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Breakthroughs in the Quest to Cure Cancer

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The breakthroughs in cancer research that have led to the discovery of new drugs for the treatment of cancer including Zytiga and Salvestrols

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Breakthroughs in the Quest to Cure Cancer

  1. 1. Breakthroughs in theQuest to Cure Cancer Professor Gerry Potter Founder of the Cancer Drug Discovery Group Leicester School of Pharmacy De Montfort University, Leicester, UK
  2. 2. Early Days
  3. 3. University of Manchester 1983-1986“Mechanism of Action of Anticancer Agents”- Most are generally toxic (cytotoxic)- Toxic to liver, kidneys, heart, white blood cells- Many are highly mutagenic & carcinogenic- Key Issue is Selectivity
  4. 4. Chemotherapy Agents Mutate DNA and are Highly Carcinogenic
  5. 5. Institute of Cancer Research 1987 - 1994 Drug Development Section, CRC Laboratory developed new selective agents for Breast & Prostate Cancer Tamandron (Antiandrogen) Idoxifene (An Improved Tamoxifen Analogue) Ribonucleotide Reductase Inhibitors Abiraterone Acetate (ZytigaTM)
  6. 6. Selective Anticancer AgentsDeveloped by Prof Potter at the Institute of Cancer Research N O N I HO Idoxifene Stilbene Antiestrogen Abiraterone Acetate Cancer Res., 55, 1070-1074 (1995). CYP17 Inhibitor OH J. Med. Chem., 38, 2463-2471 (1995). HO NMe2 O O N O O CB7653 Tamandron Stilbene Antiandrogen Non-steroidal CYP17 Inhibitor New Scientist, 16, 23 May 1992 J. Med. Chem., 38, 4191-4197 (1995).
  7. 7. Design of Abiraterone AcetateZytiga (Abiraterone Acetate) Designed by the Steroid to Haeme Juxtaposition of the Lyase Transition State #3 of a Proposed Catalytic Cycle for the Lyase/Hydroxlase Enzyme CYP 17 Derived by Professor Potter
  8. 8. Design & Synthesis of AbirateroneJournal of Medicinal Chemistry, 38, 2463, 1995
  9. 9. Potent Androgen Ablation by Abiraterone (CB7598)Journal of Steroid Biochemistry and Molecular Biology, 50, 267, 1994
  10. 10. Abiraterone (Zytiga)•Successfully completed Clinical Trials•Approved by NICE for use on the NHS in the UK•Licensed to Johnson & Johnson marketed as “Zytiga”•FDA and EMA Approved for the treatment ofadvanced Prostate Cancer after taxotere chemotherapyhas failed•Currently used worldwide by thousands of patients
  11. 11. Link Between Diet and Cancer Lower incidence of cancer correlates with Higher consumption of fruits & vegetables (Western diet correlates to high incidence of cancer) Understanding this Nobody really knows why ! link would help •cancer prevention (many theories, antioxidants, phytoestrogens, •cancer treatment polyphenols etc)
  12. 12. Discovery of a Tumour Specific Salvestrol Metabolising Enzyme (Salvestrol Activase)  Breast  Bladder  Brain  Colon  Lung  Kidney  Ovarian  Oesophagael  Prostate  StomachCancer Research, 57, 3026, 1997
  13. 13. Stomach Oesophageal Ovarian Myosarcoma
  14. 14. Normal Colon Colon Cancer Dysplasia
  15. 15. Salvestrol Activase is a Tumour Suppressor Enzyme Works as a cancer preventing enzyme acting via natural prodrug bioactivation, i.e. salvestrol activation Expressed in a variety of tumours  Generic Rescue Mechanism  Irrespective of tumour type or oncogenic origin  Cancers arise from many different mutagenic origins Induction tightly regulated  Induced by various cellular damaging effectsG.A. Potter, British Journal of Cancer, 86 (Suppl 1), S12, 2002
  16. 16. Designed Prodrugs Activated by a Tumour Specific Enzyme Synthetic Prodrugs Designed  Shows very exciting tumour selective activity  No toxic effects  Development to clinical use taking many years Realised molecular relationship to natural compounds that have cancer preventative properties  Could have a natural version of this drug  Could explain link between diet and cancerPotter et al, British Journal of Cancer, 86 (Suppl 1), S117, 2002
