Collaborative Approaches to the Management and Treatment of Cancer

Chanchal Cabrera MSc, FNIMH

Oncology Symposium, Edinburgh

May 2011

clinical case management in cancer care practical strategies and clinical pearls

• decoding the diagnosis - what do the tests mean and how to interpret that information in a clinical application

• designing a targeted treatment plan - specific strategies to address identified risks

• materia medica for cancer - the cyto-toxic herbs

• managing surgery, chemo and radiation - maximizing efficacy and mitigating harm

Carcinogen exposure

Inherited genetic factors Unknown other factors

DNA deletion, mutation or methylation

Alterations in RNA and protein expression / processing

Inactivation of

tumor

suppressor

genes

Activation of

oncogenes

Failure of DNA

repair

Angiogenesis,

invasion,

metastasis

Cancer David P. Carbone, MD, PhD

Energetic Relationships endogenous

endogenous /exogenous exogenous

Energetics of the Human Being

(Spirit - Mind - Body) assess and target

constitutional and energetic systems

Energetics of the Cancer

assess and target the cancer’s characteristics

Energetics of the surrounding

Environment

assess and target the external environmental

contributing factors

The Human Energy within

An endogenous component comprising the personal energetic processes or the core constitution of the individual patient (spirit, mind, and body) and evaluated from a highly individualized perspective.

The External Energy around

An exogenous component comprising the external

environment in which the patient lives and

operates, his/her perceptions of it and its influences

upon him/her, both psychic and physical.

The Cancer Energy

A mixed endogenous / exogenous component

comprising the energetic and physiological

processes of the cancer itself which both responds

to and alters the environment.

A comprehensive protocol will address:

1) Vital Essence, Vital Spirit and Vital Force: energy,

adaptation, protection

2) The individual energetic and constitutional profile

3) Symptoms and the specific conventional

therapies

Gardening

Nature

Music

Art

PATIENT (Spirit - Mind - Body)

ONCOLOGIST HOLISTIC PRACTITIONER

Prayer and

meditation

Common

sense

Intellect

Nutrition and diet

Exercize

Conventional

medicine

Traditional /

holistic healing

techniques

Botanical medicine

CANCER PHYSIOLOGY

Initiation

• Stress and worry

• Genetics and oncogenes

• Toxins and pollution (including drugs, diet, tobacco)

• Radiation (medical, UV)

Initiation

• Viruses (Burkitts & Hodgkins lymphomas,

nasopharyngeal carcinoma from EBV, cervical cancer

from HPV, Kaposi’s sarcoma from HIV, Hepatocellular

carcinoma from hepatitis B or C, Lymphoma from T cell

lymphotrophic virus-1)

• Hormones (estrogen, progesterone, testosterone,

growth hormone, prolactin)

• Oxidative stress

All can trigger gene transcription instability and

DNA mutations

formation of aberrant proteins

faulty enzyme function

defects in physiological processes and disturbance of

Cell Adhesion Molecules

loss of cell to cell communication and consequent

Isolation of damaged cell

failure to regulate growth and reproduction

Promotion

• Growth factors (VEGF, EGF, FGF, TNF and and other

growth stimulators or promoters)

• Cox 2 and 5, 12 and 15 LOX over expression leading to

increased thromboxanes and leukotrines

• Dysregulation of NF-k

• Copper accumulation (and zinc deficiency)

• Oxidative stress and free radicals

• Mutation of regulatory proteins such as p27 and p53

• Immunosuppressive agents eg. the cytokines IL10, TGF

and PGE2

Leads to

• disruption of signal transduction and transcription

• disruption of Extra Cellular Matrix, cell adhesion

molecules and cell to cell communication

Leads to

Proliferation

• Loss of self-control mechanisms

• Reduced apoptosis

• Hypoxia

• Glycolytic shift

• Angiogenesis

• Increased platelet count and stickiness – trend towards clots

• Migration of vascular endothelial cells

• Invasion

• Production of immunosuppressive & immune shielding

compounds immune evasion

• Metastasis (bone, brain, liver and lung)

• Cachexia

Major cell behaviors to target

1) Cellular mitochondrial energy transfer

2) Neuro-endocrine dysregulation

3) Anabolic / catabolic balance

4) Redox balance

5) Immune surveillance

6) Inflammatory response

7) Connective tissue

8) Cytotoxics

9) Anti-angiogenesis

10)Coagulopathy

Five key steps in managing cancer

1) Tumor biopsy

Confirmation and identification of cancer type and

grades / stage with drug sensitivity / resistance

screening, if applicable

Exisional biopsy

NM23 gene

Weisenthal Laboratory, Los Angeles

2) Pathology testing:

a) Proliferative markers

b) Characteristics: identification of gene mutations

and abnormalities in cell behavior,

c) Tissue biomarkers

d) Growth factors, including important regulators

of angiogenesis

Response Genetics

Oncotype

Caris Labs - Target Now

Mammaprint (breast)

Aureon Labs (prostate)

Single Nucleotide Polymorphisms

Humans contain two copies of each gene, one from the father and one from the mother (alleles)

Heterozygous is when a mutation occurs in just one copy of the gene that individual.

