Corrective Cancer Care and Cancer Stem Cell Therapy

Bradford S. Weeks, M.D.
www.weeksmd.com md@weeksmd.com

The Weeks Clinic for Corrective Medicine and Psychiatry © 2011

Original Titles
“Cancer: Striking the Root” vs. “Cancer: Don’t Kill the Messenger”

The Weeks Clinic for Corrective Medicine and Psychiatry © 2011

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Max Wicha, M.D.
Distinguished Professor of Oncology Director, University of Michigan Comprehensive Cancer Center

• “The problem is, when we treat cancer cells with chemotherapy, the cancer stem cells are being stimulated to grow too.” • “When we take mesenchymal stem cells and mix them with tumor cells, the tumors grow much more quickly in animals.”
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Cancer expert tells how treatment can be problem
Wednesday, February 24, 2010 By Mark Roth, Pittsburgh Post-Gazette

Max Wicha: Hopes cancer treatments can avoid general chemo altogether and just use targeted therapies against the stem cells. Max Wicha is coming to Pittsburgh today to deliver a startling message. Standard cancer treatments not only often fail to eradicate cancer, but can make it worse. That argument isn't coming from a fringe proponent of alternative medicine, but from the founder of the University of Michigan's Comprehensive Cancer Center and a pioneer in research on why cancers recur and spread to other parts of the body.
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..treatment is a problem (cont.)
The reason breast cancer and other malignancies often return aggressively after treatment is that when tumor cells die under assault from chemotherapy and radiation, they give off substances that can reactivate a special set of master cells known as cancer stem cells, Dr. Wicha said in an interview Tuesday…. Dr. Wicha's lab has found that inflammatory molecules secreted by dying tumor cells can hook up with the stem cells and cause them in effect to come out of hibernation.
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..treatment is a problem (cont.)
• Adult stem cells exist in most tissues, and go into action to repair damage from wounds or infections. • In cancer, they can mutate and no longer obey normal bodily signals to stop growing, Dr. Wicha said. • He and other researchers say that even when chemotherapy and radiation cause tumors to shrink dramatically, these stem cells can stay alive, living under the radar until they are once again spurred into action.
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..treatment is a problem (cont.)
• They also believe stem cells are probably the ones that break away from an original tumor and cause cancer to spread elsewhere in the body. • Chemo and radiation kill off the fastest-growing cells in the body, which applies to most cancer cells, but the cancer stem cells that create those rapidly dividing tumor cells actually grow much more slowly themselves, and are less susceptible to those therapies, he said. • One tactic to address this problem is to kill off both types of cancer cells at once, Dr. Wicha said.
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..treatment is a problem (cont.)
• A recent experimental trial with advanced breast cancer patients at the University of Michigan, Baylor University in Texas and the Dana-Farber Cancer Institute at Harvard University used standard chemotherapy along with a substance designed to block one of the biochemical pathways of stem cells. • The approach killed off more than 90 percent of the cancer stem cells, Dr. Wicha said, and researchers now hope to expand the treatment to a much larger group of patients.
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..treatment is a problem (cont.)
• Ultimately, he hopes cancer treatments can avoid general chemo altogether, with its debilitating side effects, and just use targeted therapies against the stem cells. • There is still a long road ahead, he said, and "my feeling is, to really knock these stem cells out, we're probably going to have to use multiple inhibitors.“
You Tube http://weeksmd.com/?p=5014 and http://wn.com/professor_max_wicha__breast_cancer_stem_c ell_regulation
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The Public “retraction”
“Cancer patients, follow recommended care!

An article published by the Post-Gazette claimed that our research suggests cancer treatments "not only often fail to eradicate cancer, but can make it worse" This statement has been misinterpreted by patients currently receiving radiation or chemotherapy treatments. I have been contacted by both my own patients and Pittsburgharea patients who have questioned whether they should continue with their chemotherapy. In fact, these treatments are lifesaving for many patients.
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…Retraction

(cont.)

• Our work does suggest that the resistance of a small population of tumor cells to these treatments may account for some of their limitations. Based on this, we are working to develop new approaches to target this specific cell population -- treatments that could augment chemotherapy and radiation therapy. New treatments based on this theory are in their early testing stages. Only through the conduct of rigorous clinical trials will we be able to determine whether addition of these new therapies improves the outcome for patients with cancer. • In the meantime, patients diagnosed with cancer need to follow their doctors' recommendations for treatment according to the current standards of care and inquire whether they are eligible for a clinical trial. MAX WICHA, M.D. Distinguished Professor of Oncology Director, University of Michigan Comprehensive Cancer Center Ann Arbor, Mich.”