  17. 17. Targeting Growth Factor Pathways
  18. 18. Designed Prodrugs Activated by a Tumour Specific Enzyme Synthetic Prodrugs Designed  Shows very exciting tumour selective activity (10,000-fold selective)  No toxic effects observed  Currently Undergoing Pre-clinical development at the Gray Cancer Institute, London  Phase I Clinical Studies being planned in the US  Results look very promising  Drug has real potential as a non-toxic tumour selective anticancer agentPotter et al, British Journal of Cancer, 86 (Suppl 1), S117, 2002
  19. 19. Classic Chemotherapeutic Agents Methotrexate survival (%) ± sem 125 100 Normal Breast IC50 =0.06µM 75 50 Breast Tumour IC50 =0.04µM 25 0 10 -3 10 -2 10 -1 10 0 10 1 10 2 control concentration (µM)•Most are equally toxic to normal and tumour cells•Some are actually more toxic to normal cells than tumours (e.g. Taxol, Doxorubicin, 5-FU)•Many are carcinogenic tumour promoters (Chlorambucil etc)
  20. 20. Tumour Selective Activation of DMU-212 (StilsereneTM) 125 DMU212 cytotoxicitysurvival (%) ± sem 100 Normal breast 75 IC50=4.3 µM 50 Breast tumour IC50=0.001 µM 25 0 10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2 control concentration (µM)
  21. 21. Tumour Selective Bioactivation of the Prodrug DMU212 (Stilserene) by Human Breast TissueDMU212 metabolite formation [pmol/min/mg prt] 10 9 8 7 6 DMU281 5 DMU214 DMU291 4 3 2 1 0 HBM016 HBM017 HBM018 HBM019 HBM020 HBM021 HBM022 HBM023 HBM024 HBM025 HBM026 HBM027 normal breast tumour breast tissue samples tissue samples
  22. 22. Discovery of Natural Dietary Prodrugs (Salvestrols) Realised molecular relationship to natural compounds Some of these have known cancer preventative properties Explains the link between diet and cancer prevention Generic name for natural dietary prodrugs termed as salvestrolsG.A. Potter, British Journal of Cancer, 86 (Suppl 1), S12, 2002
  23. 23. Tumour Selective Activation of Salvestrols Ez M Normal Cell Cancer Cell
  24. 24. Tumour Selective Bioactivation Normal Cells Ez Ez Ez Ez Ez Cancer Cells Cancer Cells Ez M Salvestrol Activase Salvestrol Actived Salvestrol (Non-toxic) (Highly Toxic)
  25. 25. Resveratrol The First Salvestrol to be Discovered Resveratrol is a natural molecule found in grapes(a phytoestrogen, polyphenol, and antioxidant)  Cancer preventative (unknown mechanism) Tumour CYP enzyme catalyses the bioactivation of resveratrol to generate piceatannol Piceatannol  Known anticancer activity  TK Inhibitor (src, MAPK, tubulin) Potter et al, British Journal of Cancer, 86, 774, 2002
  26. 26. Bioactivation of Resveratrol by CYP1B1 a OH OH OH CYP1B1 OH HO HO OH Resveratrol Piceatannol b OH OH HO OH HO c OH OH CYP1B1 HO HO OH Estradiol 4-Hydroxyestradiol
  27. 27. Salvestrols New class of molecule with very important activity in removing diseased cells from the human body (salve = to save) Defined as natural dietary prodrugs that are bioactivated in diseased cells Present in cancer preventative foods and diets Higher levels found in traditional medicinal plants Anti-salvestrols also identified - inhibit the positive action of salvestrols
  28. 28. Relationship of Salvestrols to Antioxidants, Polyphenols & Phytoestrogens Salvestrols are a new class of natural product Antioxidants Some are antioxidants Some are polyphenols Some are phyoestrogensPolyphenols - others are not SalvestrolsHowever…Some Anti-salvestrols are alsoantioxidants, polyphenols and phytoestrogens
  29. 29. A model of CYP1B1 Activation of a Salvestrol in a Tumour
