Researchers Have Found a Drug That Can Help Slow the Spread of Multiple Cancers


Scientists working with Cancer Research UK have discovered that a drug developed to treat organ fibrosis can block an enzyme that assists in the spread of cancer cells. In tests conducted on mice, it was able to reduce the size of tumors by up to 50 percent.


Cancer is one of the leading causes of death worldwide, according to the World Health Organization, claiming 8.8 million victims in 2015. While researchers have made significant progress in the battle against the disease, it remains notoriously difficult to treat. This is due, in part, to the wide variety of cancers known to exist today, but the matter is further complicated by our difficulty preventing cancer cells from spreading.

While treatments such as chemotherapy and immunotherapy are available, they are often rendered ineffective by the fast rate at which cancer cells spread. Now, researchers from the University of Southampton in the United Kingdom, working in partnership with Cancer Research UK, may have found a way to aid such treatments by slowing down the spread of many different types of cancer.

In a study published in the Journal of the National Cancer Institute, the researchers focused on the enzyme NOX4 and a kind of cell called cancer associated fibroblasts (CAFs). When healthy, fibroblasts keep different kinds of organs together. When infected by cancer and turned into CAFs, however, they are known to help tumors grow, spread, and even evade treatment.

“By looking at many types of cancer, we have identified a common mechanism responsible for CAF formation in tumors,” lead research Gareth Thomas said in a press release. “These cells make cancers aggressive and difficult to treat, and we can see exciting possibilities for targeting CAFs in many patients who don’t respond well to existing therapies.”


The researchers found that CAFs decrease patient survival for a number of cancer types, including head, neck, and bowel cancers. “[E]ffective methods to manipulate these cells clinically have yet to be developed,” the researchers wrote. Thankfully, through their research, they discovered that NOX4 and CAFs have a peculiar dynamic.

In many types of cancer, NOX4 enzymes are required for CAFs to form and subsequently facilitate tumor growth. In tests conducted on mice, blocking NOX4 reduced the size of tumors by up to 50 percent. This blocking was made possible using a drug that’s being developed to treat another kind of disease called organ fibrosis.

The Future of Pain Management
Click to View Full Infographic

“Some cancers are incredibly difficult to treat and can use the body’s own cells to help them grow, evade treatment, and spread around the body,” explained Áine McCarthy at Cancer Research UK in the press release. “Researchers have been trying to unlock the secrets behind this for many years, and this study is a big step forward in understanding how some cancers achieve this.”

“These findings show that CAFs can be targeted with a drug and their ‘pro-tumor’ effects can be reversed in mice, giving researchers a starting point to develop new and potentially more effective treatments in the future,” she added.

Thomas and his team believe that their work could help improve a patient’s chances of reacting positively to chemo and immunotherapy. At the very least, it could help slow down the spread of cancer, dealing a critical blow to the disease that affects so many people.


Targeted NSCLC Therapies Go Head-to-Head

It was “fight night” at the 2017 American Society of Clinical Oncology annual meeting, with two big bouts between lung cancer therapies. In the ARCHER 1050 trial, up-and-comer dacomitinib took on the seasoned gefitinib (Iressa) in patients with advanced, EGFR-mutated non-small cell lung cancer (NSCLC). In the ALEX trial, the matchup was between alectinib (Alecensa) and crizotinib (Xalkori) in patients with treatment-naive, advanced ALK-positive NSCLC.

Which targeted therapies came out on top in these phase III trials?

ARCHER: Win by Decision

“Dacomitinib is a second-generation tyrosine kinase inhibitor [TKI] … and being second generation implies two clinical features,” explained the lead investigator, Tony Mok, MD, of the Chinese University of Hong Kong. “First it forms an irreversible bond with the receptor. Second, it [has] pan ErbB inhibition with HER1, HER2, and HER4.”

Based on positive findings from the ARCHER 1017 trial, “we thought it is likely … that dacomitinib would be superior to gefitinib, a first-generation TKI, in terms of PFS,” he added.

Mok’s group found that treatment with dacomitinib extended the time to relapse or death by 41% compared with standard gefitinib therapy.

The team randomly assigned 452 previously untreated patients with stages IIIB or IV NSCLC to receive 45 mg of dacomitinib a day or 250 mg of gefitinib a day.

 The trial’s primary endpoint was progression-free survival (PFS), which was defined as progressive disease or death. PFS was measured by an independent review committee. Objective response rates (ORR), overall survival (OS), and safety data also were analyzed.

Mok noted that the patients with central nervous system (CNS) metastases were not included in the study population. “The reason is we were not certain of the penetration of dacomitinib to the CNS at the time the study was designed,” he explained, adding that the role of gefitinib in CNS metastases is also unknown.

As for the ASCO presentation, 136 patients given dacomitinib and 179 given gefitinib had either progressed (59.9%) or died (79.6%). The median PFS for patients on dacomitinib was 14.7 months versus 9.2 months for gefitinib. The hazard ratio for progression was 0.59 in favor of dacomitinib.

The ORR for the study drug was 74.9% versus 71.6% for gefitinib. However, Mok reported that the duration of response was significantly longer for dacomitinib, at 14.8 months versus 8.3 months. OS data was not mature at the time of presentation, he added.

While dacomitinib may have won the overall “fight,” the agent was down for the count when it came to toxicity. Adverse events were as follows for dacomitinib compared with gefitinib:

  • Diarrhea: 87.2% versus 55.8%
  • Paronychia: 61.7% versus 20.1%
  • Dermatitis acneiform: 48.9% versus 28.6%
  • Stomatitis: 43.6% versus 17.9%
 In all cases, more patients on dacomitinib had grade 3 adverse events compared with gefitinib. On the other hand, gefitinib patients were more likely to have increases in alanine aminotransferase at 39.3% versus 19.4% for dacomitinib.

Given that dacomitinib does offer the more potent EGFR inhibition, the higher toxicity with the agent was not a huge surprise. Mok pointed out that “the overall total incidence of serious adverse events was similar between the two agents, but the drug-related [serious adverse events] were higher with dacomitinib,” adding that about 10% of patients had to permanently discontinue the drug, versus 7% of patients who had to discontinue gefitinib.

Because of the toxicity, dose reductions had to be used. Dacomitinib had two dose levels, a reduction of of 30 mg/day and another of 15 mg/day, while with gefitinib, there was one dose reduction to 250 mg every 2 days, Mok explained.

“The time to dose reduction was about the same, approximately 3 months, but the median duration of the dose reduction was longer with dacomitinib, at 11.3 months compared with 5.2 months with gefitinib,” he said.

Dacomitinib ultimately emerged as the victor, mainly because of its impressive PFS data, commented John Heymach, MD, chairman of the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston and a designated ASCO expert. He called the extended median PFS to 14.7 months with the study drug “a really substantial advance … that would clearly put it at the front of the pack in terms of efficacy” — the “pack” being the other targeted therapies available to these patients: gefitinib, erlotinib (Tarceva), and afatinib (Gilotrif).

