Transcript Targeting Cellular Processes as a New Approach for Cancer

Targeting Cellular Processes as a New Approach
for Cancer Treatment
Ru Chih Huang, PhD
Professor of Biology
Johns Hopkins University
Oct 24th 2009, CAPA Symposium, Gaithersburg, MD
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CURRENT STATUS
“In a long drive to cure cancer, advances have been elusive” ~Gina Kolata
New York Times National , Front Page - April 24th, 2009
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“Is cancer just an impossibly hard problem?
OR
Is the United states, the only country to invest so much in
Cancer research*, making fundamental mistakes in the
way it fights cancer?”
The answer is “YES” on both counts – Gina Kolata.
*$105 Billion from NCI and billions more from drug companies and philanthropies
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A Thorough Trial Takes Time and Money
$10x106
$20x106
$45x106
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Cancer Drug Rise in Popularity
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CLINICAL TRIAL RESULT FOR TREATMENT OF BREAST METASTASIZED
CANCER (2007 – 2009)
Median Time (Months)
Treatment
Cancer progression
to start again
Patient survival
Avastin plus Paclitaxel
11.3 months
26.5 months
Paclitaxel alone
5.8 months
24.8 months
1. Severe Side Effect: 5 or 6 out of 363 died from drug Avastin
2. Received accelerated approval (Progression-Free Survival) from FDA
3. Avastin: $2.3 billion in Sales, 2007 Genentech
4. Breast cancer treatment $7,700/ month
5. FDA Panel supports Avastin to treat type of brain cancer despite the FDA’s own staff
reviewers saying that there was a lack of compelling evidence that the drug worked for
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that use (April 1st, 2009; New York Times).
Oncogenic pathway/Targeting with specific Protein Inhibitor
Targeted by specific
protein inhibitor
Months
Days
Heterogenous Tumor cells regain growth in facing drug resistances
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Common Drug Side Effects
1. Alopecia
*2. Diarrhea, Nausea, Vomiting (Effects of the dividing cells of
Gastrointestinal tract)
*3. Anemia, and Immune deficient (Effects of dividing cells of bone
marrow
4. Fatigue
5. Hypertension
6. Skin Condition
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Most Therapies by Targeting Specific Growth Protein Factors Have
Limited Impact
By Andrew Pollack
Forty years’ war
Small Victories, High Prices
1. Since most tumors are fueled by numerous often redundant, genetic anomalies
2. Only a trickle of new cancer drugs make it to market. Last year there were two and this year
there has been only one. Tarceva which costs $3500 a month for treatment of pancreatic
cancer because it improved survival for 12 days.
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Combination Therapy
Standard of care for Glioblastoma since 1978 (Surgery, Radiation, Chemotherapy)
Without treatment
Radiation alone
Radiation plus
Temozolomide ± Surgery
14 weeks
36 weeks
62.5 weeks
Ref:
1.
Predictive and Prognostic Markers in
Human Glioblastomas. Palanichamy K,
Erkkinen M, Chakravarti A. Current
treatment options in Oncology 2006,
7:490-504
2.
Radiotherapy plus concomitant and
adjuvant temozolomide for glioblastoma.
Stupp R. et. Al. N. Engl J. Med 2005,
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352(10): 987-996
A New Approach
Search for a combination drug regimen which is able to:
• eliminate the entire population of heterogeneous cancer cells,
•stop the growth of the circulating tumor cells, micro- and
macrometastasis without lasting side effects to the host.
“Targeting cellular processes that are operating on a different scale
in cancer cells”
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Cell Organelles – Mitochondrion for High ATP Synthesis and
Nucleus for High Gene Expression
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Cellular Processes
Synthesis of RNA
In Normal
cells
In Cancer
cells
+
++++
Synthesis of Proteins
+
For different
proteins, limited
time period
++++
Continuous
for oncogenic
proteins
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Structure Diagram of a
Mitochondrion
Synthesis of ATP
Normal Cells
+
Cancer cells
++++
Q: Ubiquinone
C: Cytochrome C
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Combination Drug Regimen Targets Three Cellular Processes
Cancer Cells
Drug Design
Some unique features of
cancers
Goal
Characteristics of
the drug selected
High rate of transcription,
most growth related genes
are over-expressed
Names of the
drugs
Lower the synthesis of
As global
Terameprocol
large group of mRNAs
transcription
(M4N) in
and proteins which are inhibitors which Phase I/II clinical
over-expressed in
can suppress the
trial
cancers
promoter activities
of many
oncogenes
High rate of cellular
Reduce the level of
As mitochondrial
metabolism with high energy energy in cancer cells
uncouplers for
demands
prevention of ATP
synthesis.
