Friday, August 9, 2013

Bexion's Approach to Cancer Therapy by Dr. Gilbert Chang


Dr. Gilbert Chang, MD 


Dr. Gilbert Chang is a board certified pediatrician with North Bay Healthcare in Solano County, California, a midway point between San Francisco and Sacramento.  He has served for over fourteen as a primary care physician in California, treating a multitude of illnesses in children and young adults.  Unfortunately, Dr. Chang has encountered many young cancer patients over the years and has witnessed the suffering that accompanies the complex disease and its treatment. Frustrated by the results and curious of alternative options for his patients, Dr. Chang began to browse medical journals and internet articles for any cancer therapies that showed significant promise.  Luckily, he stumbled upon Bexion’s website and was intrigued to learn more about our innovative approach to cancer treatment.
After exchanging several e-mails and phone calls, Dr. Chang was able to visit Bexion’s headquarters in 2011 and was very encouraged to meet the staff and hear our story first-hand.  Dr. Chang has been a close friend of Bexion ever since and has continued to stay in touch regarding the company’s progress towards clinical trials.  To better educate his patients, their families, and other medical professionals unfamiliar with Bexion’s drug (BXQ-350), Dr. Chang composed a step-wise explanation of Bexion’s innovative approach to cancer treatment.  His thoughtful and methodical paper gives great insight into the current state of cancer drug development and the promise of Bexion’s outside-the-box thinking.  We at Bexion are grateful for Dr. Chang’s interest and insight.  His synopsis of BXQ-350 is presented here.


Part 1

            Every now and then in life, events or discoveries occur that defy conventional wisdom and knowledge. This can occur in fields as diverse as music, anthropology, medicine, and physics. Radical new ideas are almost always met with skepticism, caution, perplexity, and sometimes outright hostility. Eventually as the new knowledge is understood with the right perspective, it becomes accepted and integrated as if the controversy never existed in the first place.
            More than 10 years ago, a medical discovery occurred that defies conventional wisdom (even today). A lone researcher working in a basement laboratory at Cincinnati Children’s Hospital Medical Center (CCHMC) found a new potential therapy for cancer—something he wasn’t looking for in the first place. In fact, he was working in the Human Genetics Department studying Gaucher’s disease—something very rare and until the discovery something considered completely unrelated to cancer.
            The researcher’s name is Dr. Xiaoyang Qi. For whatever reason, he decided to mix two cellular components that cause problems with Gaucher’s disease (Phosphotidylserine and Saposin C) with cancer cells. When he looked at the cancer cells later on, he jumped with surprise because he realized the mixture killed the cancer cells.  It’s possible he considered this possibility and wanted to test it or just as likely he may have just mixed them for another reason. But as Pasteur said: “Luck favors the prepared mind.”
            Even though Dr. Qi did research mainly with Gaucher’s disease and is an expert with the protein Saposin C, he undoubtedly learned some cancer biology during his graduate studies. After seeing his mixture work, he knew how and why it worked.
           
Here’s the basic logic:

A+B+C->Z

X = A
Y = (B+C)

Therefore: X+Y->Z

Here’s the logic with the biochemical terms:

Acid + Phosphotidylserine + Saposin C -> cell death (known to occur in with some cells in the spleen in Gaucher’s disease)

Cancer = Acid environment outside of the cells
Drug = Phosphotidylserine + Saposin C