ALEX: A Knockout

“Chromosomal rearrangements of ALK define a distinct subset of lung cancer patients for whom small-molecule TKIs of ALK are highly effective,” noted Alice T. Shaw, MD, PhD, of Massachusetts General Hospital in Boston. “The current standard of care for patients with newly diagnosed, advanced ALK-positive NSCLC is the first-generation ALK inhibitor, crizotinib.”

But patients invariably relapse on crizotonib, and one of the common and challenging sites of relapse is the CNS, she pointed out. Alectinib is more potent and more brain penetrable than crizotinib and can retain activity against crizotonib-resistant disease, she added.

For this trial, Shaw’s group randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (at 600 mg twice daily) or crizotinib (at 250 mg twice daily). ALEX’s primary endpoint was investigator-assessed PFS, and secondary endpoints included ORR, OS, and time to CNS progression.

The results showed, the team reported, that, across the board, alectinib turned in better results than crizotinib:

  • 12-month event-free survival rate (investigator-assessed PFS): 68.4% (95% CI 61.0-75.9) versus 48.7% (95% CI 40.4-56.9)
  • Event of CNS progression: 12% versus 45% (cause-specific hazard ratio 0.16, 95% CI 0.10-0.28, P<0.001)
  • ORR: 82.9% (95% CI 76.0-88.5) versus 75.5% (95% CI 67.8-82.1, P=0.09)
  • OS: “Not estimable” for either arm (HR for death 0.76, 95% CI 0.48-1.20)

For PFS, the hazard ratio for disease progression or death was 0.47 (95% CI 0.34-0.65, P<0.001), and the median PFS with alectinib was not reached, the authors stated.

In addition, a follow-up analysis for OS will be performed when approximately 50% of the patients have died, Shaw’s group wrote in the New England Journal of Medicine.

As with dacomitinib, alectinib did stumble a bit when it came to adverse events, which occurred at a higher incidence by five percentage points or more with alectinib versus crizotinib:

  • Anemia: 20% versus 5%
  • Myalgia: 16% versus 2%
  • Increased blood bilirubin: 15% versus 1%
  • Increased weight: 10% versus 0%
  • Musculoskeletal pain: 7% versus 2%
  • Photosensitivity reaction: 5% versus 0%

However, some adverse events that were common with crizotinib were nausea, diarrhea, and vomiting.

“One of the key secondary endpoints was time to CNS progression in the total population,” Shaw stated. “We found that alectinib significantly delayed time to CNS progress compared with crizotinib, with an 84% reduction in the risk of having CNS progression as the first event.”

The results represent a “watershed moment” for the treatment of ALK-mutant NSCLC, Heymach said. “Often, studies comparing similar-type agents will show incremental improvements. This one is different. There is a dramatic difference in efficacy — more than doubling the time to progression or death. It’s also accompanied by improved tolerability.

“Finally, one of the most debilitating things that can occur in these patients with ALK-mutant disease is brain metastasis,” he continued. “What’s really impressive about this study is the dramatic reduction in the risk of brain metastasis — an 84% reduction in the likelihood, which is an absolutely striking result.”

The ARCHER 1050 trial was funded by Pfizer and SFJ Pharmaceuticals Group.

Reverse Cancer with Targeted Mitochondrial Restoration

The black-or-white extremism of conventional medicine needs to be redacted in favor of a more nuanced view of oncogenesis—one where cancer represents a spectrum of deviation from the norm, where carcinogenesis is an adaptive response to a radically divergent environment from the one in which we evolved.

Instead of a cell gone rogue, where cancer is caused by the accumulation of point mutations in genes controlling the cell cycle and proliferation, cancer represents a reincarnation of a more ancient survival mechanism whereby cells coordinate their behavior to survive in an increasingly harsh cellular milieu. In this view, cancer represents a regression to a pre-programmed ancestral time, before the evolution of complex, highly differentiated eukaryotic organisms, where the hostile environment would have selected for traits favoring cellular immortalization, or resistance to apoptosis, as a primitive form of survival mode emphasizing replication, self-repair, and metastasis (1). In particular, the bio-energetic and metabolic theories of carcinogenesis, advanced by the luminaries Dr. Michael Gonzalez, Dr. Dominic D’Agostino, Dr. Garth Nicolson, and Dr. Thomas Seyfried, are perfectly situated to explain the role of mitochondria, our energetic cellular powerhouses, in cancer (2).

Mitochondria: The Conductors of the Physiological Orchestra

Mitochondria are rod-shaped, double-membrane organelles responsible for production of adenosine triphosphate (ATP), the cellular energy currency that powers metabolic reactions (3). In addition to transforming organic material into ATP, mitochondria are intimately involved in heme, amino acid, lipid, and steroid synthesis, in optimal functioning of the energetically demanding immune and nervous systems, and in dictating cell fates (4). Mitochondria mediate cellular proliferation, and regulate the energetically intensive process of apoptosis, or cell suicide, via release of cytochrome c through the mitochondrial permeability transition pore (mtPTP) (5).

Apoptosis, or the coordinated collapse of the cell, is accompanied by energy-dependent signaling cascades that result in predictable morphological changes, cellular dismantling, and engulfment of the cellular corpses by neighboring phagocytes (6). Although aberrant apoptosis is implicated in disease pathophysiology, apoptosis is essential to development and homeostasis (7). In contrast, necrosis occurs secondary to cellular injury, and results in cellular swelling, membrane fracture, and complement-mediated lysis, causing release of intracellular components and consequent inflammation. Mitochondrial function is so inextricably tied to apoptosis that tissue necrosis is one of the clinical features of mitochondrial diseases, such that extensive tissue damage can be incurred (8).

Via their production of reactive oxygen species (ROS) as metabolic byproducts, mitochondria also regulate the cellular redox state. Although often vilified for perpetuating the inflammatory molecular mechanisms underlying the pathogenesis of disease, elevated levels of ROS also serve adaptive and hormetic roles as signaling molecules in redox biology for maintenance of homeostasis (9). In fact, it is theorized that ROS evolved as a signal transduction mechanism to activate transcription factors that enable adaptation to changes in accessibility of environmental nutrients and in the oxidative environment (10, 11).

Although somatic cells can contain anywhere from two hundred to two thousand mitochondria, energy requirements dictate how many mitochondria each cell contains (12, 13). The most metabolically active cells, such as those within the brain, liver, skeletal muscle, and cardiac muscle, contain the largest number of mitochondria, whereas mature erythrocytes, or red blood cells, are the only cells devoid of mitochondria (14, 15).

The Evolutionary Origins of Mitochondria

The inner mitochondrial membrane contains the metabolic machinery for aerobic metabolism, an evolutionary adaptation to oxygen-rich environments, which coincided with the endosymbiosis, or engulfment, of the ancient autotrophic bacteria that were the predecessors of these eukaryotic organelles. One to three billion years ago, aerobic bacteria colonized an ancient prokaryote, generating energy for the host cell in return for shelter and a reliable supply of food, which was the genesis of intracellular mitochondria (5, 16).

