Improving Nanotechnology for Therapeutic Treatment for
Cancer through degrading IAPs and regulating the Oncogene
Li, Henry
Abstract:
There is currently no cure for cancer. There are only a handful of treatments for cancer treatment,
such as: Targeting the tumor itself, drug therapy, chemotherapy, and more. Current treatments
only regulate the cancer, and are unable to completely eliminate it from the body. The ingenuity
of nanotechnology has revealed new research in modern medicine. Treatment to areas that were
was once impossible to deliver drugs to (can replace with “treatment to areas that were unable to
revieve drugs) such as the brain are now utilizing nanoparticles for drug administration. [1]With
my methods, application of nanoparticles for cancer treatment will potentially allow functionality
of apoptosis in cancer cells. This will be tested by injecting nanoparticles that will degrade IAPs
by releasing small amounts of acid. The background and methods for this cancer research is
discussed in greater detail, below.
Background:
Cancer is the leading cause of deaths in the United (capitalize “s”)states alone,(.) Technological
advances are required for a new set of therapeutic treatment.[1] The improvement of
nanoparticles has progressed since it was first introduced in the late 1980s for further precision
engineering. [2] Nano (10-9) technology enables users to go at the molecular level.[2] Engineers
have developed a way of administering drugs by loading it into nanoparticles which then are able
to penetrate small pours (pores? And if so.. the brain is a pore?) such as the brain to treat brain
tumors. [1]
The onco-gene creates cancer cells by mutation. Mutation of the Oncogene leads to mutant
protein production such as a higher production of growth factor receptor proteins. The mutant
gene creates more Epidermal Growth Factor (EGF) receptors that will lead to higher chances of a
EGF binding, (and in affect, lead) leading to higher rates of replication (thereby) and becoming
tumors. [3] Since cancer cells reproduce and lack the inability of apoptosis, Schmitt has
identified (in his previous experiment…) that with his method to activate apoptosis in his
previous experiment entitled "Activation and role of caspases in chemotherapy-induced
apoptosis", (would) require the use of ced-9/Bcl proteins to regulate caspase activation, as well
(as) the use of caspase-8 drugs. As a result, Schmitt's experiment was a success. However, it
slowly lead to failure due to multiple IAPs affecting more than one caspase.[4] Drug therapy has
also (been) proven (as a) failure (to activate apoptosis) for activation of apoptosis due to
biological factors that increase drug resistance.[5] With drug therapy unable to activate
apoptosis, researchers began the search for activating apoptosis.
The IAP gene expresses two types of proteins: Anti, and Pro IAP. Eight IAPs have been
identified in the cells of humans: NAIP, c-IAP1, c-IAP2, XIAP, Survivin, BRUCE, ILP-2, and
Livin.[3] Suppressing the activation of Livin could lead to higher success rates of
chemotherapy.[3] Liu, Han, Wen, et. al. have identified the interactions of certain IAPs with
SMAC (proving ) has proven significant results with inhibition.[3] SMAC being bound to IAP is
known to promote apoptosis. Other proteins being bound to IAP (have resulted) has resulted in
the lower rates of apoptosis appearing in cells. Regulation of the Livin gene would lead to
potential lower rates of cancer, (. However) at the same time (,) by not allowing a cell to grow
could lead to reproductive dysfunction. The BIR domains are linked to caspase by the BIR
domains retarding the functionality of caspase with the assistance of the IAP. [3]
XIAP production through the X-chromosome has lead to the question of how to alter the
genomic coding to produce an (a) protein that disrupts itself from interacting with caspase-9?(uh
him pretty sure this isn’t a question..) [3-5] A point-mutation affecting the oncogene leads to
changing protein function which then leads to cancer .[6] MircroRNA regulates gene expression
by binding to mRNA, by repressing, or silencing the gene itself. [7] With the information above,
We compiled a method that will utilize nanoparticles to degrade IAPs.
Hypothesis:
What my research team would expect to see is that by denaturing the IAPs with
nanoparticles, we can expect to see an increase in caspase activity.
Methods:
For this experiment we will be using rats with cancer as model organisms. Nanoparticles will be
injected into rats, and locate the IAPs. Detecting IAPs will lead us to the second phase in which
nanoparticles with acid will be bound to an IAP which will then trigger the release of the acid.
This needs to be selectively bound to IAP since this experiment calls for a controlled
environment. By binding synthetic caspase-9 proteins to 100 nanoparticles, this will cause the
IAP in attempt to bind to the nanoparticle. When bound, the release of the acid will denature the
IAP. We will perform multiple rounds of denaturing IAPs in different quantities of nanoparticles.
There will be multiple trials conducted at the same time. Each trial is to last a month and is
measured everyday for any development such as if the cancer has spread at a slower speed.
