant cell line T98G showed a marked inhibition of migration at rather low doses of Ouabain (0.01–0.1 µM), which correlated significantly with an increase in cell membrane depolarization (p = 0.002). A similar opposite reaction pattern to Ouabain was observed in the LN229 and T98G cells in the Bcl-2 analysis i.e., only in the T98G cell line we saw a down-regulation whereas LN229 did not show any reaction. The fact, that the Bcl-2 down-regulation was detected only at very low Ouabain concentrations (0.01 nM) must be interpreted with caution, we will discuss this issue further down. In summary, while the TMZ-resistant T98G cell line is sensitive to Ouabain, the TMZ-sensitive LNN29 cell line seems to be resistant to Ouabain.

Interestingly, migrating GBM cells are per se resistant to apoptosis. Joy and coworkers revealed an activation of the phosphoinositide 3-kinase (PI3-K) survival pathway by migrating glioma cells, which renders them resistant to apoptosis [68]. Applying a specific inhibitor of PI3-K (LY294002) to migrating cells the phosphorylation of Akt was inhibited and consequently, an increased rate of apoptosis was seen. Yang and coworkers could demonstrate that Ouabain is able to prevent phosphorylation of Akt and mTOR, inhibiting cell migration and enhancing apoptosis [47]. Lefranc and coworkers also stressed the importance of an inverse relationship between migration and apoptosis in GBM and the key role of the PI3-K/Akt pathway [69].

The fact that the T98G cells reacted to the cell migration assay as well as to the plasma cell membrane potential assay at similar Ouabain concentrations strongly indicates a causal relationship between migration inhibition, depolarization of the cell membrane, and consequent induction of apoptosis.

Many authors described a correlation between plasma cell membrane (PCM) depolarization and early apoptosis, but it is not fully clear whether it constitutes a causal relationship or a mere epiphenomenon. There is evidence that PCM depolarization is a prerequisite for apoptosis. Suzuki-Karasaki and coworkers described the disruption of intracellular K + and Na + concentrations as a basic important event leading to depolarization, cell shrinkage, and hence apoptosis [70]. Bortner and coworkers reported in Jurkat T-cells a PCM depolarization immediately after application of diverse apoptotic stimuli (anti-Fas antibody, thapsigargin and the calcium ionophore A23187) followed by cell shrinkage [71]. Moreover, an early increase in intracellular Na + as well as inhibition of K + uptake was observed in response to anti-Fas, indicating an inactivation of the Na + /K + -ATPase. Interestingly, Ouabain enhanced anti-Fas-induced apoptosis. Finally, applying an anti-apoptotic signal, i.e., protein kinase C, did not only inhibit apoptosis but also prevent cell membrane depolarization in response to anti-Fas. Thus, the authors concluded that cell membrane depolarization per se is a crucial early step in anti-Fas-induced apoptosis [71].

Interestingly, the PCM depolarization was not a short-lasting phenomenon, as known from electrically excitable cells, but rather was sustained. We also saw in the T98G cell line over time (up to 6 h) a sustained PCM depolarization. This sustained PCM depolarization is an indication that upon apoptotic stimulation, the cells lose their ability to repolarize.

At this point it is important to mention the role of Bcl-2, the classic anti-apoptotic protein of the Bcl-2 family [72]. Usually, they are localized at the outer mitochondrial membrane, but recent studies discovered intracellular truncated forms in the neighborhood of the plasma cell membrane [73]. The most known function of Bcl-2 is exerted by inhibiting the oligomerization of Bcl-2-associated X protein (BAX) and Bcl-2-associated agonist of cell death protein (BAD) hereby preventing their pro-apoptotic effect.

But already decades ago the importance of Bcl-2 in modulating the plasma cell membrane has been stressed. We mentioned above the works of Gilbert and coworkers who observed that overexpression of the anti-apoptotic Bcl-2 gene is associated with membrane hyperpolarization rendering cells more resistant to radiation-induced apoptosis [61]. Further studies revealed that Bcl-2 itself has pore-forming domains similar to that of bacteria toxins and that the activation of K + channels by the myeloid leukemia cell differentiation protein (Mcl-1), a member of the Bcl-2 family, results in plasma cell membrane hyperpolarization [59, 74]. Finally, Lauf and coworkers could demonstrate a direct co-localization of Bcl-2 specifically with the NKA in the cell membrane providing the missing link to the hypothesized interaction between Bcl-2 and NKA [63].

The numerous functions of Ouabain on intracellular pathways are well described; one of them is the down-regulation of Bcl-2/Mcl-1 by accelerating its proteasomal degradation via reactive oxygen species (ROS) generation [75].

So, it seems, that Ouabain can not only depolarize the plasma cell membrane directly by inhibiting the NKA but additionally by down-regulating Bcl-2. We saw only in the TMZ-resistant T98G cell line a Bcl-2 down-regulation after treatment with Ouabain for 24 h at very low concentrations (0.01 nM) which unfortunately did not correlate with the concentrations, at which we observed PCM depolarization and cell migration inhibition. Consequently, in our study we could not confirm that Bcl-2 down-regulation contributes to PCM depolarization.

But with caution, we may interpret the down-regulation of Bcl-2 as a kind of sensitizing effect to facilitate e.g., apoptosis. Only recently, a Bcl-2 effect on cell migration was discovered [76,77,78]. In Fig. 1b we see a slight inhibitory effect of Ouabain on cell migration at very low (≤ 0.01 nM) concentrations which correlates exactly with those of Bcl-2 down-regulation (Fig. 5). As we outlined above, inhibition of cell migration is a prerequisite to apoptosis. Additional studies in future are needed and may focus not only on Bcl-2 but also on Mcl-1 expression [61, 63]. Interestingly, Wang and coworkers demonstrated that Mcl-1 causes a hyperpolarization of the PCMP through activation of K + channel activity [59] hereby preventing apoptosis.