Mitochondria produce over ninety percent of cellular energy via oxidative phosphorylation, a process that couples glucose oxidation to an electron transport chain and to the flow of protons down a gradient, which results in ATP synthesis via a rotary engine of the cell called ATP synthetase (4). Pyruvate, a downstream product of cytosol-based glycolysis, along with fatty acids, are imported into the mitochondria and processed via the tricarboxylic acid (TCA) or citric acid cycle into high-energy reduced coenzymes, nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), which consequently donate electrons into the electron transport chain (ETC) in the production of ATP (17). Electrons are successively passed down an electrochemical gradient to the final electron acceptor, diatomic oxygen (O2), via a chain of respiratory proton pumps embedded in the inner mitochondrial membrane, which is why humans need oxygen to survive (18).

The fact that mitochondria have distinct, bacteria-like circular genomes that are functionally and structurally disparate from the chromosomal assemblies residing in the nucleus supports the endosymbiosis hypothesis (19). Because most of the mitochondrial genome is scattered throughout chromosomal DNA, the mitochondria is referred to as a semi-autonomous organelle, as it relies on communication with the nucleus for expression of all its enzyme complexes and molecular constituents (5). Mitochondria, which are inherited in maternal fashion, “divide by binary fission and propagate distinct ‘lineages’ within each cell” (19, p. 269). However, unlike nuclear DNA, mitochondrial DNA (mtDNA) lacks protective histones, and hence is particularly susceptible to DNA damage from free radicals (20).

Thus, mitochondrial dysfunction has been increasingly linked to almost all pathologic and toxicologic conditions, including, “A wide range of seemingly unrelated disorders, such as schizophrenia, bipolar disease, dementia, Alzheimer’s disease, epilepsy, migraine headaches, strokes, neuropathic pain, Parkinson’s disease, ataxia, transient ischemic attack, cardiomyopathy, coronary artery disease, chronic fatigue syndrome, fibromyalgia, retinitis pigmentosa, diabetes, hepatitis C, and primary biliary cirrhosis” (3, 15, p. 84). Recently, however, pioneering researchers such as Michael Gonzalez and colleagues have elucidated a unified theory of carcinogenesis where mitochondria are at the nexus of dysfunction in cancer pathogenesis (2).

Cancer As A Pre-Symbiotic, Primordial State

Emerging data, which considers malignancy through an ecological lens, recognizes cancer not as a predetermined genetic time bomb due to defective genes, but rather as an evolutionary throwback to a time where more rudimentary cooperation between free-floating cells existed, which allowed their survival in nutrient depleted, increasingly uninhabitable environments. This view is articulated by Davies and Lineweaver (2011), who state,

“We hypothesize that cancer is an atavistic condition that occurs when genetic or epigenetic malfunction unlocks an ancient ‘toolkit’ of pre-existing adaptations, re-establishing the dominance of an earlier layer of genes that controlled loose-knit colonies of only partially differentiated cells, similar to tumors” (1).

This is similarly articulated by Davila and Zamorano (2013), who discuss how, “Some of the hallmarks of cancer such as uncontrolled cell proliferation, lack of apoptosis, hypoxia, fermentative metabolism and free cell motility (metastasis) are akin to a prokaryotic lifestyle, suggesting a link between cancer disease and evolution” (21). They note that cancer represents a phenotypic reversion to the most preliminary stage of eukaryotic evolution, that of a heterotrophic, facultative anaerobe that is suited for survival and replication in oxygen-poor, hypoxic environments (21). The authors state that this occurs due to cumulative oxidative damage to both maternally inherited mtDNA and nuclear DNA and to mitochondrial insufficiency, or uncoupling between electron transfer and chemiosmotic ATP synthesis (21).

In particular, the bioenergetic theory of carcinogenesis proposed by Gonzalez and colleagues proposes that the replacement of oxygen-dependent aerobic respiration by aerobic glycolysis and lactic-acid producing fermentation, phenomena first characterized in cancer cells over ninety years ago by Nobel Laureate Otto Warburg, favors carcinogenesis (2). In the hypoxic micro-environment in which cancer develops, a metabolic transition from obligate anaerobe to partial anaerobe, accompanied by enhanced glycolytic flux, takes place, which ensures survival in oxygen-poor conditions (22).

The switch from mitochondrial-based glucose oxidation to cytosol-based aerobic glycolysis, or glycolysis in the presence of oxygen, is why positron emission tomography (PET) scans can be used to localize tumors and metastases, since the labeled glucose gravitates towards malignant tissue with a high rate of glycolysis (2). The propensity of tumor cells for increased glycolytic flux also confers resistance to apoptosis, or programmed cell death, which allows cancer cells to evade cell suicide signals (23, 24). Without electron flow down the ETC, mitochondria also lack the energy for depolarization and synthesis of reactive oxygen species (ROS), which are crucial redox signals required for apoptosis (25, 26).

Cancer Thrives in An Acidic Body

As a corollary, cancer cells lack superoxide dismutase (SOD), one of the endogenous antioxidant defense systems that protects mitochondrial genes and proteins from the free radical byproducts of the citric acid cycle (27). As a result, free radicals impair the citric acid cycle and pyruvate is instead shuttled into lactic acid, perpetuating lactic acidosis. In fact, when succinate, a tricarboxylic acid (TCA) cycle intermediate, is added to cancer cell lines, the rate of respiration remains stagnant, which demonstrates that cancer cells cannot utilize the citric acid cycle (17).

In particular, fermentation by malignant cells facilitates the generation of acidic pH in cancerous tissues due to lactic acid production, a hallmark of aggressive cancer growth (22, 28). Production of lactate begins to dwarf that of pyruvate, which results in less activity of the TCA cycle, and less generation of the energized intermediates NADH and FADH2 to fuel oxidative phosphorylation (2). What’s more, lactate accumulation promotes tumor growth by activating angiogenesis, or the formation of new blood cells to supply the tumor with nutrients, and by degrading extracellular matrix, which allows tumor expansion and augments potential for metastasis (29).

In addition, the adverse change in pH engender voltage differences in cell membranes, which may disrupt communication, cause electrical uncoupling, induce mitosis, and lead to further derangements in proton and electron efflux (2). Further, membrane potential disruption and consequent accumulation of a surplus of negative ions in the extracellular milieu repels erythrocytes and lymphocytes, shielding cancer cells from oxygen- and immune-mediated destruction, respectively (2). This sequestering effect and decrease in immune reactivity is compounded by the formation of coagulated proteins around transformed cells, which in turn prohibits access of host immune defenses to combat cancer (2).

Compared to the complete aerobic oxidation of glucose, which generates 38 ATP per mole of glucose, substrate-level phosphorylation via glycolysis is relatively energy inefficient, yielding only 2 ATP per mole of glucose (2). In addition to diminished internal resources of the malignant cell due to preferential use of glycolysis, cancer interferes with electrical impedance, sodium-potassium membrane pump function, and the enzymes of the respiratory complexes embedded within the inner mitochondrial membrane, such that intercellular communication and membrane dynamics are jeopardized (2, 30).

