Collaborative Approaches to the Management and Treatment of Cancer Chanchal Cabrera MSc, FNIMH Oncology Symposium, Edi

1. Collaborative Approaches to the Management and Treatment of Cancer Chanchal Cabrera MSc, FNIMH Oncology Symposium, Edinburgh May 2011

2. 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

3. Carcinogen exposure Unknown other factors Inherited genetic factors DNA deletion, mutation or methylation Alterations in RNA and protein expression / processing Cancer David P. Carbone, MD, PhD

4. 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 Energetics of the Cancer assess and target the cancer’s characteristics exogenous endogenous /exogenous

5. 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.

6. 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.

7. 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.

8. A comprehensive protocol will address: • Vital Essence, Vital Spirit and Vital Force: energy, adaptation, protection • The individual energetic and constitutional profile • Symptoms and the specific conventional therapies

9. Nutrition and diet Botanical medicine Exercize Gardening Nature Music Art PATIENT (Spirit - Mind - Body) Prayer and meditation Intellect HOLISTIC PRACTITIONER ONCOLOGIST Traditional / holistic healing techniques Conventional medicine Common sense

10. CANCER PHYSIOLOGY • Initiation • Stress and worry • Genetics and oncogenes • Toxins and pollution (including drugs, diet, tobacco) • Radiation (medical, UV)

11. 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

12. 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

13. 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

14. Leads to • disruption of signal transduction and transcription • disruption of Extra Cellular Matrix, cell adhesion molecules and cell to cell communication Leads to

15. 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

17. Major cell behaviors to target • Cellular mitochondrial energy transfer • Neuro-endocrine dysregulation • Anabolic / catabolic balance • Redox balance • Immune surveillance • Inflammatory response • Connective tissue • Cytotoxics • Anti-angiogenesis • Coagulopathy

18. Five key steps in managing cancer

19. 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

21. 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)

22. 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.

24. Current Target Now Druggable Gene Targets

25. 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

26. Natural compounds that initiate apoptosis via p53 stimulation Melatonin Curcumin Resveratrol Ginsenosides Retinoic acid, interferon  and vitamin E may selectively disable mutated p53.

27. Compounds that inhibit p53 mutation Quercitin Resveratrol OPCs Curcumin EGCG Oridonon (Rhabdosia rubescens) Paw paw seed Folate Tocotrienols 6-Gingerol Withanone (Ashwagandha extract)

28. 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.

29. Lost expression or mutation of PTEN leads to • activation of EGFr and COX-2 • resistance to chemotherapy • resistance to radiotherapy • worse prognosis

30. PTEN (phosphatase and tensin homologue) PTEN activators and inhibitors of PTEN mutation include Quercitin Resveratrol Luteolin Sulphoraphrane Isoflavones

31. 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.

32. 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

33. 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. 

34. 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.

35. 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

36. Agents that normalize Bcl-2 Curcumin Green tea extract Scutellaria baicalensisHibiscus 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

38. Blood testing: • 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)

39. 4) Build a foundation protocol with botanical and nutritional formulations to enhance and sustain the vital force, organ systems, immune system, and cellular status.

40. 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

41. 3 Categories of AdaptogensThe 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 • Poriacocos • He Sho Wu • Royal Jelly • Cordyceps • Poria • Companion • - Turmeric • - Green tea • Rosemary • Grape seed & skin • (Resveratrol) • Ginger • Ginkgo Biloba

42. 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.

44. 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

45. 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

46. 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

47. 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

48. 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)

49. 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

50. Tumor growth VEGF + bFGF + TGF1 + PDGF