At this point it should be stressed that Ouabain is known to have significant effects at nanomolar concentrations [56], e.g., at 0.1 to 10 nM the NKA is stimulated in non-malignant (cardiac and neuronal) cells, interestingly, via the high glycoside affinity α3 isoform [79].

As outlined above the PI3-K/Akt pathway is one important modulator of cell migration. We revealed in T98G cells an increase in p-Akt after 24 h treatment with 0.1 µM Ouabain. In contrast, LN229 cells did not show any change in p-Akt. It contradicts the anti-migratory effect of Ouabain which we revealed at 0.1 µM in T98G cells. In fact, we expected a p-Akt down-regulation, at least after prolonged 24 h treatment similar to Chen and coworkers, who observed a p-Akt down-regulation at 2.5 µM Ouabain in U-87 GBM cells [46].

The significant decreased level of pan-Akt after 24 h Ouabain treatment at 1 µM hints to a different mechanism by which Ouabain exerts its antitumor effects. You and coworkers were concerned about the short-lasting effects of phosphorylation inhibitors and developed a pan-AKT degrader by conjugating the Akt-phosphorylation inhibitor GDC-0068 to Lenalidomide. He showed that this compound (INY-03–041) induced significant degradation of all Akt isoforms at 24 h and, interestingly, improved the anti-proliferative effects compared to GDC-0068 alone [80].

Ouabain is known to contribute to degradation of several compounds in the signalosome by internalization and disturbed intracellular trafficking [81, 82]. With specific respect to the epidermal growth factor receptor (EGFR) Hafner and coworkers described in lung cancer A549 cells a specific phenomenon called endosomal arrest. After treatment with Ouabain, Digoxin, or Acovenoside they revealed persistent granules with internalized EGF-receptor without further degradation [83].

This endosomal arrest may be considered as a crucial checkpoint in cell biology [84] by diverting growth factors either to the recycling or the degradation pathway. In case of prolonged endosomal arrest, however, they are simply “stuck there”, losing any biological function.

We assume that pan-Akt like other compounds of the signalosome is endocytosed upon prolonged Ouabain stimulation and undergoes an endosomal arrest together with NKA α-subunits and EGFR. Indeed, it was shown that endosomal Akt is associated with the intracellular trafficking of growth factor receptor complexes and thus modifying their activity in a time and location dependent manner [85].

The peak in Akt activation (p-Akt Ser473) at prolonged lower doses of Ouabain might serve as a stimulus for inducing its degradation. Kometiani and coworkers stressed the time factor in intracellular activation processes i.e., while short term activation of ERK1/2 induced cell proliferation, sustained ERK1/2 activation resulted in increased expression of the cyclin-dependent kinase inhibitor 1 (p21Cip1) resulting in growth arrest [86]. Hence, this could be the main mechanism by which e.g., pan-Akt is down-regulated resulting in inhibition of migration and induction of apoptosis. Further studies certainly are here needed.

The reciprocal response of LN229 and T98G cells to Ouabain resp. Temozolomide is striking and may have significant clinical consequences. The underlying mechanisms are not yet known. There is evidence that Ouabain induces different endocytotic trafficking and signaling pathways according to the EGFR mutation status, the NKA isoforms [56, 87] and other not yet fully analyzed factors. Many authors described the interaction between NKA and EGFR e.g., Liu and Shapiro analyzed in the renal cell line LLC-PK1 the role of the signalosome in the process of endocytosis and demonstrated that Ouabain-stimulated endocytosis of the NKA is dependent on Caveolin-1 and Clathrin as well as the activation of c-Src, transactivation of EGFR and activation of phosphoinositide 3-kinase (PI3K). They showed that c-Src, EGFR, and the extracellular signal-regulated kinases 1 and 2 (ERK1/2) all were endocytosed along with the plasmalemmal NKA [81].

We did not analyze the NKA isoforms in our GBM cell lines but as shown by Chen and coworkers the T98G cell line is characterized by a high NKA α3/ α1 isoform ratio. He stressed that the high expression of the α3 isoform in the T98G cell line was correlating with a higher sensitivity to the apoptosis inducing effect of Ouabain [46]. Xiao and coworkers proved that the knockdown of the α3 isoform with siRNA impaired the anti-proliferative effect of Ouabain, indicating that Ouabain preferentially binds to the NKA α3 isoform [88]. Future studies are warranted to analyze the exact role of EGFR- and NKA isoform expression at the cell surface in directing ouabain-induced signaling either towards enhanced or reduced cell proliferation and migration.

Last, but not least, we could demonstrate for the first time an anti-angiogenic effect of Ouabain at low concentrations (0.01 µM) which correlated significantly with the inhibitory effect on cell migration (Fig. 7). Angiogenesis is considered as prerequisite for migration and invasion of tumor cells [89,90,91] and as such it constitutes an important target for cancer therapy, especially the hypervascularized gliomas. Bevacizumab a humanized monoclonal antibody against VEGF was approved in the treatment of recurrent GBM but, at least as monotherapy, it prolonged only the progression-free survival, but not the overall survival [92, 93]. The effect of Ouabain on angiogenesis resp. endothelial cells is rarely investigated [94, 95]. Trenti and coworkers revealed that Digitoxin in therapeutic range (1–25 nM) inhibited effectively angiogenesis via focal adhesion kinase (FAK) inhibition (51). At the same time Digitoxin as well as Ouabain protected HUVEC cells from apoptosis induced by growth factor deprivation (51). Dual actions of all CTS—dependent on cell types and dose regimen—remain a scientific and therapeutic challenge we have to accept and address in future studies.

Largest Ever Brain Cancer Study Provides Key Insight Into One of Its Deadliest Forms

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This could change the way we think about brain tumours.

 
As far as cancers go, one of the worst is a type of brain cancer called glioma – the disease has a five-year survival rate of just 5 percent, and no reliable method for early detection.