  30. 30. Classic Chemotherapeutic Agents Methotrexate survival (%) ± sem 125 100 Normal Breast IC50 =0.06µM 75 50 Breast Tumour IC50 =0.04µM 25 0 10 -3 10 -2 10 -1 10 0 10 1 10 2 control concentration (µM)•Most are equally toxic to normal and tumour cells•Some are actually more toxic to normal cells than tumours (e.g. Taxol, Doxorubicin, 5-FU)•Many are carcinogenic tumour promoters (Chlorambucil etc)
  31. 31. Tumour Specific Activation of Salvestrol Q40
  32. 32. Salvestrols in Natural Foods (Fruits & Vegetables) 125 125 Resveratrol Bioactivation Salvestrol Q40 survival (%) ± sem Normal Breast Normal breast 100 IC50=60 µM survival (%) ± sem 100 IC50=21 µM IC25=30 µM 75 75 Breast Tumour IC50=60 µM 50 IC25=0.003 µM 50 25 25 Breast cancer 0 10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2 0 IC50=2 µM control concentration (µM) control 10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2 concentration (µM)Natures Way of Eliminating Cancer Cells as they form– Disease PreventionHippocrates “Let food be your medicineand medicine be your food”- referring to foods rich in salvestrol Q40
  33. 33. Salvestrols in Medicinal Herbs 125 125 Salvestrol P52 Salvestrol P54 survival (%) ± sem survival (%) ± sem 100 Normal breast 100 Normal breast IC50=16 µM IC50>100 µM 75 75 50 50 25 25 Breast cancer Breast cancer IC50=0.08 µM 0 IC50=0.5 µM 0 control 10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2 control 10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2 concentration (µM) concentration (µM)Ancient Cancer Cures used herbs rich in SalvestrolsCulpeper (1653) - This herb is under the celestial sign of Cancer“It healeth tough tumours of the breast, and for this I hold it inferior tobut few herbs that grow”Dioscorides – “this is marvellous good for the joints, and forCancers which cannot be healed by any other meanes”
  34. 34. Depletion of Salvestrols in the Modern Diet Depleted by Modern Agricultural Methods - Use of fungicides depletes plants salvestrols - Much Higher levels in Organic produce Removed by Food Processing - Fruit Juice Extraction - Filtering Only really present in wholefoods Modern processed foods have no salvestrols
  35. 35. P450 Salvestrol Activation Catalytic heme group
  36. 36. Need for a Salvestrol Food Supplement Specialist knowledge of Salvestrols Modern diet seriously depleted in Salvestrols Dietary intake random -food source, growing conditions No need for exotic foods or specialist diet Guaranteed intake of essential Salvestrols Convenient source of Salvestrols
  37. 37. Formation of Natures Defence Ltd Linked up with The Herbal Apothecary Based in Syston, Leicestershire Natures Defence Ltd Established January 2004 Salvestrol Natural Products Ltd Produce Salvestrol Rich Food Supplements
  38. 38. Salvestrols in ActionTumour Selective ActionRich in the most potent salvestrolsNon-toxic even at high doseswww.IJOPT.org
  39. 39. Salvestrol Supporting Vitamins & Minerals Biotin (Vitamin H) 0.2 – 1.0 mg Niacin (Vitamin B3) 50 mg Magnesium Iron Oxygen
  40. 40. Cancer Cure Cases & Responses using Salvestrol Therapy Terminally Ill people with Advanced Metastatic Disease (relapsed after chemotherapy and radiotherapy failed) Have made truly remarkable recoveries after taking salvestrol food supplementsSalvestrol supplements have exciting anticancer activity against: •Breast Cancer •Bladder Cancer •Prostate Cancer •Liver Cancer •Ovarian Cancer •Lung Cancer •Testicular Cancer •Colon CancerGoogle search on “Salvestrol Case Studies"
  41. 41. * experience since 2004 with practitioners & patients. max 120,000 points
  42. 42. Observer Magazine Best & BrightestInnovation Award 2005
  43. 43. AcknowledgementsCancer Drug Discovery GroupDanny BurkePaul ButlerNicola WilsherElugba WanogoeKetan RupareliaHoon TanAsma PatelDyan AnkrettSomchaiya SurichanVasilios AndroutsopoulosSaba LodhiKen BeresfordEllen GaoRandolf ArrooMeng WangToks Taiwo

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