Collaborative laborative Approaches proaches to the e Manage nageme ment nt and d Trea eatm tment nt of Cance cer 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 Activation of Failure of DNA Angiogenesis, tumor oncogenes invasion, repair suppressor metastasis genes Cancer David P. Carbone, MD, PhD
Energetic Relationships endogenous Energetics of the Human Being (Spirit - Mind - Body) assess and target constitutional and energetic systems Energetics Energetics of the surrounding of the Cancer Environment assess and target assess and target the cancer’s characteristics the external environmental contributing factors exogenous 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 PATIENT Music (Spirit - Mind - Body) Prayer and Intellect Art meditation ONCOLOGIST HOLISTIC PRACTITIONER Traditional / holistic healing Conventional Common techniques medicine sense
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 CO 2 and H 2 O 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 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
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