A giant study that pooled genetic data from tens of thousands of people could change that, finding more than a dozen new mutations for physicians to hunt for in an effort to identify who is at risk of developing glioma.

 The results could end up boosting the chances of an early diagnosis, and saving lives in the process.

Together with researchers from the US and Europe, scientists from the Institute of Cancer Research in the UK carried out two studies on the human genome in an effort to spot differences that could result in cancer of the brain’s glial cells.

Our central nervous system relies on neurons to do its ‘thinking’ work, but they’re far from the only cell in the neighbourhood. For example, glial cells provide support for the neurons by insulating them, holding them in place, and helping them access nutrients.

But like a number of tissues in the body, changes in the genes inside these ‘nanny’ brain cells can cause them to grow out of control, prompting cancerous tumours to develop.

Glioma can be further broken down into categories, depending on the type of glial cell they started out as. Glioblastoma multiforme (GBM), for example, is a common form of brain cancer that begins as a type of glial cell called an astrocyte.

Tumours that grow into glioblastomas are particularly aggressive, killing around 95 percent of patients within five years.

 GBM develops in around 3 out of every 100,000 people, mostly striking in those over the age of 60, and claiming approximately 13,000 lives in the US and 5,000 lives in the UK each year.

While many researchers have been looking for new and innovative ways to treat gliomas, early detection has often been more accidental than intentional.

An Ohio State University study conducted in 2015 identified interactions between a pair of proteins and the newly developed tumour which could lead to a test that allows oncologists to diagnose a tumour as much as five years before symptoms appear.

But by identifying the genes that increase the risk of developing glioma later in life, researchers could potentially produce a program of diagnosis and quick treatment that might prevent tumours from growing in the first place.

This recent study didn’t stop at scanning the genome; it also analysed over 30,000 people included in a number of previous studies on GBM and non-GBM cancers, producing the largest ever study into brain cancer research.

All up, the research compared 12,496 cases of glioma with 18,190 people who didn’t have the cancer, finding 13 new locations on the genome which – if changed – could lead to glioma.

“The changes in the way we think about glioma could be quite fundamental,” says Richard Houlston from the Institute of Cancer Research.

“So, for example, what we thought of as two related sub-types of the disease turn out to have quite different genetic causes which may require different approaches to treatment.”

In total, researchers now have strong evidence for 26 locations on the genome that individually increase the risk of developing a form of glioma, in one case by up to 15 percent.

That might not seem like a lot, but when the odds are stacked against those with a metastatic brain tumour, every clue could make the difference between life and death.

“Understanding the genetics of glioma in such detail allows us to start thinking about ways of identifying people at high inherited risk, and will open up a search for new treatments that exploit our new knowledge of the biology of the disease,” said Houlston.

Combining past studies to increase the pool of data is a useful way to spot small differences which have otherwise been missed.

Hopefully this is one record we’ll see broken some time soon.

Source:http://www.sciencealert.com

Atrocious State of Cancer Treatment in the U.S.

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Story at-a-glance

  • Despite a decades-long war on cancer, and the “most advanced” treatments known to 21st-century oncologists, many cancer diagnoses remain a death sentence
  • Patient requests for possible experimental, natural or outside-the-box treatments are typically denied by oncologists who refuse to deviate from the hospital’s standard protocol
  • The film “Surviving Terminal Cancer” follows the story of those who have survived terminal cancer by bucking the system and taking their health and cancer treatment into their own hands

Being diagnosed with glioblastoma multiforme, a type of brain tumor, is considered a death sentence by modern medicine.

Despite a decades-long war on cancer, and the “most advanced” treatments known to 21st century oncologists, people who develop this aggressive, fast-growing cancer are given a prognosis of about 15 months to live — if they’re lucky.

Aggressive treatment, including surgery, radiation and chemotherapy, is often started, even though oncologists know it won’t cure the disease. If you ever find yourself in this type of nightmarish scenario, you can imagine the desperation you would feel to find something, anything, that might offer hope.

Most people turn to their oncologists or neurosurgeons with such requests for possible experimental or outside-the-box treatments, but you’re unlikely to receive any help that deviates from the hospital’s standard protocol.

It’s not that such treatment options don’t exist; they do. The problem is that the oncologist can’t, or won’t, prescribe them. To do so would risk his or her reputation and even medical license, should you decide to sue.

The film interviews a number of oncologists that carefully describe their predicament. But the problem is even larger than this. Modern cancer care is not set up to treat you, an individual. Their primary goal is to validate experimental therapies for future cancer patients many years down the road.

Due to regulatory red tape, drug-company greed, failures in the scientific process and lack of a universal will to do what’s best for each and every patient, modern cancer care fails an unacceptable percentage of the time.

As Albert Einstein said, the definition of insanity is doing the same thing over and over again and expecting different results. This describes modern cancer treatment in a nutshell.

How One Man Survived Terminal Cancer

Ben Williams, Ph.D., professor emeritus of Experimental Psychology at University of California, San Diego, shouldn’t be here today. He should be one of the statistics — 1 of the more than 15,000 people who die from glioblastoma multiforme in the U.S. every year.1

Yet, he’s alive — 19 years after his initial glioblastoma multiforme diagnosis. His survival was brushed off as a rare fluke by his doctors, but Williams believes otherwise.

In his book “Surviving Terminal Cancer: Clinical Trials, Drug Cocktails, and Other Treatments Your Oncologist Won’t Tell You About,” he details the multi-faceted strategy he used to overcome the disease. You can hear him tell his story first-hand in the film “Surviving Terminal Cancer,” above.

It’s becoming increasingly clear that in order to outsmart cancer, you’ve got to attack it from multiple angles, especially in the case of complex brain cancer. And that’s what Williams did.

He described a mushroom extract that’s used routinely to treat cancer in Japan. It has zero toxicity, but it’s not even mentioned in the U.S.