Therefore: Cancer cells + Drug -> cell death



Part 2 Unusual does not always mean Unlikely

It’s now 2013 and this drug, called BXQ-350, is on the cusp of being tested on humans to check for toxicity—a phase 1 study. In the past 10 years, more research has been done, a company formed, a patent obtained, and work done to produce a drug suitable to the FDA.
In Dr Qi’s 2009 Clinical Cancer Research article, he claims that this drug will have no side effects, can kill all cancer types including those that are chemotherapy resistant, starts off as a biological entity (as a very large complex in the form of a nanovesicle), and in the end utilizes the cell’s biochemical processes to induce programmed cell death.
At this point, almost all clinical oncologists and cancer researchers should be more than a bit skeptical with such lofty claims. No cancer drugs have zero side effects. There are not any cancer drugs that can kill all cancer cell lines especially the resistant ones. Decades of research and clinical experience with surgeries, radiation therapy, chemotherapies, and the newer “personalized medicine” drugs do not correlate with his assertions. This claim would seem to be both unusual and unlikely. If BXQ-350 does work, it must be with a totally different biological aspect of cancer not targeted with today’s drugs.
Here in Part 2, it’s recognized that BXQ-350 is an unusual drug born under unusual circumstances. Later on in Parts 3 and 4 a fuller scientific explanation is provided as to why it works and why in the end it is not an unlikely therapy for cancer at all. Here’s a chart and text detailing the normal versus BXQ-350’s unusual background—unusual aspects that could plant seeds of doubt.


Normal
BXQ-350
Lead time from science to drug development
Years between target and drug discovery.
Multiple articles.
One team finds target. Another team makes the drug.
Target and drug discovered at the same time.
One article.
One scientist found target and drug.
Small molecule drug versus Large molecule drug
Small chemically based molecule enters cells.
Large biologically based molecule attacks targets on the outside of cells.
2 large combined biologically based molecules combined that can enter cells.
Inhibit versus Activate
Chemotherapy, antibodies, and “personalized medicine” drugs inhibit proteins, enzymes, others.
Activates multiple enzymes.
Science
Drugs work by inhibiting cell division and cell growth
(more in Part 3)
Drug works by utilizing specific environment created by cancer cells’ modified version of apoptosis and energy creation.
(more in Parts 3 and 4)


1)      Lead Time from science to drug development

Let’s use Lipitor, the largest money maker to date, as an example. By 1973, medical researchers Brown and Goldstein discovered and stabilized HMG-CoA reductase, the rate-controlling enzyme responsible for cholesterol. By 1985, they received the Nobel Prize for their work. That same year, a medical chemist named Roth synthesized what proved to be the best statin to inhibit the enzyme and reduce cholesterol.

Most of today’s medical discoveries, including oncology, work this way. A scientist figures out a good target—usually a protein inside the cell or a surface protein on the outside. The target protein is tested against a university’s or a pharmaceutical company’s library of chemicals that can number in the tens of thousands. When one looks promising, a medical chemist will refine the chemical and that becomes the drug. This process usually takes many years with work from many different scientists. With Lipitor, 12 years passed from when the target was found until the best drug was developed. Usually, clinical oncologists and cancer researchers have years to read about and go to meetings to hear about the newest targets and the new drugs designed to attack these targets.

With Dr. Qi’s discovery, one researcher discovered both the target and the drug at the same time. This is unusual in the world of science today.

2)      Small molecule drug vs. Large molecule drug

Most drugs, like Lipitor or chemotherapy agents, are usually chemically based small molecules that travel through the blood stream, pass through semi-permeable cell membranes and inhibit an internal protein or cell component.

The other common cancer drugs are antibodies which are “Y” shaped large molecules that are part of the immune system. Many drugs are antibodies that have been programmed to specifically attach to a protein lodged on the outside of cells—surface proteins. Some cancers have specific surface proteins which make good targets. Since antibodies are normally found in the body, they are called biologic agents.

Some hormones, like growth hormone and insulin, are also large molecules. They work by attaching to cell receptor proteins located on the cell membrane which then leads to changes inside the cell. Hormones are normal components found in the body and are also biologic agents.

The drug, BXQ-350, is a large molecular complex that’s also a biologic agent since its 2 parts are normally found in the body like hormones. However unlike antibodies and hormones, a traditional target—a surface protein—is not found on the outside of the cell. Instead Saposin C targets specific phospholipids on the cell membrane that allow it to internalize into a cell. This makes BXQ-350 unusual: It is 2 large biologically-based combined molecules, but has the ability to enter cells like chemically-based small molecules. Also, it consists of 2 components versus antibodies or hormone drugs which only have 1 component.