Homozygous genotype is when both copies of a gene are mutated.

Majority of hereditary disorders are harmful if both copies or alleles of a gene are affected, which means protein products from both genes may fail to operate properly. However heterozygous mutations can also predispose to disease.

Current Target Now Druggable Gene Targets

Tissue (pathology slide) tests for chemo responses

p53 suppressor gene, high expression mean less-favorable

prognosis

PTEN suppressor gene – high expression mean less-

favorable prognosis

Bcl-2 – suppresses apoptosis, high expression mean less-

favorable prognosis

Carbonic anhydrase 9

Natural compounds that initiate apoptosis via

p53 stimulation

Melatonin

Curcumin

Resveratrol

Ginsenosides

Retinoic acid, interferon and vitamin E may selectively

disable mutated p53.

Compounds that inhibit p53 mutation

Quercitin

Resveratrol

OPCs

Curcumin

EGCG

Oridonon (Rhabdosia rubescens)

Paw paw seed

Folate

Tocotrienols

6-Gingerol

Withanone (Ashwagandha extract)

PTEN (phosphatase and tensin homologue)

A tumor suppressor protein that normalizes gene

behaviour.

Upregulates p27 and down-regulates cyclin D1 leading

to decreased proliferation and increased apoptosis.

Inhibits phosphatidylinositol-3’-kinase (PI3K) / AKT

signaling pathway.

Activation of the PI3K / AKT pathway is associated with

increased proliferation,inhibition of apoptosis,

elevated VEGF and increased angiogenesis.

Lost expression or mutation of PTEN leads to

• activation of EGFr and COX-2

• resistance to chemotherapy

• resistance to radiotherapy

• worse prognosis

PTEN (phosphatase and tensin homologue)

PTEN activators and inhibitors of PTEN mutation include

Quercitin

Resveratrol

Luteolin

Sulphoraphrane

Isoflavones

Carbonic anhydrase 9 (CA 9)

A transmembrane enzyme that catalyzes CO2 and

H2O into carbonic acid and bicarbonate ions.

Contributes to acidification of the tumor environment

Regulates intra-cellular pH and protects cell from

apoptosis. Induced by hypoxia.

Elevated CA 9 is associated with cancer induced

hypoxia, increased VEGF and MMP-9, and with

malignant progression and poor prognosis.

Carbonic anhydrase 9 (CA 9)

Elevated CA-9 is associated with over-expression of IL8,

NFk, EGF receptor up-regulation and Her2/neu.

Elevated CA-9 is a good predictor of radio-resistance due

to prevalence of hypoxia.

Inhibition of COX-2 and enhanced PG1 can inhibit CA-9.

Curcuma longa

Omega 3 fats

Bcl-2

A normal human protein. Pivotal role in apoptosis.

Apoptosis is necessary to accommodate the billions

of new cells produced daily and to eliminate aged or

damaged cells.

Regulation of this process is mediated primarily by the

Bcl-2 protein family.

Bcl-2 is normally found in the mitochondrial membrane

where it down-regulates the release of a substance

known as cytochrome C.

Free cytochrome C activates enzymes called

caspases, which ultimately initiate in cell death.

High levels of Bcl-2 are associated with most types of

human cancer.

Bcl-2 is known to:

- Prevent programmed cell death

- Enhance metastatic potential

- Promote resistance to anticancer therapy

- Indicates poor prognosis in many cancers

Curcumin Green tea extract

Scutellaria baicalensis Hibiscus sabdariffa

beta-sitosterol 3,3'-Diindolylmethane (DIM)

Theophylline Forskolin

6-Gingerol Grape seed extract

Parthenolide Beta-lapachone

Andrographis paniculata

Flavonoids - naringenin, rutin, hesperidin, resveratrol, naringin and quercetin

Agents that normalize Bcl-2

3) Blood testing:

a) Establishing tumor marker baseline

b) Assessing terrain: identification of any disturbances

within the internal environment that can and should be

altered including nutritional status, pH, lipids,

inflammation, glucose and insulin, and other contributing

hormonal imbalances, and hypercoagulation.

c) Liver profile - Detoxification capacity of the liver - Genova

Diagnostics (Detoxigenomic profile)

4) Build a foundation protocol with botanical and nutritional

formulations to enhance and sustain the vital force,

organ systems, immune system, and cellular status.