He did his own research, finding out about the potential to use existing non-cancer medications off label to treat the deadly disease. Once a patent expires on a drug, its potential to rake in major profits plummets. As such, drug companies typically abandon them in favor of newer, more profitable pursuits.

Abandoned Drugs Show Promise but Oncologists Won’t Prescribe Them

Some of these abandoned drugs have shown promise for glioblastoma multiforme, but they’re not offered to U.S. patients. While I’m not in favor of over-prescribing medications, if you’re facing a deadly prognosis you’re probably willing to risk the side effects if it gives you a chance for survival.

High-dose tamoxifen, a breast cancer drug, is one such medication that has shown some promise in treating glioblastoma multiforme.2

The anti-malaria drug chloroquine is another.3 There’s even a good chance your neuro-oncologist may be aware of the promising studies done with these drugs, but he or she won’t offer them as a potential treatment because they’re considered experimental. As Williams said:

“It made absolutely no sense to me not to use everything that might have a benefit as long as the toxicities were acceptable. Why wouldn’t anyone want to add them? It seemed to be totally irrational that people didn’t use everything that was available.”

When Modern Medicine Fails Them, Cancer Patients Turn to Self-Medication and the Black Market

In order to survive, Williams turned to self-medicating, a dangerous prospect by any account but, again, when your life is at stake you’re willing to take the risk. And his story is not unique.

Many have traveled to other countries, forged prescriptions, feigned illnesses to get access to different medications and even traded medications and nutraceuticals on the “black market” in order to have even a chance at survival.

In Williams’ case, his daily cocktail of off-label medications and natural products worked. In just six months, his brain tumor had disappeared and it hasn’t been back since.

There are more than a handful of others who have defied odds and lived long term with glioblastoma multiforme, and they’ve taken matters into their own hands too.

Williams now spends the bulk of his time trying to help others with terminal cancer, and he makes his book, which he updates annually, free to cancer patients in need.

Natural Cancer Fighters Overlooked by Modern Medicine

Nature is an invaluable resource for fighting cancer, yet natural products, even those that have been intensely studied, are also left out of cancer patients’ treatment plans. Curcumin — one of the most well-studied bioactive ingredients in turmeric — is one glaring example.

It exhibits over 150 potentially therapeutic activities, including anti-cancer properties.

As noted by Dr. William LaValley — a leading natural medicine cancer physician whom I’ve previously interviewed on this topic — curcumin is unique in that it appears to be universally useful for just about every type of cancer.

Superficially, this appears unusual considering the fact that cancer consists of a wide variety of different nuclear genetic defects. One reason for this universal anti-cancer proclivity is curcumin’s ability to decrease the primary mitochondrial dysfunction that is likely one of the foundational causes of cancer. Once it gets into a cell, it also affects more than 100 different molecular pathways.

And, as explained by LaValley, whether the curcumin molecule causes an increase in activity of a particular molecular target or decrease/inhibition of activity, studies repeatedly show that the end result is a potent anti-cancer activity. Moreover, curcumin is virtually non-toxic, and does not adversely affect healthy cells, suggesting it selectively targets cancer cells — all of which are clear benefits in cancer treatment.

Research has even shown that it works synergistically with certain chemotherapy drugs, enhancing the elimination of cancer cells. If you have cancer, curcumin is one substance you should be taking, but your oncologist won’t recommend it.

To Survive Cancer, Many Must Defy Their Doctors

Should you bring up the fact that you are using approaches to fight cancer that are outside of your oncologist’s realm of experience — things like supplements, medical marijuana, herbal preparations, and more — you might be scolded, berated, threatened or even fired from the practice.

Williams never told his oncologists about his self-prescribed treatment; he knew it would fall on deaf ears. The cancer industry should be learning from the people who have beaten the odds and survived terminal cancer — studying their methods and trying to apply them to others — but instead they’re ignored.

It’s an unfortunate state of affairs when patients must actively defy their doctors in order to survive. As Williams explained, going against the advice of his doctors was initially an act of desperation, but it was necessary to save his life. This certainly applies to the majority of conventional oncologists, but there are exceptions — doctors who are blazing a new trail to find a cancer cure.

This includes Dr. Marc-Eric Halatsch, a professor and senior consultant neurosurgeon at the University of Ulm, Germany, who, along with colleagues have developed a new treatment protocol for relapsed glioblastoma.

It’s based on a combination of drugs (very similar to the early HIV treatments) “not traditionally thought of as chemotherapy agents, but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications.”4 As noted in the featured film, even though the protocol uses mainstream medications, he’s put his reputation on the line to step outside the conventional cancer-treatment box.

Cancer Patients Should Have Access to the Best of Eastern and Western Medicine

Dr. Raymond Chang, who is featured in the video above, is one such pioneer in the integration of Eastern and Western medicine. He is known for his work on anti-cancer Chinese botanicals especially involving bioactive polysaccharides and medicinal mushrooms.

He and colleagues with the Institute of East-West Medicine have created the Asian Anti-Cancer Materia Database, which brings together traditional Asian medicines that have potential anti-cancer activity into one database that can be accessed by all.5 In his book, “Beyond the Magic Bullet ― The Anti-Cancer Cocktail,” Dr. Chang explained:

“While scientists win occasional skirmishes in the battle against cancer, the overall war continues to go badly. Stories abound about revolutionary drugs that may be available in the future, but offer no real help to those who have cancer today. At present, conventional approaches continue to rely on a narrowly focused strategy of treatments, with doctors using, at best, only one or two drugs or other therapies at a time.

While this may be acceptable in a laboratory setting or a clinical trial, it has done little to diminish the number of people who die each year from this dread disease. Recently, however, conventional medicine’s core strategy has been re-examined, and a new, potentially more effective approach has emerged ― one that combines the best of Eastern wisdom with Western science.”