3)      Inhibit vs. Activate

Chemotherapy and antibody drugs work by inhibiting or blocking a protein or other cell structure. BXQ-350 exists as a biological entity—a single layer (a unilamellar) nanovesicle. It spreads throughout the bloodstream and even enters the brain unimpeded by the blood brain barrier. It only targets cancer cells, enters them, and engages in a biochemical process by enhancing the function of many enzymes. This too is unusual.

4)      Science

The full details provided in Parts 3 and 4.

Part 3 will show that chemotherapy and “personalized medicine” drugs work by inhibiting cell division and cell growth, respectively. And will also show that BXQ-350 works in the unique environment created by cancer’s modified versions of apoptosis and energy creation.

Part 4 will give the full story of how BXQ-350 takes advantage of the specific environment created by the modified versions of apoptosis and energy creation by cancer.

Part 3 Cell Biology and Cancer Biology

Let’s first review some basic biology. This is a simplified, 2 dimensional, static picture of a cell.


Nucleus:          Holds DNA the code for the cell
Lysosome:       Holds acid and digestive enzymes used to destroy internal debris
Mitochondria: The power generator. Uses oxygen to produce ATP
Microtubules:  Provides structure to the cell
Rough ER:      Ribosomes take RNA code and create proteins

The cell is the basis of biology. It is a self contained machine with complexity greater than many man-made machines and an internal logic more complex than any computer. In it, millions of interactions occur as thousands of different kinds of proteins, lipids, DNA, RNA, and other cellular components float around and interact inside and outside the cell.

All of us started as one cell—a single fertilized egg with all the code needed to develop an entire human being built in. It takes a lot of work to go from one cell to an adult. In fact, it’s estimated that a full grown human has about 10 trillion cells (100 trillion if you count the bacteria that reside in and on us).

Here are 5 (of many) functions needed to do this:
1)      Add
2)      Grow
3)      Change
4)      Subtract
5)      Energy

1)      Add

To go from 1 cell to 10,000,000,000,000 cells takes a lot of cell divisions: what’s also called mitosis. Here’s a picture:

As you can see mitosis is a highly organized and precise process. Any mistake could lead to 1 or even 2 defective cells. And if a defective cell continues to divide, we have ourselves a cancer.

2)      Grow

We all start off as something like this: “.” a small dot probably 50-100 times smaller than the one you just looked at and yet amazingly it grew into you. Cells have the growth signal encoded in the DNA. A self-regulated pathway connects the growth signal from the DNA to cytosol proteins and to cell surface receptors and cycles back the other direction. This pathway ensures that the cells are able to recruit substrates and create new cellular components—organelles—for growth. In fact, something as important as growth has multiple interconnected pathways to ensure growth. The redundancies provide protection in case one or more pathways gets blocked.   

3)      Change

Obviously, an adult doesn’t divide and grow into one giant blob of 10 trillion fertilized eggs. Cells change and undergo a process called cell differentiation. That’s how we get body parts as varied as fingernails, kidneys, blood cells, hearts, and brains.

4)      Subtract

Apoptosis is the term for programmed cell death. It’s actually a necessary and important feature for the development of a human. If a cell is damaged, it’s better for that cell to recognize that and induce an orderly self-destruction rather than degrade and create an immunologic response and have the surrounding normal cells affected too. During development, cells in the webbing between fingers and toes undergo apoptosis in order to produce differentiated digits. And adults are estimated to have 50-60 billion cells undergo apoptosis a day and recycle the cellular substrates.

Part 4 will have more about normal apoptosis.

5)      Energy

It takes a lot of energy to grow, divide, change, and subtract. The mitochondria inside normal cells use oxygen delivered by an RBC (red blood cell) and convert one glucose molecule into about 30-34 ATPs (an energy unit).

The Transformed Cell

When a normal cell becomes a malignant cell, the term used in medicine is transformed. It’s a good way to think about cancer cells since they have a way of hijacking and mildly tweaking all of a cell’s normal functions towards its purpose of growing, avoiding immune system detection, and propagating throughout the body. Just as a single fertilized egg will add, grow, change, and subtract to become an adult human, so too will a cancer cell utilize cell division, growth factors, cell differentiation, and even apoptosis to become a tumor and metastasize.