Resistance to aging and cell Induce rapid cell death As blockers of
death with pro-apoptotic by activating the process PI3/AKT signal
proteins inactivated
of apoptosis
transduction
pathway.
Efficacies of the
combination Drug
Regimen
Three drugs have been found
to be strongly synergistic in
treating a variety of cancer
cells in culture and in human
prostate cancer xenografts ,
eliminating orthotropic
cancer implants and
metastasis in lungs. 100% of
the treated mice are disease
free and continuing to live
beyond 300 days
Phase II Clinical Trial in
preparation
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M4N
EM1421, Terameprocol
Sp1
GGGCGGG
Consensus
M4N is a global Transcription Inhibitor.
Inhibition is by allosteric modulation of DNA unsuitable for Sp1 binding.
Ref: J Med Chem (1998) 41:3001-3007
Antiviral Res (2000) 47: 19- 28
Antiviral Res (2003) 58: 35- 45
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M4N in major groove
NMR studies have pointed
out several other NDGA
derivatives (P4N, Maltose
M3N) interact with SP1 DNA
(SPD) also in major groove
12-mer-SPD-P4N crystal as reflected by a 10Å Increase in the C-axis:
Widened major groove and exposed minor groove
172005.
J. Mol. Biol. 349, 731-744,
Sp1 Expression is Upregulated in Many Cancers and is Often a Significant Predictor of Survival
Fig. 6 from Masashi et.al
Clin. Cancer Res.
2006: 12 (21)
6395-6402
Fig. from
Jiang et.al
Cancer Epid.
Biomarkers Prev.
2008:17 (7)
1648-52
Fig. 4B from
Wang et.al
Clin. Cancer Res.
2003: 9 (17)
6371-6380
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Broad Spectrum Effect of M4N on control of Cancer Cell Growth
1. M4N is one drug with many targets.
2. M4N is also one of multiple drugs with individual single targets.
3. M4N has the unique advantage for targeting heterogeneous population of tumor cells.
M4N
M4N
Cdc2
G2/M
Deregulated Cell
Division
HIF-1α
Glycolysis
M4N
HIF-1α*
M4N
MDR1
PGp
CANCER CELL SURVIVAL
Drug Resistance
Vascularisation
Radiation Resistance
In Hypoxia Region of
The Solid Tumor
Activated AKT
AKT
* Degradation of
HIF-1α protein
VEGF
M4N
HIF-1α
M4N
M4N
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There are 22,633 known genes in the Ensemble Human Genome database.
52.5% of these genes, including Sp1, contained the Sp1 binding motif
5’GGGCGG3’ in their immediate (500 bp) upstream region.
A.K. Todd and S. Needle
N.A.Res. 2008 36 (8) 2700-2704
M4N is able to inhibit a majority of these over-expressed genes in cancer
cells.
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CONTRIBUTORS
Lab of Collaborators
Professor
J.R. Hwu
Chem. Dept.
Tsing Hwa University
R.B. Bates
Chem. Dept
Univ. of Arizona
A. L. DeLucia
Dept. Microbiology & Biochemistry
Northesten Ohio Univ.
College of Medicine
S.Kokpol
Chem.Dept.
Chulalongkorn Univ.
Y.C.Lee
Biology Dept.
JHU
Y. Ito
Lab of Physical Chemistry
NHLB, NIH
J.N. Brady
Lab of Mol.Virology
NCI
H.S. Chen
Inst. Of Medicinal Biotech.
Chinese Academy of Science
Y.Z. Cao
Chinese Academy of Science
N. Khanna
Univ. of Maryland
Medical School
H. Farzadegan
Epidemiology Dept.
JHSPH
T. C. Wu
Pathology Dept.
JHMI
E.N. Moudrianakis
Biology Dept.
JHU
Richard Cone
Biophysics Dept.
JHU
E. Freire
Biology Dept.
JHU
Research Team
David Mold, MD, PhD
Ibrahim Abd-Elazem, PhD
Kotohiko Kimura, MD, PhD
John Gnabre, PhD
Jong Ho Chun, MD
Paul Giza
Tiffany Jackson
Denise Lin
Shruthi Ramkumar
Kevin Ho
Chris Ruland
Murwan Abdallah
Alexandra McMillan
Richard Park
JHU Ph.D. 2002
Tom Chang
JHU Ph.D. 2005
John Heller
JHU Ph.D. 2002