More Than Half a Million People Expected to Die From Cancer in 2016

In 2016, nearly 1.7 million new cases of cancer are expected to be diagnosed in the U.S., while nearly 600,000 will die from the disease.6  That is nearly 1,650 people dying EVERY DAY in the U.S. alone. Public health agencies claim that we are winning the war against cancer, but from 2003 to 2012 death rates from cancer decreased by only 1.8 percent per year among men and 1.4 percent per year among women.7

Meanwhile, the 2014 World Cancer Report issued by the World Health Organization (WHO) predicted worldwide cancer rates to rise by 57 percent in the next two decades.8

The report refers to the prediction as “an imminent human disaster,” noting countries around the world need to renew their focus on prevention rather than treatment only. Christopher Wild, Ph.D., director of the International Agency for Research on Cancer, told CNN:9

“We cannot treat our way out of the cancer problem. More commitment to prevention and early detection is desperately needed in order to complement improved treatments and address the alarming rise in cancer burden globally.”

There is so much you can do to lower your risk for cancer, but please don’t wait until you get the diagnosis — you have to take preventative steps now. Cancer doesn’t typically develop overnight, which means you have a chance to make changes that can potentially prevent cancer from developing in the first place. Most of us carry around microscopic cancer cell clusters in our bodies all the time.

The reason why we all don’t develop cancer is because as long as your body has the ability to balance angiogenesis properly, it will prevent blood vessels from forming to feed these microscopic tumors. Trouble will only arise if, and when, the cancer cells manage to get their own blood supply, at which point they can transform from harmless to deadly. It’s much easier to prevent cancer than to treat it once it takes hold.

Top Cancer Prevention Strategies

I believe you can virtually eliminate your risk of cancer and chronic disease and significantly improve your chances of recovering from cancer if you currently have it, by following these relatively simple strategies.

1.Eat REAL Food: Seek to eliminate all processed food in your diet. Eat at least one-third of your food raw. Avoid frying or charbroiling; boil, poach or steam your foods instead. Consider adding cancer-fighting whole foods, herbs, spices and supplements to your diet, such as broccoli sprouts, curcumin and resveratrol.

2.Carbohydrates and Sugar: Sugar/fructose and grain-based foods from your diet need to be reduced and eventually eliminated. This applies to whole unprocessed organic grains as well, as they tend to rapidly break down and drive up your insulin level.

The evidence is quite clear that if you want to avoid cancer, or you currently have cancer, you absolutely MUST avoid all forms of sugar, especially fructose, which are dirty fuels generating excessive free radicals and secondary mitochondrial damage.

3.Protein and Fat: Consider reducing your protein levels to 1 gram of protein for every kilogram of lean body mass, or one-half gram of protein per pound of lean body mass. Replace excess protein with high-quality fats, such as organic eggs from pastured hens, high-quality grass-fed meats, raw pastured butter, avocados, pecans, macadamias, and coconut oil.

4.GMOs: Avoid genetically engineered foods as they are typically treated with herbicides such as Roundup (glyphosate), and are likely to be carcinogenic and contribute to mitochondrial dysfunction. Choose fresh, organic, and preferably locally grown foods.

5.Animal-Based Omega-3 Fats: Normalize your ratio of omega-3 to omega-6 fats by consuming anchovies, sardines, wild Alaskan salmon or taking a high-quality krill oil and reducing your intake of processed vegetable oils.

6.Optimize Your Gut Flora: This will reduce inflammation and strengthen your immune response. Researchers have found a microbe-dependent mechanism through which some cancers mount an inflammatory response that fuels their development and growth.

They suggest that inhibiting inflammatory cytokines might slow cancer progression and improve the response to chemotherapy. Fermented foods are especially beneficial for gut health, and the fermentation process involved in creating sauerkraut produces cancer-fighting compounds such as isothiocyanates, indoles and sulforaphane.

7.Exercise and Move More: Sit less, move around more and try to take 10,000 steps a day.  Exercise also lowers insulin levels, which creates a low-sugar environment that discourages the growth and spread of cancer cells. In a three-month study, exercise was found to alter immune cells into a more potent disease-fighting form in cancer survivors who had just completed chemotherapy.

Researchers and cancer organizations increasingly recommend making regular exercise a priority in order to reduce your risk of cancer and help improve cancer outcomes. Exercise may also help trigger apoptosis (programmed cell death) in cancer cells. Ideally, your exercise program should include balance, strength, flexibility, and high-intensity interval training (HIIT). For help getting started, refer to my Peak Fitness Program.

8.Vitamin D: There is scientific evidence you can decrease your risk of cancer by more than half simply by optimizing your vitamin D levels with appropriate sun exposure. Your serum level should hold steady at 50 to 70 ng/ml, but if you are being treated for cancer, it should be closer to 80 to 90 ng/ml for optimal benefit.

If you take oral vitamin D and have cancer, it would be very prudent to monitor your vitamin D blood levels regularly, as well as supplementing with vitamin K2, as K2 deficiency is actually what produces the symptoms of vitamin D toxicity.

9.Sleep: Make sure you are getting enough restorative sleep. Poor sleep can interfere with your melatonin production, which is associated with an increased risk of insulin resistance and weight gain, both of which contribute to cancer’s virility.

10.Exposure to Toxins: Reduce your exposure to environmental toxins like pesticides, herbicides, household chemical cleaners, plastics chemicals, synthetic air fresheners and toxic cosmetics.

11.Exposure to Radiation: Limit your exposure and protect yourself from radiation produced by cell phones, towers, base stations, and Wi-Fi stations, as well as minimizing your exposure from radiation-based medical scans, including dental x-rays, CT scans, and mammograms.

12.Stress Management: Stress from all causes is a major contributor to disease. It is likely that stress and unresolved emotional issues may be more important than the physical ones, so make sure this is addressed. My favorite tool for resolving emotional challenges is the Emotional Freedom Techniques (EFT).