These metabolic limitations, in concert with the decreased mitochondrial content, lead to an enormous reduction in energy reserve, with the average cancer cell having less than one-twentieth the energy of a healthy cell (2). Hypoxia-inducible factor (HIF), which is activated as a consequence of the hypoxic microenvironment in which cancer develops, up-regulates expression of glucose receptors and glycolytic enzymes in attempt to reflexively compensate for the diminished efficiency of glycolysis compared to oxidative phosphorylation (31).

In sum, incessant cellular insult, as a result of the micronutrient depletion, sedentary lifestyle, psychosocial stress, and toxicant exposure to which most of us are subjected, culminates in a transformed cell phenotype where cellular apoptotic mechanisms are compromised and cellular metabolism becomes deranged. Hence, cancer arrives on the scene as an adaptation to the traumatic living circumstances of modernity.

Mitochondrial Metabolic Correction

Restoration of mitochondrial function is of the utmost importance, since mitochondrial remodeling, or mitochondrial dysbiosis, defined as the process whereby “mitochondria can dissolve their symbiosis with the cell host, and no longer function in harmony with the cell,” is a distal molecular pathway common to all cancer cells (29, 2, p. 436). Instead of treating cancer like a foreign entity to be eradicated, cancer should be re-conceptualized as cells that have lost their way, and have begun operating as unicellular, independent entities, profligately replicating and forming a protista colony of sorts as a survival mechanism (2). In this model, cells need to be supplied with the proper conditions to be coaxed back to their normal phenotype, re-differentiate, and regain local tissue communication and architecture.

Dr. Michael Gonzalez and colleagues reiterate these foundational principles of Nobel laureate Szent-Györgyi with, “Efficient oxidative energy production is associated with organized cell structure, whereas fermentation is associated with lack of structure and the inclination to cell division” (2, p. 437). Because the cardinal difference between normal and cancer cells is the use of fermentation by the latter to meet energy demands, restoring aerobic respiration, or correcting mitochondrial function to promote induction of apoptosis in cancer cells, should be clinical priorities, rather than decimating the very immune defenses that fight cancer with radiation and chemotherapy.

Therefore, undertaking a program of mitochondrial correction, including a nutrient-dense, paleolithic diet to which our physiology is accustomed, and nutraceuticals needed for aerobic respiration, repolarization, and membrane repair, could potentially reverse cancer (2). This phenomenon is illustrated by the observation that suppression of mitochondria promotes cancer growth in normal cells, whereas inhibition of glycolysis leads to rapid death of cancer cells (2). Likewise, animal models and in vitro studies have illuminated decreased rates of tumor growth with normalization of mitochondrial function (32).

Dietary Considerations for Mitochondrial Renewal

A primarily plant-based paleo diet rich in fruits and vegetables and devoid of processed foods, high-glycemic foods, flour, sugar, coffee, and alcohol, will promote blood alkalinity, which is important since alkaline solutions favor oxygen absorption, whereas acidic solutions favor oxygen release (2). Mitochondrial matrix enzymes operate best in an alkaline environment, whereas acidity disturbs membrane potential, resulting in cellular malfunction, compromised energy production, and carcinogenesis (33, 34, 35). A nutrient-dense, phytonutrient-replete diet will provide the blood with the minerals to maintain an alkaline pH and to retain oxygen(2).

A high fat, low carbohydrate ketogenic paleo template diet is ideal, since ketogenic diets increase circulating ketone bodies while decreasing blood glucose levels, thus restricting energy supplied to cancer cells (36). Ketones, which bypass glycolysis and enter the mitochondria directly for oxidation, are a viable alternative energy source for wild-type cells with normal mitochondrial function, but cannot be utilized by cancer cells since they lack metabolic flexibility (37, 38, 39). Furthermore, ketone bodies are inherently anti-inflammatory, reducing ROS while augmenting activity of glutathione peroxidase, one of the endogenous antioxidant defense systems (37, 40).

In addition, ketogenic diets are often accompanied by dietary energy reduction (DER), which elicits anti-cancer effects through inhibition of the IGF-1/PI3K/Akt/HIF-1alpha pathway that cancer cells hijack to suppress apoptosis and to engender proliferation and angiogenesis (36). DER induces apoptosis in astrocytoma cells and has demonstrated anti-tumor effects in brain, colon, gastric, lung, mammary, prostate, and pancreatic cancer (36). The ketogenic diet administered in restricted amounts also significantly improves health and longevity of mice with malignant brain tumors relative to controls receiving a low fat high carbohydrate diet (40). The calorie-restricted ketogenic diet likewise decreases micro-vessel density in tumors and has been shown to lead to 65% and 35% lower orthotropic growth rates of implanted malignant mouse astrocytoma and human malignant gliomas, respectively, in animal models (40).

Hyperbaric Oxygen Therapy

In light of the observations that white blood cells kill cancer cells by injecting them with oxygen in the form of hydrogen peroxide, and that depleting oxygen induces cellular mutation, one of the clinical objectives of cancer treatment should be increasing cellular oxygenation (2). Promoting oxygenation, and hence better detoxification, through therapies such as hyperbaric oxygen therapy (HBOT), will promote down-regulation of the expression of cancer-related genes such as HIF-1 (41).

Poff and colleagues (2013) elucidate how, “Abnormal tumor vasculature creates hypoxic pockets which promote cancer progression and further increase the glycolytic-dependency of cancers” (36, p. e65522). Tumor hypoxia not only renders cancer cells three-times as resistant to radiation therapy than well-oxygenated cells, but it also stimulates oncogenic biochemical pathways that facilitate tumor growth, angiogenesis, metastasis, and inhibition of apoptosis via the transcription factor HIF-1 (42, 43, 44). Saturating the tumors with hyperbaric oxygen chamber therapy, in contrast, enables adequate tissue perfusion, effectively reversing the cancer-permissive effects of hypoxia (36).

In addition to inhibiting tumor growth, depleting blood vessel density within mutated cells, and promoting expression of anti-cancer genes in animal models, hyperbaric oxygen therapy up-regulates production of ROS by tumor cells to enhance efficacy of the standards of care (36). In a mouse model of metastatic cancer, the ketogenic diet in concert with hyperbaric oxygen therapy led to significant decreases in blood glucose and tumor growth rate and produced a 77.0% average increase in survival time compared to controls (36). Quintessentially, by increasing delivery of oxygen to tissues independent of hemoglobin oxygen saturation, hyperbaric oxygen therapy has the potential to restore aerobic respiration over the substrate-level phosphorylation that occurs in glycolysis (45).

Targeted Nutraceuticals

Furthermore, a cancer-mitigating diet should be rich in micronutrients needed to sustain the biochemical pathways that extract and convert energy from organic molecules into biologically accessible forms (4). Restoration of oxidative respiration will cause the synthesis of oxidation byproducts, which normally translocate from the cytosol to the nucleus, influencing gene expression in a way favoring re-differentiation away from the primitive mutagenic phenotype (46).

