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By I&C President Ryan Witt

witt.rj@gmail.com
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j Cancer j ALS
j Cardiovascular disease j Multiple Sclerosis
j Alzheimer·s Disease j HIV/AIDS
j Bacterial Infections j Hepatitis

Yes. I·ll Explain.

   

Ask Qs!
j 
 ask ´How, Why, What, and Whenµ
j Try to Understand EVERYTHING!
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j With a knowledge
knowledge--based approach, what can we
do?
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j Past: Age of One Drug Wonders
j Penicillin ² bacteria

j Now we face tougher problems«

1. Multigenetic diseases ² cancer, Alzheimer·s and Parkinson·s
diseases, cardiovascular disease, MS, HIV / viruses«
2. Disease Resistance
j Infectious Diseases
j HIV
j Cancer
 | ! 
 

j Cancer has been called hundreds of sub-

sub-diseases; reason is
because it results from multiple diff·t molecular dysfunctions.
j Molecular Signaling within cells is highly complex.
  
Arises from
1. Not fully killing the diseased cells and/or
2. Some degree of adaptive ´randomnessµ in the disease; and
3. ´Selectionµ to grow those diseased cells who were not killed or
are more adept.

With Cancer and HIV: the molecular systems driving these diseases
are constantly changing due to high mutation and growth
rates. (they adapt!)
   
" |
Chemo mutates DNA of cells to kill them!
#$%
Cancer w.
Cancer w. dysfunctional PTEN
dysfunctional PTEN
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Cancer upregulates PARP (another DNA repairman), thus defending

itself against too much DNA damage.

j ´Window of Opportunityµ with diseases where you can strike based on

armaments available, and strike HARD!
j PARP up-
up-regulated after chemotherapy, if missing DNA repair enzymes of
BRCA and PTEN family.
j As you see later, cocktail   be better!
 ›  

j The combination of two or more separate components ² be it
drugs, medical devices, or biological products (a substance
derived from a living organism), for the purpose of some end-
end-
goal.

{
a) Big attack ² not in size but strength
b) Localized attack
 | 
j It·s better to fight something with two or more small attacks
specific (molecularly) to a target, both in effectiveness 
safety, when compared to one single massive attack.
i.e., Nuke v. Targeted Assassinations

Support from Studies (all entering or in clinical validation testing

now):
1. Cocktail against brain tumors
2. MET / EGFR cocktail ² more on this later
3. Chemo targeted to liver, avoiding adverse effects to heart
4. HIV Cocktail ² Atripla (*approved)
5. Cocktail against Alzheimer·s Disease
  
1. Greater effectiveness on disease target
2. Lower side effects on host (me and you)
3. Lower chance of resistance development (from disease)
 ÷


 &

 
j Cancer

Other studies where relevance is shown

j MS j HIV
j ALS j Infectious diseases (viruses/bacteria)
j Alzheimer·s j Hepatitis B recurrent in post liver
j Parkinson·s transplant & Hepatitis C
 | 

j EGFR & MET therapy (on its way to clinical studies now)
j FUS1,, MDM2
FUS1 MDM2,, & P53 therapy (tested separately in clinical trial)
j PARP + Chemo ² breast and ovarian cancer (in clinical trail now)
j Brain Tumors ² 3 proteins targeted (on its way to clinical studies)
 
'!
MET  
 
EGFR HGF
( cancer
cancer #%
Tarceva / Iressa cancer cancer
cancer
cancer
cancer


cancer
!

j ´Our findings provide a strong rationale for combination treatment strategies as initial
therapies for some patients.µ - Pasi Jänne MD, PhD, of Dana-
Dana-Faber Cancer Institute and
Associate Professor of Medicine at Harvard Medical School
j Status: expected to move into clinical study soon

Source: http://www.medicalnewstoday.com/articles/176486.php?nfid=79262
 !!)

% 

% !!) '
'*+
*+ 


Tested in clinical trials separately.

 # 
'|
PTEN + BRCA 1/2 + PARP = DNA Repairmen

When no PTEN (or BRCA1/2), PARP is active/over-expressed, especially in

cancers after undergoing chemotherapy.
This makes sense b/c cancer cells don·t want to be mutated and die
from the chemotherapy, thus defend themselves through upregulating
PARPs (repairmen) when they don·t have PTEN or BRCA proteins.