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Brief Review
“Know your enemy intimately, See your target clearly, Set your strategy carefully, Before you attack wisely.”

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Leading Thought: Is attacking Cancer the Best Strategy? “The ideal strategy whereby one could win without fighting, accomplish the most by doing the least, bears the characteristic stamp of Taoism.”
- note by Thomas Cleary, translator, of Sun Tzu’s The Art of War
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Per Prof. Max Wicha, M.D.
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 adjunctive therapies which prevent increase of cytokines (like IL-8) when tumors are attacked with chemotherapy or radiation (and IPT).
* If they would differentiate, they would become susceptible to chemotherapy again

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What is Cancer?
Cancer is understood to be unregulated cells proliferating autonomously within the human being – either in humoral or tumorous form. (Query: Are these aggressive or confused cells?)

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What is a Tumor?
A tumor, benign or malignant, is a proliferation of cells of which, in the case of a malignant cancer, less than 1% of which are dangerous.

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Interesting Fact
99.1% - 99.6% of the tumor cells are NOT dangerous (aside from steric, obstructive factors).

“Similarly, usually less than 1% of primary tumor cells cultured in vitro can give rise to colonies.”
Diehn, M Therapeutic Implications of the Cancer Stem Cell Hypothesis Semin Radiat Oncol. 2009 April; 19(2): 78–86.

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What metastasizes?

Stem cells!
“… tumor cells are heterogeneous in their capacity to give rise to tumors upon transplantation or to form colonies in culture assays. For in vivo tumor transplantation, this is reflected in the large numbers of tumor cells that must usually be transplanted to form a tumor. For primary human and mouse tumors, this number often resides in the thousands or millions. (ibid Diehn et al)

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Only stem cells metastasize
“Considerable evidence suggests that tumors contain only a minority of cells which are capable of regrowing the tumor (ie. tumor stem cells). Since all tumor stem cells must be killed if treatment is to be successful, the number of stem cells in a tumor can be expected to be an important determinant of curability.”
Hill RP The proportion of stem cells in murine tumors. Int J Radiat Oncol Biol Phys. 1989 Feb;16(2):513-8.

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Normal Tissue Stem Cells resist Chemotherapy
“A large number of the most frequently used therapies for cancer induce cell death by inducing DNA damage. These agents are also toxic to normal stem cells and their progeny. Fortunately, normal stem cells have evolved multiple mechanisms to protect themselves from toxins and genotoxic stress, which make them relatively resistant to cell killing with cytotoxic agents.” (ibid Diehn et al)

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All Stem Cells resist chemotherapy
The apparent similarities between normal tissue stem cells (NTSC) and cancer stem cells (CSC) led to the hypothesis that CSC may be relatively resistant to common chemotherapeutic agents compared to their more differentiated non-tumorigenic counterparts and that improvements in patient outcomes might be achieved by directly targeting CSC . Mounting evidence suggests that this is the case. (ibid Diehn et al)

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Cancer Stem Cells resist Chemotherapy
Baker, M Stem cells: Fast and furious. Nature. 2009 Apr 23;458(7241):962-5.

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Cancer stem cells are resistant to chemotherapy
“The apparent similarities between normal stem cells and CSC led to the hypothesis that CSC may be relatively resistant to common chemotherapeutic agents compared to their more differentiated non-tumorigenic counterparts and that improvements in patient outcomes might be achieved by directly targeting CSC. Mounting evidence suggests that this is the case. Recent studies have shown that “cancer stem cell-like cells” present in some established cell lines and in long-term xenografts appear to be relatively resistant to cytotoxic chemotherapeutics.” (ibid Diehn et al)

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Chemotherapy and Radiation is only effective in non-aggressive cancer cells (tumor cells, not cancer stem cells).
Invasive Carcinoma

CANCER is spread and kept alive by Cancer Stem Cells

Normal Cells Cancer Stem Cell Tumor cells

•Chemo-Therapy •Radiation

Aggressive cancer stem cells survive chemo

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

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and Cancer Stem Cells are resistant to Radiation Therapy also
“Thus, CSC in some tumors appear to be resistant to cytotoxic chemotherapies. As is discussed elsewhere in this issue, CSC in some tumors also appear to be resistant to radiotherapy. These findings suggest the overcoming CSC resistance mechanisms to cytotoxic therapies may result in higher cure rates.” (ibid Diehn et al)