            Since cancer hijacks and tweaks the normal machinery in cells to become transformed cancer cells, drugs have been developed to take advantage of the differences. The greater the difference the target is on cancer versus normal cells, the less likely normal cells will be affected.

            For example, penicillin targets the cell walls of bacteria which are drastically different from normal human cells. Bacteria are prokaryotic microorganisms which have a peptidoglycan on its cell wall which no eukaryotic (human) cells have. This makes it a good target and allows penicillin to be very safe and effective.

Below we’ll look at how transformed cells add, grow, change, subtract, and gain energy and show the difference versus normal cells. The differences provide the targets for cancer drugs.

1)      Add

It’s been known for decades that cancer cells undergo prolific cell division. Chemotherapy drugs are designed to take advantage of this feature by stopping mitosis: This is done by blocking DNA synthesis, inhibiting the microtubules, and damaging topoisomerase (a DNA wrapping protein). Unfortunately, chemotherapy drugs also enter fast dividing normal cells and lead to hair loss, nausea, vomiting, tiredness from anemia, and a depressed immune system which can lead to sepsis.

It’s been shown that chemotherapy agents inhibit mitosis and cause damage; when a certain level of damage is done an internal mechanism (currently not understood) is turned on; and then apoptosis occurs. (see picture below)

In addition to the bad side effects from chemotherapy and radiation therapy, sometimes DNA is damaged enough in normal cells (anywhere in the body) and that can lead to secondary cancers later in life.

As can be seen with the picture below, many steps occur between where a chemotherapy drug targets and the final apoptosis process. Cancer cells can develop resistance at any step or at multiple steps in between the target and apoptosis. (i.e. p53)
 


2)      Grow

Cancer cells utilize the growth factor pathways to help grow tumors.
Some cancers have specific gene defects that create specific proteins which encourage fast growth and cell division. Newer drugs are being developed to inhibit these specific proteins since they are usually not found in normal cells; thus providing a target in cancer cells but not normal cells. Unfortunately, there are hundreds of genes that create proteins that cause cancers to grow. Scientists are working to isolate many of these genes and corresponding proteins and hope to then create drugs for them. This is a part of a larger trend called “personalized medicine” now getting more popular with medical schools and pharmaceutical companies.  

Gleevac is the drug that started it all. CML is a rare leukemia that sometimes occurs when one gene from chromosome 9 combines with another gene from chromosome 22. The 2 genes combine and form a protein that’s a combination of 2 normally separate proteins. This combined protein causes the CML by increasing cell division and growth. Gleevac is a small chemically based molecule that blocks it, though it does not substantially induce apoptosis. Resistance has been known to occur and newer drugs are needed to control the cancer.
              
In spite of the large number of genes and resistance with the “personalized medicine” drugs, the author of “The Emperor of All Maladies”, Dr. Mukherjee, is optimistic that there might only be 11-15 common pathways and if enough drugs could be created to block them all, cancer could be turned into a controlled chronic disease.

James Watson, the co-discoverer of the structure of DNA, has a more pessimistic view of “personalized medicine” as shown in a recent article he wrote:

“By now we know that mutations in at least several hundred human genes become serious drivers of the abnormal cell growth and division process that generates human cancer.” “Most importantly, there exist multiple molecular pathways that bring about cell growth and proliferation, each with their own specific surface receptors, cytoplasmic transducers, and promoters and enhancers of gene expression.”
“Much potential cross talk exists between these pathways, allowing new DNA mutations to create new pathways to cancer when pre-existing ones are blocked. Already we know that the emergence of resistance to the gene BRAF-targeted anti-melanoma drug Zelboraf frequently results from driver pathway cross talk.”
“Given the seemingly almost intrinsic genetic instability of many late-stage cancers, we should not be surprised when key old timers in cancer genetics doubt being able to truly cure most victims of widespread metastatic cancer.”

And he concludes with this:

“The biggest obstacle today to moving forward effectively towards a true war against cancer may, in fact, come from the inherently conservative nature of today’s cancer research establishments. They still are too closely wedded to moving forward with cocktails of drugs targeted against the growth promoting molecules (such as HER2, RAS, RAF, MEK, ERK, PI3K, AKT, and mTOR) of signal transduction pathways.”