Idea for Cancer Therapy is giving PARP 
 to people who

have already undergone chemotherapy to prevent this defense
mechanism m PARP inhibitors, with chemo, as a first line treatment.

j Being tested in clinical trial now, with ´very promising

results.µ ² Medscape article
Sources: http://www.medscape.com/viewarticle/704990; http://news.bbc.co.uk/2/hi/health/8256494.stm;
http://breastcancer.about.com/od/targetedbiologictherapies/p/parp_basics.htm
 
  

1. Interleukin 13 receptor alpha 2 (IL-
(IL-13R-
13R-alpha),
2. Ephrin receptor A2 (EphA2)
3. Fos--related antigen 1 (Fra-
Fos (Fra-1)
Among 76 patients with brain tumors, all with GBMs had one
marker present and 95% had at least two of these markers.

´The three markers were not found in healthy brain tissue,

suggesting that the proteins are highly suited as targets for
therapies designed to kill cancer cells and spare healthy brain
tissue.µ

Source: http://www.drugresearcher.com/Emerging-targets/A-drug-cocktail-to-bust-brain-tumours
 #, 
j ´This is why it's so important to be able to use a combination of more than
one drug. If the virus mutates to become resistant to one drug, it is still
sensitive to the other drugs.µ
drugs.µ
- Genhong Cheng, Research team member at the UCLA Center for Cell Control and
UCLA's Jonsson Comprehensive Cancer Center
j ´Drug combinations can also be used effectively to inhibit infectious diseases
because resistance to a single drug is very common« If we can apply multiple
drugs against one infectious agent, it probably will prevent the occurrence of
drug resistance.µ
- Ren Sun, UCLA Professor of Molecular and Medical Pharmacology and research
team member
From a study finding that total inhibition of a virus occurred at much lower
drug doses than would be necessary if the drugs were used alone (~10% less
than required when each drug is adminstered individually)
   


j 
 ask: Why, How, What, and ›

# -  
 |.#

j Only one approved cocktail comes to mind ²
1. HIV, there is now one ´cocktailµ pill you can take
which includes all three primary therapies for the
disease.
j Approved post approval of each individual component.
2. Combo, chemotherapies + monoclonal Antibodies
like Herceptin / EGFR targets
j Approved after testing one experimental therapy in
combo with already approved chemo drugs.
 ›
j › matters!

If you don·t get why after these next few slides, stop me
in my tracks!!
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1. Two or more approved therapies
x Dosage and interactions are untested!
x Possibly can try to predict dosage/interactions

 

2. An approved therapy with (i) an investigational or (ii) another

approved therapy
x Avg time for development ² 6


 for a cancer therapy!
x Many pharmas know  of possible combo benefits, but
test each drug one at a time anyway..
3. Combo of two investigational therapies
x Never happened to my knowledge

 
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j Each individual component is tested for max tolerable dose«
j Hence, when combining two or more drugs, physicians have
no idea what dose to give patients
j Also: potential interactions between drugs are unknown.
 (   ›
.
j The development of cocktails from pharmas (where dosage
and safety are tested prior to administration to patients)
j Drug repositioning

But, for now

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j Combination therapies are primarily created by physicians
through ´off-
´off-label useµ or already approved chemotherapy-
chemotherapy-
combo regimens.
 ›
j Ask your physician about being treated with a
potent, specific regimen²
regimen²targeted to  

disease²
disease²especially, if you are dealing with a
seriously compromising illness.

Ask your doc Qs: ´How, what, why, and when?µ

 ›('|

j Bringing innovation to you at the fastest rate
possible is our goal.
1. Community-based education and resource sharing
Community-
2. Building an interface to empower you to make a difference
3. Working to integrate these innovations and patient options
into physicians· workflow.
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j 





j IsoFlow
j Ultrasound released therapy (untested in humans)
j UV activated therapy (untested in humans)
j Drug repositioning / finding for your disease
j GeneGo ² Metacore
j Biovista
j Targeted approach specifically for cancer²
cancer²
j N-of-
of-One
j Intervention Insights / GeneGo
j ICAN