The Management of Estrogens, Estrogen Receptors and...

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The Management of Estrogens, Estrogen Receptors and Estrogen Metabolism in the Treatment of Cancers A4M – Orlando, April 8, 2011 Presented By: Walter H. Wainright, President Haelan Research Foundation

Transcript of The Management of Estrogens, Estrogen Receptors and...

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The Management of Estrogens, Estrogen

Receptors and Estrogen Metabolism in the Treatment

of CancersA4M – Orlando, April 8, 2011

Presented By:

Walter H. Wainright, President

Haelan Research Foundation

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The Complex Relationship between the two Estrogen Receptor α and β

Fig. 3

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SOY PHYTOESTROGENS ARE NOT ESTROGENS

1. There are no studies that show soy phytoestrogens are estrogens – they are anti-estrogenic

2. Estrogens are absorbed in the liver which only has alpha Estrogen Receptors

3. Estrogens have a greater affinity for ER-alpha sites and phytoestrogens have a greater affinity for ER-beta receptor sites

4. If soy phytoestrogens were estrogens

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GENE Alteration with DNA-Micro-Array-Chip-Technik

Untreated

Untreated

1mg Estradiol

Soy isoflavones

1mg Estradiol +Soy isoflaovnes

20 year old womenPostmenopausal women

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Soy isoflavones reduce metastasis risk of postmenopausalen women

Gene-Expression of Matrix-Metalloproteinase (9)MCF-7 Breast-Cancer Cells incubated with

Blood from postmenopausal Women

0

0,25

0,50

0,75

1,0

Relative Gene Expression of Matrixmetallo-proteinase-9-Gen

Untreated

Estradiolca. 120 x higher

Soy

Estradiol + Soy

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6

Summary of Viennese GENE Investigation

Cancer risk Metastasis

risk

Untreated

Soy

Soy +Estradiol

Estradiol-intake

Quelle: Imhof et al., World Congress of Gynecological Endocrinology; Florence 2006Quelle: Imhof et al., World Congress of Gynecological Endocrinology; Florence 2006; * Alsifemin® Soja-Hormon-Balance

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Hormonal Changes in Women

Quelle: Rohr, Gyne 2005

High Cancer Risk Low Cancer Risk

Puberty Menopause

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Schematic Rise and Fall of Estradiol and 3ß-Adiol

unfruchtbare Phase

- 12 Yrs

fruchtbare Phase

- 40 Yrs

Perimenopause

- 55 Yrs

Hormone in BloodArbitrary units

Alter

Post-menopause

65 + Yrs

No hormonalrisks

Increasing Hormonal risks

No Hormonalrisk

Strong hormonal risks and Chronic deseases

3ß-Adiol

Estradiol

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9Estrogen-Receptor -

ER-

suppresses

Estrogen-Receptor - ß

YING – YANG of Estrogen Receptors JA Gustafsson 2003

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Breast Cancer Res Treat. 2009 May 12. [Epub ahead of print]

Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells.Treeck O, Lattrich C, Springwald A, Ortmann O.Department of Obstetrics and Gynecology, University of Regensburg, 93053,

Regensburg, Germany, [email protected].

Estrogen receptor beta (ERbeta) is widely expressed in mammary epithelium. ERbeta expression is reported to decline during carcinogenesis of the breast and other tissues. In this study, we examined the consequences of a loss of ERbeta expression in mammary epithelial cells. We knocked down ERbeta transcript levels in human mammary epithelial MCF-10A cells and in MCF-7 breast cancer cells by means of stable transfection with a specific shRNA plasmid. ERbeta knockdown resulted in a significant growth increase of both cell types in a ligand-independent manner. This effect was accompanied by elevated cyclin A2 expression in MCF-10A cells and by

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Markus Metka : Warum nicht

2-Methoxy-Estradiol durch Ernährung erhöhen ?

Estradiol 2-hydroxy-Estradiol

COMT

2-Methoxy-Estradiol

James D.Yager et al.:Estrogen Carcinogenesis in Breast Cancer, N Engl J Med. 2006; 354: 270-82

4-Hydroxy-Estradiol

16-Hydroxy-Estradiol

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Estrogen-Receptor beta Gene Expression in CTCs

Rel. Gene Expression

before treatment

Prostate Cancer Breast Cancer Ovarian Cancer

After 100 days treatment with fermented soy

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Tagawa et al. 2004

Pregnancy and Immunity

non pregnant pregnancy

Trimester

Postpartum Month

1. 2. 3. 1 2-4 6-7 10-11

Adiol(pmol/L)