Translation: The multiple growth pathways are interrelated and if one gets inhibited, a new pathway could be created or a different pathway could be turned on thus making the drug useless.

3)      Change

Just as a fertilized egg will differentiate into all the different cell types, cancer cells are known to dedifferentiate. One example is the EMT—the epithelial-to-mesenchymal transition. This process turns discrete stable cells into cancer cells that have the ability to gain motility, invade other tissues, and become resistant to chemotherapy. Last year, Drs. Gurdon and Yamanaka won the Nobel Prize in Medicine for being able to take adult cells and dedifferentiate them into stem cells. Perhaps in the future some new insight or therapy could come from this field for cancer.

4)      Subtract

 How cancer modifies apoptosis will be discussed in Part 4.

5)      Energy

How cancer creates energy will be also be discussed in Part 4.


Normal cell biology
Cancer cell biology
Therapy
Add
Cell division occurs depending on the organ and the need of the body.

Cell division is increased regardless of the body’s needs.

Chemotherapy kills fast growing normal cells. Chemotherapy kills the fast growing cancer cells.
Grow
Growth is controlled by various signals.
Growth is uncontrolled with aberrant signals from gene defects.
“Personalized medicine” drugs can inhibit specific aberrant signals.
Change
Cells differentiation is a normal developmental ability.
Cancer cells can dedifferentiate and become harder to kill.
All-trans retinoic acid can differentiate APML
Subtract
Apoptosis
(more in Part 4)
Modified Apoptosis (more in Part 4)
BXQ-350
(see Part 4)
Energy
Produces 30-34 ATP from 1 glucose molecule.
Produces 2 ATP from 1 glucose molecule using fermentation. Excess acid is extruded outside of cells. (more in Part 4)
BXQ-350
(see Part 4)

Part 4 New Target and New Drug

            As noted in Part 1, a seemingly simple biochemical process can lead to cancer cell death:

Acid (on the outside of cancer cells) + (Phosphotidylserine + Saposin C) -> cell death

Obviously, the reality is a lot more complicated than that.

1)      New Target

As shown above, cancer cells hijack various normal cellular functions so that it can survive, grow, divide, and change. Chemotherapy takes advantage rapid cell division with cancer cells. “Personalized medicine” cancer drugs take advantage of the specific aberrant signals developed depending on the gene defect. Neither is perfect.

Cancers also create a unique environment due to the modification of the apoptosis and energy creation processes.

a)      Modified Energy Creation: Acidic extracellular environment (Normal=neutral exterior)

With energy production, cancer cells mainly use the less efficient cytosol based glycolysis process to produce 2 ATPs per glucose molecule instead of the more efficient aerobic mitochondria based system that produces 30-34 ATPs per glucose molecule. This seems counterintuitive, considering that cancer cells are growing and dividing at a rapid rate. However, the glycolysis rate is increased to a much higher rate than normal cells. It’s now understood that the rate limiting step for cancer cell growth and division may be in accruing cellular parts, but not the ATPs.

Due to the glycolysis process, a lot of lactic acid is produced and ejected outside of the cells creating an acidic environment. Normal tissues have a neutral outside extracellular environment of pH 7. Cancer cells have been measured to as low as pH 6 due to this process.

The acid acts as both a defensive and offensive tool. Immune system cells that try to attack a cancer cell might not be able to handle an acidic environment. Also the acid, lysosomal enzymes, and other enzymes ejected from cancer cells can help cancer spread locally by killing nearby normal cells.

b)      Modified Apoptosis: Anionic Phosphotidylserine on outer leaflet of membrane (Normal=Neutral Phosphotidylcholine dominant outer membrane)

When normal cells, approach the end of the apoptotic process the cell membrane develops multivesicular bodies which bleb off into small apoptotic bodies. These small 30-100nm membranes are taken up by phagocytes and all the parts are recycled for use elsewhere.