In Oncology, adaptogens benefit patients

in the following ways:

1. As biological response modifiers, restore immune surveillance, increase non-specific resistance

2. Building bone marrow and blood counts, while reducing infections

3. Protect organs and cells throughout the body including liver, kidney, heart, and GI tract

4. Increase anti-tumor/cytotoxic effects of chemotherapy and radiation therapy

5. Inhibit multi-drug resistance

6. Improve recovery and healing after surgery, chemotherapy and/or radiation therapy

7. Inhibit cancer metastasis and/or reoccurrence

8. Reduce levels of immune dysfunctional stress hormones

3 Categories of Adaptogens The Platform from which to build a protocol while on

chemotherapy

Primary – Panax ginseng

– Mumie

– Eleuthero s.

– Rhodiola r.

– Ashwagandha

– Rhaponticum

– Aralia m.

– Holy basil

– Pantocrine

Secondary – Licorice

– Astragalus

– Gotu Kola

– Reishi

– Poria cocos

– He Sho Wu

– Royal Jelly

– Cordyceps

– Poria

Companion - Turmeric

- Green tea

- Rosemary

- Grape seed & skin

(Resveratrol)

- Ginger

- Ginkgo Biloba

5) Formulate a specific, targeted protocol that

integrates the holistic model, the multiple layers of

botanical formulations, and when appropriate the most

useful conventional medicine treatment options.

Second level intervention – start to treat cancer in general

guided by blood and tissue tests

• Induce apoptosis in cancer cells – flavonoids,

cytotoxics, anti-neoplastics

• Disrupt cancer cell metabolism and normalize growth

factors, signal transduction and signal transcription

• Support bone marrow and immune activity, reduce

local inflammation

Third level intervention – address specific cellular and

systemic imbalances as determined by blood and tissue

testing

• Normalize angiogenesis

• Strengthen blood vessel walls, inhibit collagenases

and proteases, inhibit hyper coagulation

• Correct for specific genetic defects

Response Genetics

Oncotype

What makes up a treatment protocol?

• List of supplements (nutritional/botanical/other), When and how to take,

Medicinal Smoothie recipe

• Specific lifestyle recommendations (exercise, meditation, prayer)

• Other supportive treatments - acupuncture, massage, chiropractic, etc.

• Potential drug treatments that would be useful and why

• Personalized formulations

– Herbal tonic

– Herbal tea

– Topical formulas

– Suppositories

– Inhalation formula

– Enemas & douche formulas

• List of tests to have run

Stabilizing of DNA

Immune system activation / regulation

Inhibition of Inflammation

Modulation of growth factors

Anti angiogenesis and anti-metastatic

Cytotoxic and apoptotic

activating agents

Hormonal modulation & detoxification

GROWTH FACTORS

Epidermal growth factors (EGF)

Fibroblast growth factor (FGF)

Insulin like growth factors (IGF)

Platelet derived growth factor (PDGF)

Transforming growth factor alpha (TGH)

Transforming growth factor beta (TGH)

Vascular endothelial growth factor (VEGF)

Growth factor → PTK or PKC receptor site (structural

and functional protein) on extra-cellular domain →

transmembrane domain → intracellular domain →

phosphorylation cascade (signal transduction) →

nuclear membrane → activation of transcription factors

→ gene transcription → new structural or functional

protein.

Cascade of phosphorylation

Tumor growth

VEGF + bFGF + TGF1 + PDGF

Natural compounds that inhibit PTK

Caffeic Acid Phenethyl Ester (CAPE) (from Propolis)

Curcumin

Emodin

Flavonoids including apigenin, luteolin, quercetin, genistein

Hypericin (light activated)

Parthenolide

Catechins from green tea especially EGCG

Forskolin from Coleus forskolii

Ursolic acid from Rosmarinus off and Ocimum sanctum

Natural compounds that inhibit PKC

CAPE (from Propolis)

Curcumin

Emodin

Flavonoids including apigenin, luteolin, quercetin, EGCG

Hypericin (light activated)

Omega 3 fatty acids (EPA / DHA)

Selenium

Vitamin E

IP6 (inositol hexaphosphate)

Emodin

- most abundant anthraquinone of rhubarb,

capable of induction of apoptosis, inhibiting cellular proliferation and prevention of metastasis.

- acts through tyrosine kinases, phosphoinositol 3-kinase (PI3K), protein kinase C (PKC), NF-kappa B (NF-kappaB), and mitogen-activated protein kinase (MAPK) signaling cascades.

Aloe-emodin

- another major component in rhubarb with anti-tumor properties. Anti-proliferative property is through p53 and its downstream p21 pathway

Vascular endothelial growth factor

Induces endothelial proliferation and vascular

permeability as well as angiogenic budding.