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Invasive Carcinoma

•Chemo-Therapy•Radiation

Cancer-Stem-Cell survive

Krebs-Stamm Zellen

Normale Zellen

Nicht-kanzerogene Krebs-zellen

Nicht-kanzerogene Krebs-zellen

CANCER is spread and kept alive by

Cancer-Stem-Cell

Linheng Li and William B. NeavesCancer Res 2006; 66: (9). May 1, 2006

Chemotherapy isonly effective in Non aggressive cancer cells

aggressive cancer cellsSurvive all

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Bone

Haematopoeises and cell differentiation

from stem cells in bone marrow

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Leukemia Treatment by Bone Marrow Transplant

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Prof. Wicha

Chemotherapy increases numbers of dangerous cancer stem cells by increasing cytokines like IL-8 so that cancer stem cell cannot differentiate *, which cause treatment resistance.

The goal is to combine chemotherapy with mechanism which prevent increase of cytokines (like IL-8) in tumors.

If the cancer stem cells would differentiate ----they would become terminal and susceptible to chemotherapy again

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CYTOKINES LIKE IL-8, TNF-α inhibit Stem Cell Differentiation

CD34+ cells towards CD14+

O Berthier-Vergnes et al.. Human melanoma cells inhibit the earliest differentiation steps of human Langerhans cell precursors but failed to affect the functional maturation of epidermal Langerhans cellsBritish Journal of Cancer (2001)

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Depression

Immune Cells

Tumor

Recurrence and Progression

InflammationPsychologicalDistress

Drug Resistance

SarcopeniaCachexia

Fatique Cognitive Impairment

Cytokinesfrom tumors

Stomach

Cancer StemCells leave

Metastasis

Joint

Uwe D Rohr et al. 2010Uwe D Rohr et al. 2010

Cytokines(IL-1, IL-6, IL-8, etc.) Cytokines(IL-1, IL-6, IL-8, etc.)

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Note: in the Blood Circulting Tumor Cells are more aggressive than the primary tumor :

Less Differentiated !!!!!

Rohr et al 2010

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Invasive Carcinoma

•Chemo-Therapy•Radiation

Cancer-Stem-Cell survive

Cancer Stem Cells Normal CellsNicht-kanzerogene Krebs-zellen

Nicht-kanzerogene Krebs-zellen

The worst case Scenario

Resistence

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Cytokines which inhibit Stem Cell Differentiation are increased by doxorubicin in H460 tumor cells,

In vitro

Int J Cancer, 2009, NIH-PA

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CHEMOTHERAPY INCREASE CYTOKINES IN TUMORS

Levina et al. Chemotherapeutic drugs and human tumor cells cytokine network. Int J Cancer. 2008

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ADIOL AND/OR FERMENTED SOY by ER-b and NF-Kb

mechanismsMAY PREVENT TUMOR CELLS FROM SPREADING BY MAKING

THEM LESS LEAKY

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•Chemo-Therapie•Radiation

Cancer-Sem Cell Normal CellNicht-kanzerogene Krebs-zellen

Nicht-kanzerogene Krebs-zellen

Fermented Soy transforms Resistant Cancer Cells into „Normal Cancer Cells“ which can then be treated with

Chemo-Therapy, which are then treatable

Invasive CarcinomaResistence

Fermented Soy

Silent Cancer – Stem

Cell

Fermented Soy

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ANTI-ANGIOGENESIS

Stabilizing blood capilarities in cancer patients is the new goal in severe diseases, reducing them from being leaky to becoming stable again

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Anti-Angiogenesis

Cancer cells are fast growing and stack up on top of each other - Where are the capillaries?

Oxygen starved cells produce VEGF (Vascular Endothelian Growth Factor)

VEGF in tissues cause blood vessels to grow to that area

Pharmaceutical product (Avastin) shut off cellular VEGF [$100k for 6 months (2 shots/mo)– lengthens life span 2 – 5 months]

Side effects – UCLA Study - endothelial cells die because they need VEGF to survive -- in addition Blood Clots

Fermented soy is anti-angiogenic but does not shut off VEGF – no side effects

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Successfully Treating a Pregnant Women With Breast Cancer

Normal Breast Tissue

April 26th 2006

June 10th , 2006

H&E Ki67

Quelle: Karen McCarron and Regina Chorsky

F8

REDUKTION der ANGIOGESE und Zell-WachstumEines invasiven duktalen Brust-Karzinoms

Nach 16 Tagen mitfermentiertem Soja

April 26th 2006

June 10th , 2006

H&E Ki67

Quelle: Karen McCarron and Regina Chorsky

F8

REDUKTION der ANGIOGESE und Zell-WachstumEines invasiven duktalen Brust-Karzinoms