Have You Been Diagnosed With Cancer?

One of the most essential strategies I know of to treat cancer is to starve the cells by depriving them of their food source. Unlike your body cells, which can burn carbs or fat for fuel, cancer cells have lost that metabolic flexibility. Dr. Otto Warburg was given a Nobel Prize over 75 years ago for figuring this out, but virtually no oncologist actually uses this information.

You can review my interview with Dominic D’Agostino, Ph.D. below for more details. Integrating a ketogenic diet with hyperbaric oxygen therapy is deadly to cancer cells. It debilitates them by starving them of their fuel source. This would be the strategy I would recommend to my family members if they were diagnosed with cancer.

Watch the video discussion. URL:https://vimeo.com/119006145

Source:mercola.com

Researchers find new way to combat brain cancer

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Activating a specific family of proteins may stop the spread of the most lethal and aggressive brain cancer Glioblastoma Multiforme (GBM), new research has found.

M_Id_401779_cancer

GBM is the most common brain tumour in adults and people with GBM often live fewer than 15 months following diagnosis because, despite surgery, radiation and chemotherapy, individual cancer cells escape and invade healthy surrounding tissue, making additional treatment attempts increasingly difficult.

“New therapies for GBM are desperately needed,” said Corresponding Author on the study Kathryn Eisenmann, Assistant Professor at University of Toledo Health Science Campus in Ohio, US.

“We hope our latest finding will lead to a novel and effective treatment for this extremely aggressive cancer,” Eisenmann noted.

  • M_Id_416836_B

The study expands upon an earlier discovery of a bioactive peptide called DAD (Diaphanous Autoregulatory Domain) and small molecules called Intramimics.

Both DAD and Intramimics activate a family of proteins called DIAPHs or mDIA, which are known to play vital roles in GBM spread.

The new study found that locking DIAPH into an “on” state using DAD, Intramimics stops GBM cells from invading normal brain tissue.

The researchers hope to soon evaluate the effectiveness of this new strategy in preclinical models, a crucial step in translating this discovery to the clinic and patients.

“GBM is lethal because it so effectively escapes and evades therapy,” Eisenmann said.

“Our hope is this discovery will prove to be an anti-tumour strategy and one that will be safe and effective for patients,” Eisenmann noted.

 

Targeting Invasive Glioma Cells.

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Name of the Trial
Phase I Trial of AZD7451, a Tropomyosin-Receptor Kinase (TRK) Inhibitor, for Adults with Recurrent Gliomas (NCI-12-C-0005). See the protocol summary.

Principal Investigators
Dr. Katharine McNeill, NCI Center for Cancer Research, and Dr. Howard Fine, New York University Cancer Institute

Why This Trial Is Important

Glioblastoma is the most common malignant brain tumor in adults, with about 12,000 new cases diagnosed each year in the United States. It is also one of the deadliest, with a median survival following diagnosis of about 14 months.

Surgery to remove as much of the tumor as possible is the standard primary treatment for glioblastoma. After surgery, doctors use radiation therapy and treatment with the chemotherapy drug temozolomide to try to delay the growth of the remaining cancer. Although these measures may delay disease progression for a while, they cannot prevent it, and death usually occurs within a few months. Currently, the only therapy that has proven effective in delaying death in patients with progressive glioblastoma is bevacizumab, which helps block the tumor’s ability to induce the formation of new blood vessels.

Glioblastoma is particularly difficult to treat because of its highly invasive nature. Although the bulk of the tumor may be well defined, malignant cells have usually migrated away from the tumor by the time it is discovered. Some of these cells inevitably remain behind after surgery and, if left unchecked, will eventually kill the patient.

Progress in the treatment of glioblastoma has been hampered by the absence of preclinical tumor models that mimic the invasiveness of the cancer. However, NCI researchers recently developed new cell lines from a subset of glioblastoma tumor-initiating cells that more accurately replicate the invasiveness of human glioblastoma in animal models. Using the new models, they were able to determine that cells near the edge of glioblastoma tumors express a set of proteins that help make them highly invasive. Subsequently, they identified a compound that may be effective in blocking the function of one of these key proteins.

A protein called tropomyosin-receptor kinase, or Trk, is commonly found on brain cells and helps regulate the development, function, and survival of nerve cells. In glioblastoma, Trk is highly expressed on the cells around the edges of the tumor and on the infiltrative cells that have migrated away from the tumor mass, whereas those cells in the bulk of the tumor show lower levels of Trk expression. Doctors want to see if inhibiting the function of Trk will help block the invasiveness of glioblastoma cells and reduce the likelihood that the tumor will progress.

In this first-in-class phase I trial, patients with glioblastoma that has not responded to standard postoperative therapy or that has progressed will be treated with varying amounts of a Trk inhibitor called AZD7451 to determine the maximum tolerated dose and the side effects of this drug. Doctors will also look for signs of clinical activity.

“Regardless of the extent of tumor resection, there are always residual tumor cells because these cells are highly invasive and infiltrate normal brain tissue,” said Dr. Fine, former chief of NCI’s Neuro-Oncology Branch. “So surgery is never curative in this disease; some type of postoperative therapy is always required to try to address these remaining infiltrative tumor cells.

“We became interested in trying to study this invasive process in the laboratory in hopes of identifying new molecular targets for therapy,” he continued. “We were able to find that this molecule called Trk was expressed specifically on glioblastoma cells that were invading and [that] Trk was signaling to these tumor cells in a way that was important for the cells to move within the brain. Further, by inhibiting Trk we were able to shut off the invasive process in these models.”

The trial is taking place at the NIH Clinical Center in Bethesda, MD, and at the New York University Cancer Institute in New York City.

