Download high expression mean less-favorable prognosis Bcl-2

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
Unknown other factors
Inherited genetic factors
DNA deletion, mutation or methylation
Alterations in RNA and protein expression / processing
Inactivation of
tumor
suppressor
genes
David P. Carbone, MD, PhD
Activation of
oncogenes
Failure of DNA
repair
Cancer
Angiogenesis,
invasion,
metastasis
Energetic Relationships
endogenous
Energetics
of the Human Being
(Spirit - Mind - Body)
assess and target
constitutional and
energetic systems
Energetics
of the surrounding
Environment
assess and target
the external environmental
contributing factors
exogenous
Energetics
of the Cancer
assess and target
the cancer’s characteristics
endogenous /exogenous
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
Nutrition and diet
Botanical medicine
Exercize
Gardening
Nature
Music
Prayer and
Art
meditation
PATIENT
(Spirit - Mind - Body)
HOLISTIC
PRACTITIONER
Traditional /
holistic healing
techniques
Intellect
ONCOLOGIST
Common
sense
Conventional
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 lessfavorable prognosis
Bcl-2 – suppresses apoptosis, high expression mean lessfavorable 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
Agents that normalize Bcl-2
Curcumin
Scutellaria baicalensis
beta-sitosterol
Theophylline
6-Gingerol
Parthenolide
Andrographis paniculata
Green tea extract
Hibiscus sabdariffa
3,3'-Diindolylmethane (DIM)
Forskolin
Grape seed extract
Beta-lapachone
Flavonoids - naringenin, rutin, hesperidin, resveratrol,
naringin and quercetin
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
–
–
Companion
–
–
- Turmeric
–
- Green tea
–
- Rosemary
- Grape seed & skin –
–
(Resveratrol)
–
- Ginger
- Ginkgo Biloba
Licorice
Astragalus
Gotu Kola
Reishi
Poria cocos
He Sho Wu
Royal Jelly
Cordyceps
Poria
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
Hormonal
modulation &
detoxification
Immune system
activation / regulation
Inhibition of Inflammation
Cytotoxic
and apoptotic
activating agents
Modulation of
growth factors
Anti angiogenesis
and anti-metastatic
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 +
TGF1
+
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 3kinase (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 antitumor 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, PA1, 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