Nach 16 Tagen mitfermentiertem Soja

Reduction of Angiogenesis and Cell-Growthof an invasive ductal Breast Carcinoma

After 16 days of Treatment

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Manage While You Treat Apoptosis – the normal death of a cell

BCL2 – Anti-apoptosis gene

BAX – Pro-apoptosis gene

MDR1 – Multi-Drug Resistance Gene

The P53 Gene – arrests cell cycle, repairs DNA, stops uncontrolled cell replication, kills cells when DNA is not repairable

Anti-Angiogenesis – cancers cannot grow larger than a pencil point without a fully functional independent blood supply

BRCA1, BRCA2, Her2, cachexia & more

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Cell Differentiation induced by the management of estrogens and the

inflammatory cytokines may produce a dramatic increase in

cancer patient survival

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For the First Time Ever

Fermented soy has been shown totransform circulating tumor cells In the in vivo human situation

into a more differentiated less aggressive treatable cells

May have caused dramatic increase in survival

Rohr et al. Horm Mol Biol Clin Invest 2010;3(2):391–409

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GENE EXPRESSION IN CIRCULATING TUMOR CELLS WITH FERMENTED SOY

Rohr et al. Horm Mol Biol Clin Invest 2010;3(2):391–409

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Fermented Soy increases ER-ß Gene Expression in dissiminated Tumor Cells

Fermented Soy increases ER-ß Gene Expression in dissiminated Tumor Cells

ER-ßGen Expression

Fold increase Single cases

300

200

100

0

300

200

100

0 Time (Month)

Time (Month)

0 1,5 30 1,5 3

Patient consumed Isoflavones regularly Patients with high GLEASON Factor(High Malignicy)

facher Anstieg

Ursula Jacob et al , 2009

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Gene Expression of Cell Cycle Inhibitor p21 in CTC

rel. Gene Expression

n= 5

Prostate-Ca Patients Breast-Ca

n= 7

Ovarian Ca

n= 5

Ursula Jacob et al , 2009

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SURVIVAL OF HIGHLY AGRESSIVE OVARIAN CANCER

Month

Survival

Stage III/IV

Stage IV Fermented Soy treated (n=6)

Stage III/IV

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Prostate CancerSurvival

Biochemical after Biochemical Recurrence, y

Gleason Score 8-10

Gleason Score <7

Treated with fermented Soy (n=5)

Freedland SJ, et al. JAMA. 2005 Jul 27;294(4):433-9.

SURVIVAL OF HIGHLY AGRESSIVE PROSTATE CANCER

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Patients with T3-T4 Breast Cancer treated with fermented Soy (n=5) Patients with T3-T4 Breast Cancer treated with fermented Soy (n=5)

SURVIVAL OF HIGHLY AGRESSIVE BREAST CANCER

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The Soy Controversy – All Soy Products Are Not Equal

Fermented vs Unfermented

Selection of Soybeans

Minerals in the Soil

Age of Beans When Picked

Processing of the Beans

Estrogen Positive Breast Cancer

Liquids vs powders (pills, powders or capsules)

Poorly designed Studies (8 out of 9,000+ )

What is a soy study??? Whole soy versus components in soy

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The ER Positive Breast Cancer & Fermented Soy Benefits

Lowers Total Circulating Estrogens 30 - 40% (Lu J; Univ. of Texas –Aromatase Inhibition Activity

Improves Ratio of 2/16 Hydroxyestrogens

Blocks Receptor Sites (26% for Tamoxifen vs 36% Soy) Soy +Tamoxifen is 62%)

Anti-Angiogenesis

Repairs DNA

Anti-Cancer Metabolites (Equol)

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Cachexia Kills 80% of Advanced Cancer Patients – Its more than

calories! It is caused by inflammatory cytokines

Mitochondrial & Other DNA Damage

The MyoD Gene – allows rebuilding of lean muscle mass

DNA damage to MyoD by Cytokines TNF , Interferon gamma (IFN-y), and NF-Kb

Soy compounds protect MyoD DNA damage by cytokines TNF , IFN-y and NF-Kb

Fermented Soy protects MyoD Gene damage, Builds Muscles & Improves Electron Transport in the Mitochondria