With cancer cells, the apoptosis process is hijacked and instead of multiple apoptotic bodies formed, individual microvesicles 40-100nm in size bleb off. Normal cells have a neutral extracellular environment (pH 7) and the outer leaflet of the cell predominantly has the neutral phospholipid phosphotidylcholine. As stated above, cancer cells have an acid extracellular environment (lots of positively charged H+ and pH 6) and a lot of the anionic (negatively charged) phospholipid Phosphotidylserine.

Phosphotidylserine is a phospholipid that in normal cells face inwards to the cytosol. It’s now been shown that when cancer cells hijack and modify the apoptosis process, the Phosphotidylserine will flip to the outer leaflet, reduce membrane rigidity, encourage blebbing and form a microvesicle.

Sometimes it blebs with an RNA or tumor DNA. These microvesicles have been shown to travel throughout the body, attach to other cells, and transfect the new cell. This is another way cancers can metastasize.

It’s also been shown that cancer cells filled with cisplatin (a chemotherapy drug) can create a microvesicle that has a higher concentration of the drug than what’s inside the cell—a detoxification. Thus, microvesicles provide cancer cell with multidrug resistance. Tumor microvesicles also allow evasion of the immune system, increase angiogenesis, and improve overall tumor growth.


When chemotherapy or radiation therapy is given, some of the cancer cells undergo apoptosis. Paradoxically (from a treatment standpoint), the cancer cells that are stressed by the therapies but do not die end up increasing the amount of Phosphotidylserine on the outer leaflet of the cells and create more tumor-derived microvesicles which can lead to metastasis, multidrug resistance, and all the other issues mentioned before and in the picture below.




 
2)      New Drug

As can be seen above, a drug that could survive or even utilize an acid environment and use Phosphotidylserine as a target would be ideal. BXQ-350 is a drug that can do that.

BXQ-350 has 3 steps in its progression through the body:
a)      Large biologically based molecules in nanovesicle form
b)      Entry into cells via acid and Phosphotidylserine
c)      Biochemical activation

a)      Large biologically based molecules in nanovesicle form

BXQ-350 has two parts: Phosphotidylserine (a phospholipid) and Saposin C (a protein). They are combined into one structure. Since Phosphotidylserine is a phospholipid and exists in membranes, the Phosphotidylserine-Saposin C combo can be mixed to form a vesicle. In BXQ-350’s case it will be one layer (unilammelar) instead of a normal membrane that has 2 layers. Since Phosphotidylserine-Saposin C is formed as a membrane layer, the drug is the membrane. This is an unusual set-up. There are other drugs that use membranes, but usually it’s to cover a drug that’s toxic to the body. For example PEG-amphotericin is an anti-fungal whose membrane prevents the kidney toxicity seen when amphotericin is given alone.

Since the drug is the membrane and forms a vesicle, different entities can be put inside of it like fluorescence, MRI contrast material, or even RNA which could be used as a drug. Thus BXQ-350 can also be a super accurate diagnostic tool and as a drug delivery system. Another positive point, the drug mimics other vesicles normally found in the body and that might be the reason it can enter the brain.


Apoptotic bodies
Tumor microvesicles
BXQ-350
Size
30-100 nm
40-100 nm
100-400 nm
Inside
Cell parts
RNA, tumor DNA, removed chemotherapy drugs
Nothing. But MRI, fluorescent, or RNA can be put inside
Membrane
Phosphotidylserine
Phosphotidylserine
Phosphotidylserine

On the negative side, developing a drug that is a nanovesicle about 100-400 nm in diameter (190 nm average) in a form the FDA approves is a technical challenge. If PEG-amphotericin loses some membrane, the drug can still work. If the BXQ-350 membrane has difficulty, the actual drug part may be compromised.

Dr. Qi does not report any side effects with BXQ-350 and that will hopefully hold true. Most drugs are small chemically based molecules. These molecules enter the blood stream, pass through the semi-permeable membranes, and then attach to a protein or enzyme. These small molecules work by fitting on the various nooks that different proteins present. The better it binds, the better its efficacy. Unfortunately, small molecules can also bind nooks on different proteins inside other cells and any organ throughout the body. This leads to all the side effects listed with many drugs.