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Chemotherapy increases Cancer Stem Cell proliferation
Since it remains to be determined how representative such “cancer stem cell-like” cells are of CSC in primary tumors, another group analyzed human CD44+ESA+ colon cancer stem cells … were enriched in xenografts that had been treated with cyclophosphamide compared to untreated control tumors. (ibid Diehn et al)

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The worst case scenario
(aka the „Standard of Care“)

Chemotherapy or Radiation
Invasive Carcinoma

Cancer Stem Cells survive

Resistence!

Tumor cell (non stem cell)

Cancer Stem Cell

Normal cell

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Chemotherapy increases cancer stem cell number and virulence
“Enrichment was documented both as an increased percentage of cancer stem cells as measured by flow cytometry and as higher tumor forming capacity in limiting dilution assays.”
Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100:672–9.

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“Primum Non Nocere”
“Chemotherapy and Radiation make Cancer worse.”
Prof. Max Wicha, M.D. Director U. Michigan Comprehensive Cancer Center

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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. Chemotherape utic drugs and human tumor cells cytokine network. Int J Cancer. 2008

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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 cellsHuman melanoma cells inhibit the earliest differentiation steps of human Langerhans cell precursors but failed to affect the functional maturation of epidermal Langerhans cells . British Journal of Cancer (2001)

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New Directions in Cancer Treatment
“Recent insights into tumor biology….indicate that in many cancers only a subset of malignant cells has the potential to proliferate indefinitely and therefore to give rise to macroscopic metastases or to cause tumor recurrence after treatment” “It is this subset of cells, often called cancer stem cells (CSC), that needs to be targeted and eliminated in order to achieve cures, since the remaining cancer cells (called nontumorigenic cells) are destined to stop dividing or to die.” (ibid
Diehl et al)

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New Directions in Cancer Treatment (cont.)
The CSC hypothesis suggests that agents targeting these cells should ultimately lead to improved outcomes for cancer patients.”
http://cirmresearch.blogspot.com/2011/04/shifting-balance-of-stem-cell-renewal.html

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Going Forward
Assessing the efficacy of such treatments will require the advent of new approaches to assessing CSC frequency and viability within tumors. Furthermore, classic mechanisms of treatment resistance, such as clonal selection and the tumor microenvironment, will continue to present obstacles for achieving cure. It is therefore likely that combinations of cytotoxic, biologic, and CSC-directed therapies will ultimately allow the largest possible improvements in patient outcomes.

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We need a targeted therapy
“One vexing dilemma in the nascent field of CSC-based therapeutics is the high similarity between CSC and normal tissue stem cells, which complicates the second aforementioned goal of CSC-directed therapy – avoiding normal stem cell toxicity.” (ibid Diehn et al)

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Certainty in Clinical Practice

“I stand firmly upon the shifting sands of clinical science.”
Dr. Weeks’ disclaimer to patients, the state medical board and esteemed colleagues (and his mother).

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IPT is better than conventional Rx
“Those wicked creatures yet do look wellfavored, when others are more wicked; not being the worst stands in some rank of praise – I’ll go with thee: thy fifty yet doth double five and twenty, and thou art twice her love…”
Lear, speaking to daughter Goneril when insulted by daughter Regan - Act 2 scene 1

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But….
IPT, being chemotherapy (albeit low dose and targeted “kinder and gentler”) nevertheless still worsening cancer prognosis since it still kills ONLY cancer tumor cells (not the cancer stem cells): the resulting IL-8 “SOS” signal still goes out to muster reinforcements from the mesenchymal stem cells which increase the number and virulence of cancer stem cells.

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RX: IPT with Adjuvant Therapies
Stem cell “re education”

Adjunctive therapies along with IPT to entice cancer stem cells to differentiate and become normal tissue stem cells or normal tissue cells.

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“The Cordelia Effect”
Current Approach: Killing the Messenger (Cut, Burn, Poison) Better Approach: Bring the cancer stem cells back in line because re-differentiation is better than death.

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The Cordelia Effect

(cont.)