Targeted orthomolecular use of mitochondrial support, such as alpha lipoic acid, acetyl-L-carnitine, coenzyme Q10, magnesium, D-ribose, PQQ, creatine, and B complex may also be warranted (4). Phospholipids replacement therapy is also integral to mitochondrial repair since damage to the lipid bilayer and to the dual-layered mitochondrial membrane precedes mitochondrial damage (47).  Further, ascorbate, or vitamin C, administered intravenously in particular, may restore normal apoptosis in cancer cells by augmenting electron flux, increasing generation of ATP, and facilitating re-differentiation to a normal phenotype (4, 33).\

Removal of Offending Agents

Lastly, exposure to mitochondrial toxicants, such as xenobiotics and persistent organic pollutants which damage the mitochondrial membrane, should be minimized (4). Importantly, medications such as psychotropic drugs, analgesics, anti-inflammatory agents, antibiotics, anticonvulsants, statins, steroids, chemotherapy, and drugs for diabetes and HIV/AIDS are major contributors to mitochondrial damage (4). Although many medication side effects and drug-induced toxicities are a direct consequence of mitochondrial dysfunction, the U.S. Food and Drug Administration (FDA) still does not mandate mitochondrial toxicity testing for pharmaceuticals (48).

According to Neustadt and Pieczenik (2007), medications can directly disable elements of the electron transport chain, inhibit transcription of electron transport chain complexes, or inhibit the enzymatic processes involved in beta-oxidation or glycolysis. Pharmaceutical drugs can also deplete endogenous antioxidants or nutrients required for mitochondrial function, or generate free radicals which damage mitochondrial structures (3).

Where Oncology is Failing, Mitochondrial Regeneration Can Succeed

The decision to use toxic chemotherapy, radiation, or trauma-inducing surgery—the only legally sanctioned cancer therapies, fraught with conflicts of interest and vested fiscal agendas—is a personal one, and should be made in concert with a licensed physician and your intuition as a guide. However, studies have shown that the percentage increase in five-year survival rate due to adjuvant and curative cytotoxic chemotherapy is only 2.1% in the United States and 2.3% in Australia (49). Another comprehensive analysis of over 3,000 clinical trials determined that there is no direct evidence that chemotherapy prolongs survival in advanced carcinoma, apart from small-cell lung cancer (50).

Researchers state, “Many oncologists take it for granted that response to therapy prolongs survival, an opinion which is based on a fallacy and which is not supported by clinical studies” (50). In other words, tumor shrinkage does not translate into survival advantages over ‘watch and wait’ approaches in many cancers (51). Further, because chemotherapy and radiation do not target the self-renewing cancer progenitor cells known as cancer stem cells, secondary cancers that re-emerge are usually more aggressive and fatal. In fact, radiation generates therapy-resistant cancer stem cells, such that lingering cancer cells become more malignant (52).

A more holistic vantage point should be adopted regardless of the therapies a cancer patient employs, addressing latent infections, micronutrient and fatty acid deficiencies, hormonal imbalances, toxicant exposures, dysbiosis, inflammatory underpinnings, psychospiritual stress, and mitochondrial insufficiency, all of which contribute to a hostile, threatening environment which cause cells to harken back to a pathological, undifferentiated, cancerous phenotype.

Researcher and clinician Dr. Michael Gonzalez, who is using some of these targeted therapies in his clinic, has witnessed better quality of life and increased survival time in cancer patients compared to use of conventional therapies alone. He states, “I truly believe that the bioenergetic theory of carcinogenesis describe the root of cancer…and will pave the way for a new understanding of cancer as a metabolic mitochondrial disease, leading to more effective, less toxic, and user-friendly treatments”.


Vitamin C kills tumor cells with hard-to-treat mutation

PET scans reveal glucose-hungry tumors (here lung masses) that may be susceptible to vitamin C therapy.

PET scans reveal glucose-hungry tumors (here lung masses) that may be susceptible to vitamin C therapy.

Maybe Linus Pauling was on to something after all. Decades ago the Nobel Prize–winning chemist was relegated to the fringes of medicine after championing the idea that vitamin C could combat a host of illnesses, including cancer. Now, a study published online today in Science reports that vitamin C can kill tumor cells that carry a common cancer-causing mutation and—in mice—can curb the growth of tumors with the mutation.

If the findings hold up in people, researchers may have found a way to treat a large swath of tumors that has lacked effective drugs. “This [could] be one answer to the question everybody’s striving for,” says molecular biologist Channing Der of the University of North Carolina, Chapel Hill, one of many researchers trying to target cancers with the mutation. The study is also gratifying for the handful of researchers pursuing vitamin C, or ascorbic acid, as a cancer drug. “I’m encouraged. Maybe people will finally pay attention,” says vitamin C researcher Mark Levine of the National Institute of Diabetes and Digestive and Kidney Diseases.

In 1971, Pauling began collaborating with a Scottish physician who had reported success treating cancer patients with vitamin C. But the failure of two clinical trials of vitamin C pills, conducted in the late 1970s and early 1980s at the Mayo Clinic in Rochester, Minnesota, dampened enthusiasm for Pauling’s idea. Studies by Levine’s group later suggested that the vitamin must be given intravenously to reach doses high enough to kill cancer cells. A few small trials in the past 5 years—for pancreatic and ovarian cancer—hinted that IV vitamin C treatment combined with chemotherapy can extend cancer survival. But doubters were not swayed. “The atmosphere was poisoned” by the earlier failures, Levine says.

A few years ago, Jihye Yun, then a graduate student at Johns Hopkins University in Baltimore, Maryland, found that colon cancer cells whose growth is driven by mutations in the gene KRASor a less commonly mutated gene, BRAFmake unusually large amounts of a protein that transports glucose across the cell membrane. The transporter, GLUT1, supplies the cells with the high levels of glucose they need to survive. GLUT1 also transports the oxidized form of vitamin C, dehydroascorbic acid (DHA), into the cell, bad news for cancer cells, because Yun found that DHA can deplete a cell’s supply of a chemical that sops up free radicals. Because free radicals can harm a cell in various ways, the finding suggested “a vulnerability” if the cells were flooded with DHA, says Lewis Cantley at Weill Cornell Medicine in New York City, where Yun is now a postdoc.

Cantley’s lab and collaborators found that large doses of vitamin C did indeed kill cultured colon cancer cells with BRAF or KRAS mutations by raising free radical levels, which in turn inactivate an enzyme needed to metabolize glucose, depriving the cells of energy. Then they gave daily high dose injections—equivalent to a person eating 300 oranges—to mice engineered to develop KRAS-driven colon tumors. The mice developed fewer and smaller colon tumors compared with control mice.