Large biologically-based molecular drugs usually do not have the same side effect issues. For example, hormone drugs like insulin and growth hormone attach to a surface protein. This protein is connected with internal pathways which lead to different functions turned on. Side effects are limited to a dosing effect of the hormone drug or the material it’s made with.

Since BXQ-350 does not have a surface protein to even attach to, no hormone-like side effects are expected. Saposin C and Phosphotidylserine are large biologically-based molecules and cannot enter all cells like the small molecules. As a matter of fact, Saposin C is unable to enter cells with predominant phosphotidylcholine outer leaflets which is what normal cells have. This makes for a very selective drug.

b)      Entry into cells via Acid and Phosphotidylserine

When BXQ-350 reaches the cancer cells, the Saposin C not only survives in the acid environment, it actually needs the acid to activate it. The Saposin C portion will then attach itself to the Phosphotidylserine on the membrane of cancer cells, cause membrane destabilization, and enter the cell.

 



c)      Biochemical activation

Once inside, the Saposin C-Phosphotidylserine complex will activate the Glucocerbrosidase enzyme in the lysosome and increase ceramide levels. When the ceramide level reaches a certain point, the apoptosis pathway is triggered and cell death occurs.

As mentioned before, James Watson wrote an article published December 2012 about his thoughts on cancer therapies today. He was pessimistic that “personalized medicine” could “truly cure victims of widespread metastatic cancers.” Since 2008, he’s felt that the curing of cancer should come from the biochemistry of cancer cells as opposed to their genetic origins. BXQ-350 would seem to qualify.

BXQ-350 currently works on all resistant cancer cell lines. Part of why it does is because it works at the apoptosis stage. It skips and has flanked around many of the steps where resistance has developed due to chemotherapy. (i.e it induces apoptosis many steps downstream and after the p53 step.)

To review, the 2 large biologically based combined molecules form the drug BXQ-350. It mimics other biological vesicles. It’s activated by the acid outside of cancer cells and enters via the Phosphotidylserine on the membrane. It cannot enter normal cells that have neutral extracellular environments and phosphotidylcholine dominant membranes—normal cells. Once inside, both components of the drug act as co-enzymes to increase ceramide and start apoptosis.



Part 5 The Connection between Gaucher’s disease and Cancer

What is Saposin C? How does BXQ-350 seem to work so well? It’s as if the acid and Phosphotidylserine environment created by cancer is one jigsaw puzzle piece and the Phosphotidylserine-Saposin C is another that perfectly fits. There’s never been anything like this in medicine before. The cancer cell creates an externalized lysosomal-like environment (with the acid, Phosphotidylserine on the outer leaflet of the cell membrane, and lysosomal enzymes) and BXQ-350 is the complex that matches perfect with it.

Saposin stands for Sphingolipid Activator Protein. They are essential for lysosomal glycosphingolipid degradation. Glycosphingolipids are found on the outer leaflet of cell membranes. They aggregate together into lipid rafts and these rafts may play a role with the insulin receptor, epidermal growth factor receptor, and the nerve growth factor receptor. They're thought to be used with cell-to-cell communication and with protein interaction on the same cell membrane.

Glucosylceramide is one type of glycosphingolipid. When they need to be recycled, endocytosis occurs (blebbing inwards) and after passing through some endosomes, the glycosphingolipids sit inside a lysosome either on the inner leaflet of the surrounding lysosome membrane (see A in picture below) or on an intralysosomal vesicle also facing the lysosomal environment. (see B)

The enzymes degrade the sugars and the lipids integrate with the membranes. The degradation requires the enzymes, sphingolipid activator proteins (saposins), and anionic lipids (i.e. Phosphotidylserine).

Saposin C is an essential co-enzyme with the enzyme Glycocerebrosidase which converts Glycosylceramide to Ceramide. It works inside the lysosome and requires acid to fully activate—best enzymatic activity estimated around pH 5.75.

Glucosylceramide + H2O ßà ceramide + glucose

Enzyme: Glycocerebrosidase
Co-enzymes: Phosphotidylserine and Saposin C.


