Targeting Cellular Processes as a New Approach for Cancer Treatment

Ru Chih Huang, PhDProfessor of Biology

Johns Hopkins UniversityOct 24th 2009, CAPA Symposium, Gaithersburg, MD

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CURRENT STATUS

“In a long drive to cure cancer, advances have been elusive” ~Gina KolataNew 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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$10x106

$20x106

$45x106

A Thorough Trial Takes Time and Money

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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 that use (April 1st, 2009; New York Times). 6

Oncogenic pathway/Targeting with specific Protein Inhibitor

Targeted by specific protein inhibitor

DaysMonths

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 TherapyStandard of care for Glioblastoma since 1978 (Surgery, Radiation, Chemotherapy)

Without treatment 14 weeks Radiation alone 36 weeks Radiation plus Temozolomide ± Surgery 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, 352(10): 987-996 10

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 In Cancer cells cells

+ ++++

Synthesis of Proteins

+ ++++

For different Continuousproteins, limited for oncogenictime period proteins

Structure Diagram of a Mitochondrion

Synthesis of ATP

Normal Cells Cancer cells+ ++++

Q: UbiquinoneC: Cytochrome C

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Combination Drug Regimen Targets Three Cellular Processes Cancer Cells

Some unique features of cancers

Drug Design

Efficacies of the combination Drug

RegimenGoalCharacteristics

of the drug selected

Names of the drugs

High rate of transcription, most growth related genes

are over-expressed

Lower the synthesis of large group of mRNAs and proteins which are

over-expressed in cancers

As global transcription

inhibitors which can suppress the

promoter activities of many

oncogenes

Terameprocol (M4N) in

Phase I/II clinical trial

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

High rate of cellular metabolism with high energy

demands

Reduce the level of energy in cancer cells

As mitochondrial uncouplers for

prevention of ATP synthesis.

Resistance to aging and cell death with pro-apoptotic

proteins inactivated

Induce rapid cell death by activating the process

of apoptosis

As blockers of PI3/AKT signal

transduction pathway.

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GGGCGGG Consensus

M4N is a global Transcription Inhibitor.

Inhibition is by allosteric modulation of DNA unsuitable for Sp1 binding.

M4NEM1421, Terameprocol

Ref: J Med Chem (1998) 41:3001-3007Antiviral Res (2000) 47: 19- 28Antiviral Res (2003) 58: 35- 45

Sp1

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1712-mer-SPD-P4N crystal as reflected by a 10Å Increase in the C-axis: Widened major groove and exposed minor groove

NMR studies have pointed out several other NDGA derivatives (P4N, Maltose M3N) interact with SP1 DNA (SPD) also in major groove

J. Mol. Biol. 349, 731-744, 2005.

M4N in major groove

Sp1 Expression is Upregulated in Many Cancers and is Often a Significant Predictor of Survival

Fig. 6 from Masashi et.alClin. Cancer Res. 2006: 12 (21) 6395-6402

Fig. 4B fromWang et.alClin. Cancer Res.2003: 9 (17)6371-6380

Fig. fromJiang et.alCancer Epid. Biomarkers Prev.2008:17 (7)1648-52

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Broad Spectrum Effect of M4N on control of Cancer Cell Growth

M4NCdc2

G2/M

Deregulated Cell Division Survivin

M4N

Mitochondrial

Survivin

CANCER CELL SURVIVAL

M4NMDR1PGp Drug Resistance

Radiation ResistanceIn Hypoxia Region ofThe Solid Tumor

Activated AKT

M4N

AKT

M4N

M4N

Glycolysis

HIF-1α

Vascularisation

VEGF

M4N

HIF-1α

M4N HIF-1α*

* Degradation of HIF-1α protein

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.

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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. NeedleN.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 ProfessorJ.R. Hwu Chem. Dept.

Tsing Hwa UniversityR.B. Bates Chem. Dept

Univ. of ArizonaA. 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 ChemistryNHLB, NIH

J.N. Brady Lab of Mol.VirologyNCI

H.S. Chen Inst. Of Medicinal Biotech.Chinese Academy of Science

Y.Z. Cao Chinese Academy of ScienceN. Khanna Univ. of Maryland

Medical SchoolH. Farzadegan Epidemiology Dept.

JHSPHT. C. Wu Pathology Dept.

JHMIE.N. Moudrianakis Biology Dept.

JHURichard Cone Biophysics Dept.

JHUE. 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

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