Now that leaves us with the issue of how to target the remaining IAP. The way to approach that
is (through the use of nanoparticles which should… )the nanoparticles should have been able to
reduce the amount of IAP by a significant percentage. With the decline of IAP there will be
caspases that are activated since all proteins are not inhibited. The idea here is to reduce the
number of IAP but at the same time being able to minimize the cost to produce the technology.
In terms of clinical trials, since we will be using rats as a model organism, there is no ethical
laws that restrict us from advancing cancer research. As for clinical trials for humans, we will be
performing standard procedures to continue. By finding terminal cancer patients that agree to the
trial. This include informing the patient that this procedure may decrease their time spam from
what they had originally were informed.
Rationale:
Destruction of BIR and IAP would prove that the inhibition of caspase is the reason behind the
inability of cells to perform apoptosis. With the experiment we expect to(and hope) as well be
able to apply this through gene-therapy. If by chance we do come across a mutation this could
lead to an advantageous mutation that could lead to the production of cells being unable to
perform apoptosis to become benign.
This is one of the first types of application through the use of nanorobots. If the success of this
research proves the advancement manipulating cell death, this could potentially lead to activation
protein production for multiple diseases. If failure was (were) to come across my research team,
we can assume that we disrupted the "known" IAP and will get more researchers to identify the
others. By being able to identify all IAP we can lead the new doors for cancer research, this is
also if we improve and heighten nanorobotic engineering. With improving nanotechnology, this
will not only improve cancer research but as McKeown et al. have predicted, will improve
interchangeability of components, improve quality control through higher accuracy, and other
technological improvement.
McKeown's final notes in his research stated that the design of nanorobots during the 1980's
were still not a good tool used for measurement. However, with improved engineering as well
(as) new methods to conduct with this research(incomplete thought..). Kawasaki and Player's
design on nanotechnology and nanomedicine has shifted medical application in a new direction.
Nanoparticle application has improved medicine with drug administration that we are now able
to target areas that were once thought to be impossible to target. As for cancer and nanoparticle
application, targeting cancer initiators is now possible. An IAP called Livin can be targeted with
this application to be denatured. Liu, Han, Wen e.t. al, noted in their research that reducing Livin
interaction can increase success rates in chemotherapy. However, we are still limited to the
amount of factors known for anti-cancer proteins (caspases) as well what drives the inhibition of
such proteins.
One of the many goals through improving nanoparticles and through this experiment is the
application for gene therapy. Applying nanorobotics, could lead to altering miRNA at such a
large scale at the size it is doing so. Since the onco-gene is responsible for cancer cells, changing
the miRNA to restrict certain gene expression such as the onco-gene, can lead to further research
between miRNA and onco-genes. In relevance to IAP and BIR, by improving gene therapy, the
discovery and method to inactivate the BIR and IAP, genetically and through gene expression, is
waiting to be looked into.
Budget:
By working in a cancer research facility, we will require a high amount of funding. This will also
be considered a nanorobotic research as well. The proposed budget will be starting at
approximately $300,000 for one year of research. This will initially cover the following:
Use
Staff 2-3 (Scientists)
2 Undergradaute Researchers
Equipment
Materials
Lab
Travel (conferences)
Cost in $
240,000 (80,000 Each)
3000 (1,500 Each)
40,000
10,000
5,000
5,000
Data Management:
All data and notable observations will be transcribed onto computers that will be shared and
analyzed among the research team. After, (we?) will be noting those with repeated trials and
comparing(compare with) from previous trials. Noting the deviations will be based on
responsibility of(from) each Ph.D, and assessment of each individuals trials will take place every
other week. There (during that time) we will assess the progress that the team has made and
discuss further adjustments for the research.
Lay Proposal:
My father and grandfather are both smokers. When I was in grade school, I was taught
(that) smoking is(was) bad and can cause cancer. Being a simple kid, I told my dad to quit
because cancer is bad. He said to me, "I'm not afraid because doctors will one day find a cure for
it." The purpose of me writing this is because I want to be one of the doctors that will one day
end cancer, and my proposal may help get us a step closer to that goal.
According to the American Cancer Society, There will be over 570,000 cancer deaths by
the end of this year1. Researchers have formulated multiple treatments for cancer, however we
only see deaths decay by a small percentage. Cancer by definition is a mutation in a cell that
lacks the ability to kill itself. By replicating itself over multiple cycles, the cancer will then
become invasive and start spreading into tissues which will then start causing damage. The
inability of initiating apoptosis (cell death), is caused by caspases (initiator of apoptosis) being
targeted by IAPs (Inhibitor of Apoptosis Protein)2.