Cantley hopes to soon start clinical trials that will select cancer patients based on KRAS or BRAFmutations and possibly GLUT1 status. His group’s new study “tells you who should get the drug and who shouldn’t,” he says. Cancer geneticist Bert Vogelstein of Johns Hopkins University, in whose lab Yun noticed the GLUT1 connection, is excited about vitamin C therapy, not only as a possible treatment for KRAS-mutated colon tumors, which make up about 40% of all colon cancers, but also for pancreatic cancer, a typically lethal cancer driven by KRAS. “No KRAS-targeted therapeutics have emerged despite decades of effort and hundreds of millions of dollars [spent] by both industry and academia,” Vogelstein says.

Others caution that the effects seen in mice may not hold up in humans. But because high dose vitamin C is already known to be safe, says cancer researcher Vuk Stambolic of the University of Toronto in Canada, oncologists “can quickly move forward in the clinic.”

One drawback is that patients will have to come into a clinic for vitamin C infusions, ideally every few days for months, because vitamin C seems to take that long to kill cancer cells, Levine notes. But Cantley says it may be possible to make an oral formulation that reaches high doses in the blood—which may be one way to get companies interested in sponsoring trials.

Contraceptive pill could increase breast cancer risk more than experts first thought, study finds

Nonetheless, experts say birth control has a positive effect on the lives of women

 Taking the contraceptive pill could increase your risk of breast cancer more than previously feared, new research suggests.

A study from the University of Michigan has revealed that some commonly prescribed birth control pills may quadruple levels of synthetic oestrogen and progesterone hormones.

Both of which are thought to play a part in stimulating breast cancers to grow, which is why some breast cancer patients are prescribed hormone therapy to block their effects on cancer cells.

The research showed that blood taken from women who use birth control pills contained much higher levels of hormones compared to women who don’t.

And, that four out of seven formulations tested were found to quadruple the levels of progestin, a synthetic version of the hormone progesterone.

Another formulation also resulted in 40 per cent higher exposure to ethinyl estradiol,  synthetic version of oestrogen.

Despite the findings, the study’s lead author, human evolutionary biologist Beverly Strassmann, stressed that the contraceptive pill has had such a positive effect on the lives of so many women.

But, that it’s also important for companies to design birth control pills in a way that doesn’t contribute to a greater risk of breast cancer.

“Not enough has changed over the generations of these drugs and given how many people take hormonal birth control worldwide — millions — the pharmaceutical industry shouldn’t rest on its laurels,” she said.

Previously commenting on the links between breast cancer and birth control, the NHS states that, “the baseline risk of women of a fertile age developing breast cancer is small,” and that “Unfortunately, there are often no easy answers when weighing up the benefits and risk.”

Cancer Research UK currently advises that as little as one per cent of breast cancers in women are a result of oral contraceptives.

“The protective effects of the pill against womb and ovarian cancers last longer than the increased risks of breast and cervical cancers,” it says.

“Overall, this means that the protective effects outweigh the increased risk of cancer if you look at all women who have taken the pill.”

Gene therapy technique may help prevent cancer metastasis. 

The spread of malignant cells around the body, known as metastasis, is the leading cause of mortality in women with breast cancer.

Now, a new gene therapy technique being developed by researchers at MIT is showing promise as a way to prevent breast cancer tumors from metastasizing.

The treatment, described in a paper published today in the journal Nature Communications, uses microRNAs—small noncoding RNA molecules that regulate gene expression—to control metastasis.

The therapy could be used alongside chemotherapy to treat early-stage breast cancer tumors before they spread, according to Natalie Artzi, a principal research scientist at MIT’s Institute for Medical Engineering and Science (IMES) and an assistant professor of medicine at Brigham and Women’s Hospital, who led the research in collaboration with Noam Shomron, an assistant professor on the faculty of medicine at Tel-Aviv University in Israel.

“The idea is that if the cancer is diagnosed early enough, then in addition to treating the primary tumor [with chemotherapy], one could also treat with specific microRNAs, in order to prevent the spread of cancer cells that cause metastasis,” Artzi says.

The regulation of gene expression by microRNAs is known to be important in preventing the spread of cancer cells. Recent studies by the Shomron team in Tel-Aviv have shown that disruption of this regulation, for example by genetic variants known as single nucleotide polymorphisms (SNPs), can have a significant impact on gene expression levels and lead to an increase in the risk of cancer.

To identify the specific microRNAs that play a role in breast cancer progression and could therefore potentially be used to suppress metastasis, the research teams first carried out an extensive bioinformatics analysis.

They compared three datasets: one for known SNPs; a second for sites at which microRNAs bind to the genome; and a third for breast cancer-related genes known to be associated with the movement of cells.

This analysis revealed a variant, or SNP, known as rs1071738, which influences metastasis. They found that this SNP disrupts binding of two microRNAs, miR-96 and miR-182. This disruption in turn prevents the two microRNAs from controlling the expression of a protein called Palladin.

Previous research has shown that Palladin plays a key role in the migration of breast cancer cells, and their subsequent invasion of otherwise healthy organs.

When the researchers carried out in vitro experiments in cells, they found that applying miR-96 and miR-182 decreased the expression of Palladin levels, in turn reducing the ability of breast cancer cells to migrate and invade other tissue.

“Previous research had discussed the role of Palladin in controlling migration and invasion (of cancer cells), but no one had tried to use microRNAs to silence those specific targets and prevent metastasis,” Artzi says. “In this way we were able to pinpoint the critical role of these microRNAs in stopping the spread of breast cancer.”

The researchers then developed a method to deliver engineered microRNAs to breast cancer tumors. They embedded nanoparticles containing the microRNAs into a hydrogel scaffold, which they then implanted into mice.

They found that this allowed efficient and precise delivery of the microRNAs to a target breast cancer tumor site. The treatment resulted in a dramatic reduction in breast cancer metastasis, says Artzi.

“We can locally change the cells in order to prevent metastasis from occurring,” she says.

To increase the effectiveness of the treatment even further, the researchers then added the chemotherapy drug cisplatin to the nanoparticles. This led to a significant reduction in both the growth of the primary tumor, and its metastasis.

“We believe local delivery is much more effective (than systemic treatment), because it gives us a much higher effective dose of the cargo, in this case the two microRNAs and the cisplatin,” she says.

“The research offers the potential for combined experimental therapeutics with traditional chemotherapy in cancer metastasis,” says Julie Teruya-Feldstein, a professor of pathology at Mount Sinai Hospital in New York, who was not involved in the study.

The research team, which also includes MIT post doc Joao Conde and graduate student Nuria Oliva, both from IMES; graduate student Avital Gilam and postdoc Daphna Weissglas-Volkov, from Tel-Aviv University; and Eitan Friedman, an oncogeneticist from Chaim Sheba Medical Center in Israel, now hopes to move on to larger animal studies of the treatment.

“We are very excited about the results so far, and the efficacy seems to be really good. So the next step will be to move on to larger models and then to clinical trials, although there is still a long way to go,” Artzi says.


The business of cancer. 