STUDY PROTOCOL

AZD7451 for Recurrent Gliomas

Basic Trial Information

Phase

Type

Status

Age

Sponsor

Protocol IDs
Phase I Biomarker/Laboratory analysis, Treatment Active 18 and over NCI 120005
12-C-0005, NCT01468324

Trial Description

Summary

Background:

  • AZD7451 is a drug that may help interfere with brain tumor cell growth. It can prevent glioma cells from entering into normal brain tissue, and slow or stop the growth of additional tumors. Researchers want to see if AZD7451 is effective against gliomas that have not responded to surgery, radiation, or chemotherapy.

Objectives:

  • To see if AZD7451 is a safe and effective treatment for gliomas that have not responded to standard treatments.

Eligibility:

  • Individuals at least 18 years of age who have gliomas that have not responded to standard treatments.

Design:

  • Participants will be screened with a physical exam, medical history, blood and urine tests, heart function tests, an eye exam, and imaging studies.
  • Participants will take AZD7451 daily by mouth for 28-day cycles of treatment.
  • Participants will keep a medication diary and record any side effects. Treatment will be monitored with frequent blood tests and imaging studies.
  • Treatment will continue as long as there are no serious side effects and the tumor does not start growing again….

Further Study Information

BACKGROUND:

Recurrent glioma patients have very limited treatment options. A major cause of gliomarelated morbidity and mortality is the extensive infiltrative and invasive nature of glioma cells. Thus, inhibition of glioma invasion is a potentially promising strategy.

Work in the laboratory of Dr. Howard Fine has identified TrkA as an important signaling receptor for mediating glioma cell invasion. Both genetic and pharmacological inhibition of Trk potently inhibits glioma invasion and tumor progression in vitro and in vivo.

AZD7451 is a first in-class inhibitor of Trk.

OBJECTIVES:

To establish the maximally tolerated dose (MTD) of continuous once daily AZD7451 in patients with recurrent malignant gliomas not on enzyme-inducing anti-epileptic drugs (EIAED).

To generate pharmacokinetic data on continuous twice a daily AZD7451 dosing.

ELIGIBILITY:

Patients with histologically proven glioblastoma are eligible for this study. Patients should have failed prior standard treatment with radiotherapy.

DESIGN:

This study will accrue up to 60 evaluable patients. Cohorts of 3 to 6 patients will receive continuous AZD7451 twice a day orally for 28 days. The MTD will be based on the tolerability observed during the first 4 weeks of treatment only. Up to three patients may be enrolled simultaneously at each dose level. The dose of AZD7451 can be progressively escalated if only 0/3 or 1/6 patients experience a dose limiting toxicity at the prior dose level.

At the end of Cycle 1, patients may choose to continue to receive AZD7451 until disease progression or until they experience unmanageable drug related toxicity, as long as they are continuing to derive clinical benefit and do not fulfill any of the criteria for removal from protocol therapy. Each cycle during this extension period will last 28 days.

Eligibility Criteria

  • INCLUSION CRITERIA:
  • Patients with histologically proven malignant primary gliomas who have progressive disease after radiotherapy will be eligible for this protocol.
  • Patients must have an MRI scan performed within 14 days prior to registration and on a fixed dose of steroids for at least 5 days. If the steroid dose is increased between the date of imaging and registration a new baseline MRI is required.
  • Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply:

1. Patients will be eligible four weeks after surgery if they have recovered from the effects of surgery.

2. Residual disease following resection of recurrent tumor is not mandated for eligibility into the study. To best assess the extent of residual disease postoperatively, an MRI should be done:

  • no later than 96 hours in the immediate post-operative period or
  • at least 4 weeks post-operatively, and
  • within 14 days of registration, and
  • on a stable steroid dosage for at least 5 days.

If the 96 hour scan is more than 14 days before registration, the scan needs to be repeated. If the steroid dose is increased between the date of imaging and registration, a new baseline MRI is required on a stable steroid dosage for at least 5 days.

  • Patients must have failed prior radiation therapy.
  • Ability of subject or Legally Authorized Representative (LAR) (if the patient is deemed by the treating physician to be cognitively impaired or questionably impaired in such a way that the ability of the patient to give informed consent is questionable) to understand and the willingness to sign a written informed consent document indicating that they are aware of the investigational nature of this study.
  • Patients must be greater than or equal to18 years old, and must have a life expectancy > 8 weeks. Because no dosing or adverse event data are currently available on the use of AZD7451 in patients < 18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.
  • Patients must have a Karnofsky performance status of greater than or equal to 60
  • Patients must be at least 4 weeks from radiation therapy. Additionally, patients must be at least 6 weeks from nitrosoureas, 4 weeks from temozolomide, 3 weeks from procarbazine, 2 weeks from vincristine and 2 weeks from last bevacizumab administration. Patients must be at least 4 weeks from other cytotoxic therapies not listed above and 2 weeks for non-cytotoxic agents (e.g., interferon, tamoxifen) including investigative agents. With the exception of alopecia, all toxicities from prior therapies should be resolved to CTCAE less than or equal to grade 1.
  • Patients must have adequate bone marrow function (WBC less than or equal to 3,000/microl, ANC > 1,500/mm(3), platelet count of > 100,000/mm(3), and hemoglobin greater than or equal to 9 gm/dl), adequate liver function (AST, ALT and alkaline phosphatase less than or equal to 2.5 times ULN and bilirubin less than or equal to 1.5 times ULN), and adequate renal function (creatinine less than or equal to 1.5 times ULN and/or creatinine clearance less than or equal to 50 cc/min calculated by Cockcroft-Gault) before starting therapy. Patients must also have serum potassium greater than or equal to 3.5 mmol/L, magnesium greater than or equal to 0.75 mmol/L, phosphate and calcium levels within normal levels; supplementation is allowed. In cases where the serum calcium is below the normal range, 2 options would be available: 1) the calcium adjusted for albumin is to be obtained and substituted for the measured serum value. Exclusion is to then be based on the adjusted for albumin values falling below the normal limit. 2) Determine the ionized calcium levels. Exclusion is then to be based on whether these ionized calcium levels are out of normal range despite supplementation. These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.
  • Patients must either not be receiving steroids, or be on a stable dose of steroids for at least five days prior to registration.
  • The effects of AZD7451 on the developing human fetus are unknown. For this reason and because AZD7451 is known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or herpartner is participating in this study, the treating physician should be informed immediately.
  • A 12 lead electrocardiogram (ECG) to be performed within 2 weeks of trial entry with QTc less than or equal to 470 msec.
  • Patients must have normal left ventricular ejection fraction (LVEF greater than or equal to 55% or normal by NIH Clinical Center criteria).