Saposin C, Phosphotidylserine, and Glycocerebroside play an important role for cell membrane functionality by recycling the glycosphingolipids. Some people have a defect with the protein Glycocerebrosidase and can have dramatically decreased enzyme function. This is called Gaucher’s disease type 1. Since the enzyme defect is with a lysosomal enzyme, this is considered part of the family of diseases called Lysosome Storage Diseases. When this happens, the membranes of cells that get stressed a lot like RBCs and WBCs (white blood cells) get fragile. The cells with fragile membranes get eaten by macrophages (cleaner cells). Since the enzyme is blocked, the RBCs and WBCs have lots of substrate inside: mainly glucosylceramide and a little Saposin C and Phosphotidylserine.


The macrophages get stuffed with the fatty lipid and instead of filtering through the spleen, they get caught. These fatty macrophages have a “crinkled tissue paper” look on light microscopy. A very small minority of the cells found in the spleen are dead from apoptosis: a combination of the macrophage’s acid mixed with increased levels of the co-enzymes Saposin C and Phosphotidylserine. Thus we’ve come full circle from Part 1.

Acid + Phosphotidylserine + Saposin C -> cell death

BXQ-350 could only have been discovered by a Gaucher researcher. In fact only someone with intimate knowledge and understanding of Saposin C like Dr. Qi. Even though there’s only one article with BXQ-350 with cancer, he’s published many articles on Saposin C.


If BXQ-350 proves itself through Phase1, 2 and 3 trials, questions need to be asked: “Can we learn anything else from other genetic diseases?” “Can we find a therapy through another biological and biochemical combination?”

Hopefully if successful, BXQ-350 will spur others to look at all the pathologies of all the genetic diseases. As a comparison, the NCI has a yearly budget of $5.8 billion and NORD (The National Organization of Rare Diseases) has a budget of $13.5 million. Science can happen anywhere with any field. Sometimes we need to expand our scope of interests and consider more possibilities. Genetic diseases number in the hundreds each with a multitude of seemingly insignificant pathologies like the splenic apoptotic cells with Gaucher’s disease. Just as universities and pharmaceutical companies have tens of thousands of chemicals to test as possible future drugs, perhaps a library of all the genetic disease pathologies should be made. After all, what better laboratory is there to test combinations of cellular components than the human body?

If Dr. Qi never discovered BXQ-350, it’s possible no one would in the future since there are so few Gaucher’s disease researchers.

With rare diseases these 3 criteria are needed:
1)      Patient numbers
2)      Research talent
3)      Money

In our high debt-low growth economic environment, NIH funding is vulnerable to cuts. Also, some people are making an effort to reduce the incidence of some autosomal recessive diseases. A Rabbi named Joseph Ekstein started an organization called Dor Yeshorim after losing 4 of his 5 children to Tay-Sachs disease. People can sign up with the group and get tested for the 9 diseases below:

1)      Familial dysautonomia
2)      Cystic fibrosis
3)      Canavan disease
4)      Glycogen storage disease (type 1)
5)      Fanconi anemia (type C)
6)      Bloom syndrome
7)      Niemann-Pick disease
8)      Mucolipidosis (type IV)
9)      Gaucher’s disease (only by request)

The results stay closed except to the organization, but if a man and a woman start dating and want to get serious, they can call the program. If potential offspring are at risk, they’re told they are “not compatible.” The program has been a huge success with near total disappearance for some of these conditions in the ultra-orthodox community. If a program like this expanded (especially as genetic testing gets cheaper), it’s not hard to imagine the numbers of Gaucher’s disease or other genetic diseases dramatically reducing and consequently interest and funding with genetic diseases reducing too.

On another note, scientists have guessed that Gaucher’s disease started as an autosomal recessive disease after bottleneck population declines sometime from 1100-1400A.D. (possibly The Black Plague) and 75A.D. with the Jewish diaspora. It’s amazing to think that a clue to a therapy for cancer has been inside the spleens of people passed on generation after generation for over 600-900 years.

It wasn’t until Philippe Gaucher described a case in 1882 that the disease was formally recognized. And Saposin C wasn’t isolated until 1971. And then it took one random combination in 2002 to find this new cancer therapy.