The word called cancer is a lie…You might not believe this but cancer is not a disease; it is a business.Cancer consists of only a deficiency of vitamin B17. It is nothing else.Cancer has become widespread; it has affected the old, young, baby and everyone.Sharing this wonderful post will expose many of the hidden hands of the world’s manipulators and annoy them.
Do you know that the book “World Without Cancer” has up till now been prevented from being translated into many world languages?

Know this: there is no disease called cancer. Cancer consists of only a deficiency of vitamin B17. It is nothing else.

Avoid chemotherapy, surgery and or taking medicines with strong side effects.

You would recall that in the past, quite a large number of seamen lost their life to a named disease (scurvy); a disease that took the life of numerous people as well. And a number of people got an enormous income from it. Afterwards, it was discovered that scurvy was just a deficiency of vitamin C. That means it wasn’t a disease (illness).

Cancer is also just like that! The colonizing world and the enemies of humanity established the cancer industry and made it into a business. from which they earn billions in income.

The cancer industry flourished after world war II. To fight cancer, all these delays, details and enormous expenditures are not needed. They only go to line the pockets of colonizers, especially since the cure for the condition was found long ago.

The prevention and cure of cancer will be obtained simply through the following strategies:

Those who have cancer should first try to know what cancer is. Do not panic! You should investigate the condition.

Nowadays does anyone die of an illness called scurvy? No. Because it gets cured.

Since cancer is only a deficiency of vitamin B17, eating 15 to 20 pieces of apricot stone/nucleus (fruit stone) everyday is enough.

Eat wheat bud (wheat sprouts). Wheat bud is a miraculous anti-cancer medicine. It is a rich source of liquid oxygen and the strongest anti-cancer matter named laetrile. This matter is present in the fruit stone of apple and is the extracted form of vitamin B17 (Amygdalin).

The American medicinal industry has started implementing the law forbidding laetrile production. This medicine is being manufactured in Mexico and gets smuggled into USA.

Dr. Harold W. Manner, in a book named “Death of Cancer” has stated that the success of cancer treatment with laetrile is as high as above 90%.

Sources of Amygdalin (Vitamin B17)

The foods containing vitamin B17 include the following:

-The fruit stone or grain(seed) of fruits. This contains the highest amount of vitamin B17 in nature. This includes fruit stone of apple, apricot, peach, pear, and prune (dried plum).

-Common beans, corns(grains), which include bean, lentil sprout (lentil bud) Lima (Lima beans) and pea.

-Kernels: Bitter Almond (Richest source of vitamin B-17 in nature) and Indian almond.

-Mulberries: almost all mulberries such as black mulberry, blueberry, raspberry and strawberry.
-Seeds (Grains): sesame and linseed (seed of linen/flax seed).
-Groats of oats, barley, brown rice, groats of block wheat, linseed, millet and rye.
This vitamin is found in grains and fruit stones of apricot, brewer’s yeast, rough rice (paddy) and sweetmeat pumpkin.
List of Anti-Cancer Foods

•Apricots (kernels/seeds)

•seeds from other fruits like apples, cherries, peaches, prunes, plums, pears

•Lima beans

•Fava beans













•Macadamia nuts

•Bean sprouts

All are the highest sources of absorbable vitamin B17.
Ingesting dish washing liquids (used in the kitchen) and hand washing liquid (used in the restroom) is the main cancer causing factor so your eating of them should be restricted.You will surely say that we do not eat them!

However, you daily wash your hands with hand washing liquid and wash your plates with dish washing liquid.The liquid is absorbed and will not leave the plate with washing. When cooking or eating food, the soap in the plate or dish gets attached to the hot food and so we end up eating the dish washing liquid with our food. Even if you rinse the plate hundreds of times, that will be of no use.
But the solution is to pour half of the dishwashing liquid and hand washing liquid and top it up with vinegar.

It is as simple as that.Do not eat blood cancer causing agents and also save your family from this danger.Similarly, seriously desist from washing vegetables with even a few drops of dishwashing liquid because irrespective of how much you would rinse them, the chemicals would have already entered the tissues of the vegetable and will not get rinsed away.Instead, soak fruits and vegetables with salt and then rinse with water. And to keep them fresh, add vinegar.

Mediterranean diet could slash risk of deadly breast cancer by 40pc


A table with Mediterranean food laid out
A diet high in fruit, vegetables and olive oil could stave off heart attacks and strokes 
Eating a Mediterranean diet can help reduce risk of one of worst types of breast cancer by 40 per cent, a major study suggests.

The research which tracked more than 60,000 women over two decades found that those who ate a diet rich in fruit, vegetables, fish, nuts, whole grains and olive oil had a far lower chance of developing an aggressive form of the disease.

Every year, 53,000 women in the UK are diagnosed with breast cancer.

The major new study funded by the World Cancer Research Fund, which tracked women aged between 55 and 69 for 20 years, found that those who adhered most closely to a Mediterranean diet had a far lower chance of disease.

Overall, they had a 40 per cent reduced risk of oestrogen-receptor negative breast cancer.

Around one in three cases of breast cancer falls into this category, which is more deadly than other types of disease.

The Mediterranean Diet pattern is one that includes a high intake of plant-based proteins, such as nuts, lentils and beans, whole-grains, fish and monounsaturated fats – also known as “good fats”, such as olive oil.

This diet also has a low intake of refined grains such as white bread or white rice, red meat and sweets.

Med diet
The Mediterranean diet has been linked to a longer lifespan 

Although the traditional Mediterranean Diet involves moderate consumption of alcohol, in this study alcohol was excluded from the criteria, as this is a known risk factor for breast cancer, and linked to 12,000 cases annually.

Breast cancer is the most common cancer in women in the UK with over 53,000 new cases each year.

Around 40 per cent of all cancers are linked to lifestyle, with breast cancer risks heightened by excess weight, poor diet, alcohol and smoking.

Dr Panagiota Mitrou, Director of Research Funding at World Cancer Research Fund, said:

“This important study showed that following a dietary pattern like the Mediterranean Diet, could help reduce breast cancer risk – particularly the subtype with a poorer prognosis. With breast cancer being so common in the UK, prevention is key if we want to see a decrease in the number of women developing the disease.

“We would welcome further research that helps us better understand the risk factors for the different breast cancer subtypes.”

Professor Piet van den Brandt, lead researcher on this study at Maastricht University said:

“Our research can help to shine a light on how dietary patterns can affect our cancer risk.

“We found a strong link between the Mediterranean Diet and reduced estrogen-receptor negative breastcancer risk among postmenopausal women, even in a non-Mediterranean population. This type of breast cancer usually has a worse prognosis than other types of breast cancer”.

Emma Pennery, Clinical Director at Breast Cancer Care, said the findings were “intriguing”.

“This study adds to evidence that a healthy diet, full of ‘good’ low-saturated fats, plays a part in lowering risk of the disease,” she said.