The goal of the “Cordelia Effect” (Corrective Cancer Care) is to control the variables including the local tumor environment so as to shift the cancer stem cells’ metabolism away from proliferation and towards differentiation, in order to decrease tumor size, growth and virulence.
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The Cordelia Effect
(examples of Corrective Cancer Care)

1) Proteolytic Enzyme Therapy (pancreatic enzymes) 2) MEBO (moist exposed burn ointment) 3) Anti-inflammatory agents (tumeric, etc.) 4) Fermented Soy products (Haelan 951)

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Proteolytics Enzymes

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MEBO
Moist Exposed Burn Ointment

Create a healthy environment which allows nutrition, detoxification and differentiation for cancer stem cells wherein cancer can not persist. Therapy in concordance with the human being’s powerful momentum towards health.

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Tumors are wounds, that do not heal. Every cancer medication should improve wound healing.
- Rudolph Virchow, 1865

Today we know that cytokines (inflammation) inhibit cell differentiation and wound healing.

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Anti-Inflammatory Agents
Goal: To interrupt the IL-8 cytokine “SOS” and allow differentiation of cancer stem cells

Reprotaxin -CXCR1 receptor blocker- (Wicha) Oxygen (hypoxemia stimulates CSCs) Tumeric MEBO Fermented Soy

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Anti-Inflammatory Agents in Corrective Cancer Care

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CANCER STEM CELLS AND FERMENTED SOY

1) Soy decreases cytokines (including IL-8)
Handayani, R Soy Isoflavones Alter Expression of Genes Associated with Cancer Progression, Including Interleukin-8, in Androgen-Independent PC-3 Human Prostate Cancer Cells1 J. Nutr. 136:75-82, January 2006

2) Fermented soy promotes cell differentiation

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CANCER STEM CELLS AND FERMENTED SOY

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CANCER STEM CELLS AND FERMENTED SOY
BasisWerte Serum TNF-a
(pg/ml)
40 50

Isoflavone
(125/Tag)

Nach Einnahme

30

20

Ursula Jacob et al , 2009

10

0 -5 0 5 10 15 20 25 Zeit (Wochen)

Isoflavones reduce cytokines in the blood
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ERalpha vs. ERbeta
Prostate cancer growth depends, in its earlier stages, on androgens and is usually pharmacologically modulated with androgen blockade. However, androgen-ablation therapy may generate androgen-independent prostate cancer, often characterized by an increased invasiveness.

We have shown that the dihydrotestosterone metabolite 5alphaandrostane-3beta,17beta-diol (3beta-Adiol), a steroid which does not bind androgen receptors, but efficiently binds the estrogen receptor beta (ERbeta), exerts a potent inhibition of prostate cancer cell migration through the activation of the ERbeta signaling.
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Note: in the Blood Circulating Tumor Cells are more aggressive Than the primary tumor : Less Differentiated !!!!!

Rohr et al 2010

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

ER-ß Gen Expression Fold increase
Single cases

300

200

100

0 0

1,5

3

Time (Month)

Ursula Jacob et al , 2009

Patient consumed Isoflavones regularly

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Patients with high GLEASON Factor (High Malignicy)

Soy Increases Anti-tumor Factor p21, p53 In Circulating Tumor Cells
Prostate Ca Breast Ca

Rel. Gen-Expression von Zellzyklus Inhibitor p 21

Single Cases

Single Cases

Ovary Ca
untreated With fermented soy

Ursula Jacob et al , 2009
Single Cases The Weeks Clinic for Corrective Medicine and Psychiatry © 2011

Cachexia in Cancer Patients

N= 164

N= 78

%

Rohr et al, Hormone Molecular Biology and Clinical Investigation 2010

Chemotherapy + fermented soy

Chemotherapy + Placebo

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CANCER STEM CELLS AND FERMENTED SOY
Haematopoeises (Cell Differentiation) Bone Marrow Transplant in Children

In leukemic Children increases a) transplant efficiency and b) reduces hospital stay of children
4 month with Conventional transplantation
1 1/2 month if treated with fermented soy Dramatic increase of Cell differentiation

Hospital Stay of Children

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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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CANCER STEM CELLS AND FERMENTED SOY

Anti-Angiogenesis
Stabilizing blood capillaries in cancer patients is the new goal in severe diseases. Adiol (and/or Fermented Soy) inhibits stem cell metastastasis by this anti-inflammatory mechanism.