Synergist with PDGF, EGF, TGFα , TGF, ILGF

Upregulated by oncogenes: Hras, Kras, PTEN,

mutated p53, c-jun

Down regulated by strong social support

Natural Compounds that Inhibit VEGF

Andrographolides (Chiretta)

Angelica sinensis (dong quai)

Artemisia annua (Chinese wormwood)

Camellia sinensis EGCG

Centella asiatica (gotu kola)

Coriolus versicolor (tuekey tail)

Curcuma longa (turmeric)

Ginkgo biloba – 27% Flavones and 7% terpenes

Magnolia seed cones – 50% honokiol

Ocimum spp. (Basil) Ursolic acid

Polygonum cuspidatum (Japanese knotweed) – 20% resveratrol

Rabdosia rubescens (Rabdosia)

Scutellaria baicalensis (Chinese Baical skullcap) – 95% baicalin and other compounds,

mostly flavonoids

Silybum marianum (milk thistle) – 80% Silymarin

Tomato products and soy protein

Taxus breviflora (Pacific yew) – taxol and other related taxins

Viscum album (Mistletoe)

Vitus vinifera (grape seed extract) – 95% OPCs

Epidermal Growth Factor 1 (her 1)

Promotes cell proliferation, mobility, invasion and

metastases. High EGFR expression correlates with poor

prognosis.

Noted in non-small cell lung cancer, prostate, brain,

renal, pancreatic, breast, squamous cell carcinomas of

head and neck and colon solid tumors.

Targeted by monoclonal antibodies

• Iressa and Tarceva – first generation

• Cetuximab, Erlotinib and Gefitinib – second generation

small-molecule EGFR tyrosine kinase inhibitors

Natural compounds that down regulate EGF 1

Genistein

Curcumin

Licorice

Cysteine (whey)

Resveratrol

Vitamin D3

Selenium

Quercitin

Use diaphoretics with monoclonal antibodies to

induce interferon

Angiogenesis

Copper is an obligatory co-factor in angiogenesis

and acts an on / off switch.

Copper increases the binding of angiogenic factors

to the endothelial cells

Levels should be in the lowest 20th percentile.

Specialized angiogenic tests

• Il-6 (predictor of cancer-related inflammation)

• Il-8 (predictor of response to anti-VEGF therapy)

• Il-10 (predictor of cancer progression)

• Il-6 (pro-inflammatory)

• Plasminogen activator inhibitor (PAI-1)

• MMP-2, 3 and 9 (Matrix metalloproteinase-2, 3 and 9)

• TGF-B1 (Transforming growth factor-beta)

• Her II neu (cancer that over-express EGF2)

• TIMP-1 (Tissue inhibitor of metalloproteinases-1) elevated

levels indicate anti-apoptotic and pro-angiogenesis tendency

• MCP-1 (monocyte chemotactic protein-1) stimulates growth of

prostate and breast cancer

• Serum Cytokeratin 19

Copper is an obligatory co-factor in angiogenesis and acts

an on / off switch.

Copper increases the binding of angiogenic factors to the

endothelial cells

Levels should be in the lowest 20th percentile.

Decrease vascular permeability and inhibit

angiogenesis

By degrading fibrin, normalizing vascular

permeability, regulating prostaglandin (PG2)

production, reducing COX-2, VEGF, FGF, histamine,

lactic acid, IGF-1, copper and iron

Inhibitors of angiogenesis

• Chelation of copper:

Zinc

Molybdenum

Lipoic acid

Resveratrol

Luteolin

Camellia sinensis

HYPERCOAGULATION

Activation of extrinsic coagulation system and the

fibrinolytic cascade within a tumor contributes to growth and

invasion.

Cancer increases venous thromboembolism risk by 4 – 6 x.

20% of all VTEs occur in cancer patients

Tests for risk of hypercoagulation

Fibrinogen measures clotting potential

D-dimer measures fibrinolysis

CRP (C reactive protein) measures endothelial inflammation

which significantly increases risk of clotting

Plasminogen activators

Plasminogen activators (PAs)

A family of proteolytic enzymes including plasmin, PA-

1, PA-2, u-PAR, u-PA and t-PA.

Reduced plasmin and increased levels of u-PA, u-PAR and PAI-1 lead to increased fibrin formation → associated with increased tumor aggressiveness and

poor prognosis.

Plasminogen activators (PAs)

Patients with cancer have a 7 fold increase in blood

clots of legs or lungs

Increased PAs at time of surgery for cancer is

associated with increased likelihood of recurrence and

metastases

Anti-coagulant herbs and natural medicines

Allium sativum

Gingko biloba

Curcuma longa

Vitamin E

Fish oils