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Cachexia in Cancer Patients

n= 164 n= 78

%

Chemotherapy + fermented soy

Chemotherapy + Placebo

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Cell Cycle Inhibitors

MDM2

Cyclin D1

CDK4

Cyclin E

CDK2

block

block

Cell cycle inhibitor

block

Fig. 3

Cell cycle inhibitor

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NFκB and Apoptosis

mitogens

proliferation

apoptosisblocking

• Apoptosis is blocked by BCL2

• BAX increases Proliferation

Pro-inflammatory cytokines stimulate cell-mediated, humoral and/or allergic immunity. The major cytokine mediating cell-mediated immunity is interferon-γ (IFNγ). Humoral immunity is mediated by B cells and production of antibodies; interleukin 4 (IL4), IL10, IL13 and transforming growth factor-β (TGFβ)trigger isotype switching of antibodies. Some cytokines have predominantly anti-inflammatory and immunosuppressive effects (for example, IL10 and TGFβ) or both pro- and anti-inflammatory effects (for example, IL6). Innate immune cells are the major source of IL1, IL6 and tumour necrosis factor-α (TNFα), which direct activity of adaptive immunity and inflammation. GM-CSF, granulocyte macrophage-colony stimulating factor; IL1RA, IL1 receptor antagonist; IL1RII, IL1 receptor type II; TNF, tumour necrosis factor; SCF, stem cell factor.

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GADPH: Cancer cell killing was measured by the GAPDH gene expression. Only live cells have GAPDH gene expression. The GAPDH chart in the study measures cancer cell kill and survival by the agent being tested:

Results: Breast Cancer - Cancer Cell Survival DOXORUBICIN CHEMOTHERAPY FERMENTED SOY TREATMENT: ` Cells ` Surviving Doxorubicin : Surviving(%) BAX BCL2 Fermented Soy Cells(%) BAX BCL2 .5 % Strength 82% 1.05 .4575 .5%^Strength 58% 2.55 1.2468 1.5% Strength 56 % 1.09 .2222 2.5 % Strength 14 % 1.91 .1163 1.5 % Strength 20 % 2.94 .4675 3.75 % Strength 2.3 % .98 .0693 5.0 % Strength 4.6 % .71 .051 3.0 % Strength 4.8 % 3.97 .026 Combined Treatment: .5% Doxorubicin + 3 % Fermented Soy 14% NOTE: HIGHER BAX (PRO APOPTOSIS GENE EXPRESSION) IS BETTER THAN LOWER BAX LOWER BCL2 (ANTI-APOPTOSIS GENE EXPRESSION) IS BETTER THAN HIGHER BCL2

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Platinum Chemotherapy Resistant Ovarian Cancer

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Does Femented Soy Reduce The Effectiveness of

Chemotherapy Treatments ?

National Cancer Institute (US), Office of Cancer, Complementary and Alternative Medicine: Best Case Series Program –Fermented Soy Program

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.

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Relapse of Breast Cancer Cases under different Adjuvant Therapy Regimens

Untreated

Tamoxifen Tamoxifen + Arimidex®

Tamoxifen + Soy

Tamoxifen + Soy

Tamoxifen + Soy

Relapse(100% = 1,0)

0,2

0,4

0,0

ER+, after 8 years, menopausal Women

Fig. 1

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Why Fermented Soy?Because it is synergistic with chemotherapy

treatments and has positive effects on NF-kB, MDR1, BAX, BCL2, BRCA1 & BRCA2 , Her2,

address the cachexia problem, reduces stress and depression, improves quality of life ----AND

IT DOES A LOT MORE

Results of a $20 Million U.S. Government Study on anti-cancer compounds in fruits and vegetables

Five Super Stars – all in Soy

1. Isoflavones

2. Protease Inhibitors

3. Saponins

4. Phytosterols

5. Phytic Acid Compounds

(Journal of the National Cancer Institute April 17,1991)

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PROPERTIES OF THE WHOLE SOYBEAN

ANTI-ALLERGY

ANTI-VIRAL

ANTI-INFLAMMATORY

VASODILATOR

ANTI-CANCER

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Mechanisms of Action That Help The Physician Manage Disease

While Treating It With IPT

MDR1 Apoptosis

DNA Repair P21 Increased

Anti-angiogenesis Estrogen Metabolism

Reduces Estrogen Levels Increased ER-beta receptors

Decreased ER-alpha receptors Produces Anti-Cancer metabolites

Prevents Protein Calorie Malnutrition Shuts Down NF-kB Mutation Pathway Decreases Viral and Bacterial Burdens

Non-Specific Immune Stimulation Increased 700%

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Thank you for your attention

Walter H. Wainright

Haelan Research Foundation

Cell tel: (425) 269-7798

Haelanresearch.org

[email protected]

Woodinville, WA