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.
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Normal
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BXQ-350
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Lead time from
science to drug development
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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.
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Small molecule drug versus Large molecule drug
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Small chemically based molecule enters cells.
Large biologically based molecule attacks targets on the
outside of cells.
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2 large combined biologically based molecules combined
that can enter cells.
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Inhibit versus Activate
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Chemotherapy, antibodies, and “personalized medicine”
drugs inhibit proteins, enzymes, others.
|
Activates multiple enzymes.
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Science
|
Drugs work by inhibiting cell division and cell growth
(more in Part 3)
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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.
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Normal cell biology
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Cancer cell biology
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Therapy
|
Add
|
Cell division occurs depending on the organ and the need
of the body.
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Cell division is increased regardless of the body’s needs.
|
Chemotherapy kills fast growing normal cells. Chemotherapy
kills the fast growing cancer cells.
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Grow
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Growth is controlled by various signals.
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Growth is uncontrolled with aberrant signals from gene
defects.
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“Personalized medicine” drugs can inhibit specific
aberrant signals.
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Change
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Cells differentiation is a normal developmental ability.
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Cancer cells can dedifferentiate and become harder to
kill.
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All-trans retinoic acid can differentiate APML
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Subtract
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Apoptosis
(more in Part 4)
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Modified Apoptosis (more in Part 4)
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BXQ-350
(see Part 4)
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Energy
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Produces 30-34 ATP from 1 glucose molecule.
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Produces 2 ATP from 1 glucose molecule using fermentation.
Excess acid is extruded outside of cells. (more in Part 4)
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BXQ-350
(see Part 4)
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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).
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.