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Severe Stress In Soldiers like PTSD

Trauma

Pregnancy Prevents Miscarriage

Fermented Soy is structurally and functionally similar to the hormone ADIOL

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Fermented Soy transforms Resistant Cancer Stem Cells into “differentiated cancer cells” which can then be treated with Chemo or Radiation therapy.
Cancer Stem Cell Differentiating

Primary

Invasive Carcinoma

Mets

Chemotherapy

Radiation

Fermented Soy

Tumor Cells (non stem cell)

Cancer Stem Cell

Normal Cell

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CANCER STEM CELLS AND FERMENTED SOY

“Fermented soy transformed circulating cancer stem cells (in vivo, human) into more differentiated and therefore more “targetable“ treatable cancer tumor cells.“

This mechanism may be the reason for dramatic increase in survival we see in clinic.
An example of the “Cordelia Effect“

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Summary: Stem Cells and Cancer
1) Cancer mortality is directly related to cancer stem cell activity (metastatic and proliferative processes) 2) Chemotherapy and radiation do not kill cancer stem cells 3) Chemotherapy and radiation make cancers grow faster and more virulent 4) Treatment of (people with) cancer requires adjunctive care and not just chemotherapy or radiation 5) Treatment which fails to address the toxicity of cancer stem cells is futile and irresponsible

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Summary: Stem Cells and Cancer

(cont.)

6) IPT, while “kinder and gentler”, must not be given unless adjunctive care is taken to minimize cancer stem cell stimulation 7) Adjunctive treatment modalities represent a significant improvement over traditional IPT.

8) This is a therapeutic message which our patients, as well as our oncology colleagues, are ready to hear.
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Thank You for your Attention
• • • • • • References / Recources Inspiration People to watch in stem cell work Key Articles re. stem cells and cancer Epic Poetry Feel free to email me for further discussion

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The Oath of Paracelsus
This is my Vow: To perfect my medical art and never to swerve from it so long as God grants me my office, and to oppose all false medicines and teachings. Then to love the sick, each and all of them, more than if my own body were at stake. Not to judge superficially, but by symptoms, nor to administer any medicine without understanding, nor to collect any money without earning it. Not to trust any apothecary, nor to do any violence to any child. Not to guess, but to know.

Paracelsus
1493 - 1541
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Ode to the Totipotent Hematopoetic (sic) Stem Cell
My musing on stem cells, circa 1987

“Sirens sang from Science rocks and caught my ear, despite the plug nestled deep of orthodox which churches plant, so proud and smug. Orphans each adrift we are; homeless, steering course by star. The winds would change, time was short. The moment asked of me resolve. So digging deep within my heart, I chose, swung prow, intent to solve the only question man must ask; the only truly human task …
For the rest of the epic poem, see Appendix and http://weeksmd.com/?p=5456

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Further Reading on Stem Cell Treatment
1) Therapeutics formulated to target cancer stem cells: Is it in our future?
Stephanie Clayton, Cancer Cell Int. 2011; 11: 7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073868/

2) Therapeutic Implications of the Cancer Stem Cell Hypothesis Maximilian Diehn,
MD/PhD and Michael F. Clarke, MD http://weeksmd.com/?p=5465

3) Eradication of Cancer Cells via Regeneration Xu Rongxiang, M.D.
http://en.mebo.com/Achievement/ShowInfo.asp?InfoID=262

4) Haelan 5) Powerpoint on Proteolytic Enzymes Bradford S. Weeks, M.D. Presentation at 2010
IPT Conference www.

6) The Enzyme Treatment of Cancer and its Scientific Basis John Beard, D. Sc. 1911 7) The Trophoblast and the Origins of Cancer Nicholas Gonzalez, M.D. New Spring
Press 2009

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People to Watch
Max Wicha, M.D. (Dir. U. Michigan Cancer Center) Michael Clark M.D. Dir. Stanford Institute for Stem Cell & Regenerative Medicine. Max Diehn M.D. (Oncology radiologist Stanford) Ursula Jacob, M.D. and Walter Wainright (Haelan) Xu Rongxaing, M.D. (MEBO) John Beard, M.D. (deceased) / Nicholas Gonzales, M.D.
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Cordelia quotations from King Lear
“Time shall unfold what plighted cunning hides; who covers faults, at last shame them derides.” “We are not the first who with best meaning incurred the worst. Kent: “Vex not his ghost: O, let him pass: he hates him that would upon the rack of this tough world stretch him out longer.”
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