“However, it’s important to remember while lifestyle choices like eating a well-balanced diet and taking regular exercise can help reduce the risk of cancer, they don’t guarantee prevention. So it’s crucial women know the signs and symptoms of breast cancer, and contact their GP with any concerns.”

 A plate of fish
Swapping red meat for fish and upping fruit and vegetable intake lowers the chance of heart problems 

Separate US research found that women already being treated for breast cancer could boost survival chances by eating a diet rich in soy.

Women with estrogen-receptor negative breast cancer who added the Japanese ingredient to their diet were able to reduce their risk of dying by up to a fifth, the study found.

Scientists founds that foods rich in isoflavones – the active ingredient in soy – appeared to boost survival.

The ingredient is found in meat replacement foods such as tofu, as well as in soy sauce, Miso soup, soy milk and edamame beans.

Study leader Dr Esther John, of the Cancer Prevention Institute of California, said: “Whether lifestyle factors can improve survival after diagnosis is an important question for women diagnosed with this more aggressive type of breast cancer.

“Our findings suggest that survival may be better in patients with a higher consumption of isoflavones.”

Berkeley Doctor Claims People Die From Chemo, Not Cancer

According to one scientist, refusing chemotherapy may be the key to beating cancer.

Dr Hardin B Jones, formerly of Berkeley, says that compared to people who undergo chemo, patients who refuse treatment live an average of 12 and a half years longer.

Given that approximately 1 in 2 men and 1 in 3 women will develop cancer in their lifetimes, this is quite an extraordinary claim.

In the stunning video below, Dr Jones, a former professor of medical physics and physiology at the University of California, Berkeley, says ‘leading edge’ cancer treatment is a sham.

His personal research, he says, concludes that chemotherapy does more harm than good.

“People who refused chemotherapy treatment live on average 12 and a half years longer than people who are undergoing chemotherapy,” said Dr. Jones of his study, which was published in the New York Academy of Science.

According to the physician, the only reason doctors prescribe chemotherapy is because they make money from it.

Such an accusation doesn’t seem unreasonable, as cancer treatment runs, on average, between $300,000 – $1,000,000 per treatment.

Watch the video discussion. URL:

Pembrolizumab Approved for Tumors with Specific Genetic Features. 

On May 23, the Food and Drug Administration (FDA) granted accelerated approval to the immunotherapy pembrolizumab (Keytruda®) for patients with solid tumors that have one of two specific genetic features known as mismatch repair deficiency and high microsatellite instability. The approval covers adult and pediatric patients whose cancer has progressed despite prior treatment and who have no alternative treatment options.

This is the first time that FDA has approved a cancer treatment based solely on the presence of a genetic feature in a tumor, rather than the patient’s cancer type.

“I think this is a step forward for precision medicine,” said James Gulley, M.D., Ph.D., head of the immunotherapy section of NCI’s Center for Cancer Research.

The approval provides another option for some patients who would not otherwise be candidates for treatment with pembrolizumab, such as those with pancreatic cancer, Dr. Gulley continued. But for some cancer types, he cautioned, only a small number of patients typically have these genetic features.

Mismatched DNA

The process of mismatch repair enables cells to correct mistakes in their DNA code that sometimes occur during DNA replication. It’s “like a spell-checker” for DNA, explained Dr. Gulley. Mismatch repair deficient (dMMR) cells, which lack this failsafe process, acquire multiple DNA mutations. Some dMMR cells acquire alterations in short, repetitive DNA sequences called microsatellites and are referred to as microsatellite instability-high (MSI-H).

Tumors that are dMMR and MSI-H are found in patients with Lynch syndrome, a genetic disorder caused by mutations in genes that control DNA mismatch repair. In addition, these genetic features can spontaneously occur in tumors and have been found in patients with several cancer types—most commonly colorectal, endometrial, and gastrointestinal cancers.

Compared with other tumors, dMMR and MSI-H tumors have a higher frequency of DNA mutations and, as a result, higher levels of abnormal antigens. Because immune cells attack cells that have abnormal antigens, researchers have hypothesized that immune cells may be more likely to recognize and attack dMMR and MSI-H tumor cells. Studies have suggested that this vulnerability, in turn, may make these tumors more susceptible to therapies like pembrolizumab that ramp up the immune response.

Regardless of Cancer Type

Patients with certain cancer types, like lung cancer and melanoma, typically have good responses to immune checkpoint inhibitors such as pembrolizumab. But not every patient with one of these cancer types responds well to the treatment. More recently, researchers have found that it’s the patients with tumors that have more DNA mutations, like dMMR and MSI-H tumors, that are most likely to respond.

So “why group tumors by cancer type,” when these genetic features are the more telling characteristic, remarked Dr. Gulley. What’s novel about the studies that led to the FDA approval, he explained, is that the investigators included any patient with a dMMR or MSI-H tumor, regardless of the cancer type.

The FDA approval is based on combined results from five single-arm clinical trials that evaluated the efficacy of pembrolizumab.

The investigators used standard lab tests to identify a total of 149 patients with 15 different types of cancer whose tumors were MSI-H or dMMR. All patients received one of two doses of pembrolizumab. Altogether, 40% of patients with MSI-H or dMMR tumors had measurable tumor shrinkage after treatment, and for 78% of these responders, their tumors shrank or stayed the same size for 6 or more months.

In an interim analysis of one of the five trials, the investigators reported that, among patients with colorectal cancer, 40% of those with dMMR tumors and 0% of those with mismatch repair-proficient tumors responded to the treatment. The FDA approval includes patients with colorectal cancer whose disease has progressed after treatment with certain chemotherapy drugs.

In a more recent analysis of the same study, the investigators evaluated 86 patients with dMMR tumors from 12 different cancer types. After several weeks of treatment with pembrolizumab, they found that 53% of the patients had measurable tumor shrinkage and 21% had no signs of cancer.

To estimate the fraction of patients whose tumors have these genetic features, the investigators then evaluated the mismatch repair status of more than 12,000 tumors from 32 different cancer types and found that about 5% were dMMR. This translates to approximately 60,000 cases of cancer in the United States each year, they noted.

Among the five clinical trials, common side effects included fatigue, itchy skin, diarrhea, and rash. Although not reported in the studies, pembrolizumab can also cause serious, sometimes life-threatening, inflammation in a number of organs.

With the FDA approval, dMMR and MSI-H are now definitively considered biomarkers for predicting a good response to treatment with pembrolizumab, Dr. Gulley said. Ongoing studies are examining whether they are also biomarkers for treatment with other immune checkpoint inhibitors, he added.

Having a biomarker to identify patients who are most likely to respond is “an area we have widely anticipated as being the next step in understanding how to better use immunotherapies,” said Dr. Gulley. “It’s a welcome first step, and there’s much more yet to be done.”

Under FDA’s accelerated approval, the drug manufacturer must verify and further describe the clinical benefit of the treatment. In one follow-up trial, called KEYNOTE-177, investigators will compare pembrolizumab with standard therapy for patients with dMMR or MSI-H colorectal tumors. The trial is currently recruiting participants.