With the application of nanoparticles, we can denature IAPs. The process that I am
proposing is through the nanoparticles delivering an acidic compound such as uric acid. Through
that the denatured IAPs will be unable to inhibit caspase-(a protein that initiates apoptosis).
Having this information, my research team will run trials to prove that this experiment will work.
With you as a supporter, the way you can help us is through a generous donation. The
distribution of the funding will help go towards hiring experts to UC Merced to help with this
research. Not only that but the funding will go towards necessary tools and materials to conduct
these trials. (furthermore,)As well we will be traveling around the globe to speak in seminars
about our research and get the word out to the scientific community (consisting) of the new
branch of research that will be booming with new discoveries. We hope this will bring you to
help us down the road to defeating cancer, once and for all.
1
American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American Cancer Society; 2012,
http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf
2
Boaz Nachmias, Yaqoub Ashhab, Dina Ben-Yehuda, The inhibitor of apoptosis protein family (IAPs): an emerging
therapeutic target in cancer, Seminars in Cancer Biology, Volume 14, Issue 4, August 2004, Pages 231-243, ISSN
1044-579X, 10.1016/j.semcancer.2004.04.002.
(http://www.sciencedirect.com/science/article/pii/S1044579X04000197)
Keywords: Apoptosis; Cancer; IAP; Caspase; Molecular targets
Works Cited
1. Ernest S. Kawasaki, Audrey Player, Nanotechnology, nanomedicine, and the development of
new, effective therapies for cancer, Nanomedicine: Nanotechnology, Biology and Medicine,
Volume 1, Issue 2, June 2005, Pages 101-109, ISSN 1549-9634, 10.1016/j.nano.2005.03.002.
(http://www.sciencedirect.com/science/article/pii/S1549963405000559)
Keywords: Nanotechnology; Nanomedicine; Nanoparticles; Quantum dots; Drug delivery;
Cancer therapy
2. P.A. McKeown, The Role of Precision Engineering in Manufacturing of the Future, CIRP
Annals - Manufacturing Technology, Volume 36, Issue 2, 1987, Pages 495-501, ISSN 00078506, 10.1016/S0007-8506(07)60751-3.
(http://www.sciencedirect.com/science/article/pii/S0007850607607513)
Keywords: Advanced Manufacturing Technology; Precision Engineering; Dimensional
Tolerances; Nanotechnolgy; Design of Ultra Precision Machines; Topografiner; Scanning
Tunnelling Engineering
3. Bin Liu, Mei Han, Jin-Kun Wen, Ling Wang, Livin/ML-IAP as a new target for cancer
treatment, Cancer Letters, Volume 250, Issue 2, 8 June 2007, Pages 168-176, ISSN 0304-3835,
10.1016/j.canlet.2006.09.024.
(http://www.sciencedirect.com/science/article/pii/S0304383506005520)
Keywords: Livin; ML-IAP; KIAP; Apoptosis; Caspase; Cancer therapy
4. Estelle Schmitt, Alain-Théophile Sané, Richard Bertrand, Activation and role of caspases in
chemotherapy-induced apoptosis, Drug Resistance Updates, Volume 2, Issue 1, February 1999,
Pages 21-29, ISSN 1368-7646, 10.1054/drup.1999.0065.
(http://www.sciencedirect.com/science/article/pii/S1368764699900651)
5. Boaz Nachmias, Yaqoub Ashhab, Dina Ben-Yehuda, The inhibitor of apoptosis protein family
(IAPs): an emerging therapeutic target in cancer, Seminars in Cancer Biology, Volume 14, Issue
4, August 2004, Pages 231-243, ISSN 1044-579X, 10.1016/j.semcancer.2004.04.002.
(http://www.sciencedirect.com/science/article/pii/S1044579X04000197)
Keywords: Apoptosis; Cancer; IAP; Caspase; Molecular targets
6. R. Taramelli, F. Acquati, The human genome project and the discovery of genetic
determinants of cancer susceptibility, European Journal of Cancer, Volume 40, Issue 17,
November 2004, Pages 2537-2543, ISSN 0959-8049, 10.1016/j.ejca.2004.07.030.
(http://www.sciencedirect.com/science/article/pii/S0959804904006793)
Keywords: Gene; Gene interaction; Complex diseases; Linkage disequilibrium; Association;
SNPs; Cancer; Susceptibility; Mouse; QTL
7. Ying Poi Liu, Ben Berkhout, miRNA cassettes in viral vectors: Problems and solutions,
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1809, Issues
11–12, November–December 2011, Pages 732-745, ISSN 1874-9399,
10.1016/j.bbagrm.2011.05.014.
(http://www.sciencedirect.com/science/article/pii/S1874939911000897)
Keywords: RNAi; siRNA; miRNA; Gene therapy; Viral vector; Vector tropism