EXCLUSION CRITERIA:

  • Patients who, in the view of the treating physician, have significant active hepatic, renal, pulmonary or psychiatric diseases are ineligible.
  • 2 Prior treatment with AZD7451.
  • History of hypersensitivity to active metabolites or excipients of AZD7451.
  • Clinically significant cardiovascular event (e.g. myocardial infarction, angina pectoris, coronary artery bypass graft, angioplasty, vascular stent, superior vena cava syndrome (SVC), New York Heart Association (NYHA, Appendix I) classification of heart disease > 2 within 6 months before entry; or presence of cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmia.
  • Hemorrhagic or ischemic stroke, including transient ischemic attacks and other central nervous system bleeding in the preceding 6 months that were not related to glioma surgery. History of prior intratumoral bleeding is not an exclusion criterion; patients with history of prior intratumoral bleeding, however, need to undergo a non-contrast head CT to exclude acute blood.
  • Ventricular arrhythmias requiring continuous therapy or asymptomatic sustained ventricular tachycardia within 12 months before study entry. Continuous or intermittent atrial fibrillation requiring treatment. Patients with significant ECG abnormalities such as complete left bundle block and third degree heart block are not eligible.
  • QTc prolongation with other medications that required discontinuation of that medication.
  • Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age. QTc with Bazett’s correction that is unmeasurable, or > 470 msec on screening ECG. (Note: If a subject has a QTc interval > 470 msec on screening ECG, the screen ECG may be repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs must be less than or equal to 470 msec in order for the subject to be eligible for the study. Patients who are receiving a drug that has a risk of QTc prolongation are excluded if QTc is greater than or equal to 460 msec.
  • Any concurrent medication that may cause QTc prolongation or induce

Torsades de Pointes 1) Drugs listed in Appendix H, Table 2, that in the investigator’s opinion cannot be discontinued are allowed; however, must be monitored closely.

  • Concomitant medications that are moderate or potent inducers or inhibitors of CYP3A4 are not permitted within the specified wash-out periods prior to or during treatment with AZD7451
  • Patients with a history of corneal disease such as corneal ulcers, corneal dystrophies, keratoconus.
  • Refractory nausea and vomiting or significant gastrointestinal impairment, as judged by the investigator, that would significantly affect the absorption of AZD7451, including the ability to swallow the oral solution.
  • Patients known to have active hepatitis B or C (testing not required for entry on study).
  • Other concomitant anti-cancer therapy except corticosteroids.
  • Patients with a peripheral neuropathy CTCAE > 1 in the prior 4 weeks or active muscle diseases (including dermatomyositis, polymyositis, inclusion body myositis, muscular dystrophy and metabolic myopathy) or family history of myopathy. Patients with pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi syndrome or renal tubular acidosis.
  • Evidence of active infection or active bleeding diatheses.
  • Pregnant women are excluded from this study because AZD7451 is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD7451, breastfeeding should be discontinued if the mother is treated with AZD7451. Female patients must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening:
  • Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
  • Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
  • Patients known to have a malignancy (other than their malignant glioblastoma) that has required treatment in the last 12 months and/or is expected to require treatment in the next 12 months (except for non-melanoma skin cancer, carcinoma in situ in the cervix or ductal carcinoma in situ).
  • Major surgery within 4 weeks or incompletely healed surgical incision before starting therapy.
  • Patients known to be HIV-positive (testing is not required for entry on study) and on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD7451. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Howard A Fine, M.D. Principal Investigator

 

Tracy Cropper, R.N. Ph: (301) 402-6298
  Email: tcropper@cc.nih.gov

 

Howard A Fine, M.D. Ph: (301) 402-6298
  Email: hfine@mail.nih.gov

 

Source: NCI

 

 

 

Occult tumors presenting with negative imaging: analysis of the literature.

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Some patients presenting with neurological symptoms and normal findings on imaging studies may harbor occult brain tumors that are undetectable on initial imaging. The purpose of this study was to analyze the cases of occult brain tumors reported in the literature and to determine their modes of presentation and time to diagnosis on imaging studies.

Methods

A review of the literature was performed using PubMed. The authors found 15 articles reporting on a total of 60 patients with occult tumors (including the authors’ illustrative case).

Results

Seizures were the mode of initial presentation in a majority (61.7%) of patients. The initial imaging was CT scanning in 55% and MRI in 45%. The mean time to diagnosis for occult brain tumors was 10.3 months (median 4 months). The time to diagnosis (mean 7.5 months, median 3.2 months) was shorter (p = 0.046) among patients with seizures. Glioblastoma multiforme (GBM) was found more frequently among patients with seizures (67.6% vs 34.8%, p = 0.013). The average time to diagnosis of GBM was shorter than the time to diagnosis of other tumors; the median time to diagnosis was 3.2 months for GBM and 6 months for other tumors (p = 0.04). There was no predilection for side or location of occult tumors. In adult patients, seizures may be predictive of left-sided tumors (p = 0.04).

Conclusions

Based on the results of this study, the authors found that in patients with occult brain tumors, the time to diagnosis is shorter among patients with seizures and also among those with GBM.

Source: Journal of Neurosurgery.