Breakthroughs in the Breakthroughs in the Quest to Cure CancerQuest to Cure Cancer

Professor Gerry PotterProfessor Gerry Potter

Founder of the Founder of the

Cancer Drug Discovery GroupCancer Drug Discovery Group

Leicester School of PharmacyLeicester School of Pharmacy

De Montfort University, Leicester, De Montfort University, Leicester, UKUK

Early DaysEarly Days

University of ManchesterUniversity of Manchester1983-19861983-1986

““Mechanism of Action of Anticancer Agents”Mechanism of Action of Anticancer Agents”

- Most are generally toxic (cytotoxic)Most are generally toxic (cytotoxic)- Toxic to liver, kidneys, heart, white blood Toxic to liver, kidneys, heart, white blood

cellscells- Many are highly mutagenic & carcinogenicMany are highly mutagenic & carcinogenic- Key Issue is SelectivityKey Issue is Selectivity

Chemotherapy Agents Mutate DNA and are Highly Carcinogenic

Institute of Cancer Institute of Cancer ResearchResearch

1987 - 19941987 - 1994Drug Development Section, CRC Drug Development Section, CRC

LaboratoryLaboratory

developed new selective agents fordeveloped new selective agents for

Breast & Prostate CancerBreast & Prostate Cancer Tamandron (Antiandrogen)Tamandron (Antiandrogen) Idoxifene (An Improved Tamoxifen Idoxifene (An Improved Tamoxifen

Analogue)Analogue) Ribonucleotide Reductase InhibitorsRibonucleotide Reductase Inhibitors Abiraterone Acetate (ZytigaAbiraterone Acetate (ZytigaTMTM))

Selective Anticancer AgentsSelective Anticancer AgentsDeveloped by Prof Potter at Developed by Prof Potter at

thetheInstitute of Cancer ResearchInstitute of Cancer Research

OH

HO

I

ON

ONMe2

O

N

HO

ON

O

IdoxifeneStilbene AntiestrogenCancer Res., 55, 1070-1074 (1995).

TamandronStilbene AntiandrogenNew Scientist, 16, 23 May 1992

CB7653Non-steroidal CYP17 InhibitorJ. Med. Chem., 38, 4191-4197 (1995).

Abiraterone AcetateCYP17 InhibitorJ. Med. Chem., 38, 2463-2471 (1995).

Design of Abiraterone Design of Abiraterone AcetateAcetate

Zytiga (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

Design & Synthesis of Design & Synthesis of AbirateroneAbiraterone

Journal of Medicinal Chemistry, 38, 2463, 1995

Potent Androgen AblationPotent Androgen Ablationby Abiraterone (CB7598)by Abiraterone (CB7598)

Journal of Steroid Biochemistry and Molecular Biology, 50, 267, 1994

Abiraterone (Zytiga)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 of advanced Prostate Cancer after taxotere chemotherapy has failed

•Currently used worldwide by thousands of patients

Link Between Diet and Link Between Diet and CancerCancer

LowerLower incidence of cancer correlates incidence of cancer correlates withwith

HigherHigher consumption of fruits & consumption of fruits & vegetablesvegetables

(Western diet correlates to(Western diet correlates to

high incidence of cancer)high incidence of cancer)

Nobody really knows why !Nobody really knows why !

(many theories, antioxidants, (many theories, antioxidants, phytoestrogens, polyphenols etc)phytoestrogens, polyphenols etc)

Understanding this link would help•cancer prevention•cancer treatment

Discovery of a Tumour Discovery of a Tumour Specific Salvestrol Specific Salvestrol

Metabolising EnzymeMetabolising Enzyme(Salvestrol Activase)(Salvestrol Activase)

BreastBreast BrainBrain LungLung OvarianOvarian ProstateProstate

BladderBladder ColonColon KidneyKidney OesophagaelOesophagael StomachStomach

Cancer Research, 57, 3026, 1997

Stomach Oesophageal

Ovarian Myosarcoma

Normal Colon Colon Cancer Dysplasia

Salvestrol Activase is a Salvestrol Activase is a Tumour Suppressor EnzymeTumour Suppressor Enzyme Works as a cancer preventing enzyme acting via Works as a cancer preventing enzyme acting via

natural prodrug bioactivation, i.e. salvestrol natural prodrug bioactivation, i.e. salvestrol activationactivation

Expressed in a variety of tumoursExpressed in a variety of tumours Generic Rescue MechanismGeneric Rescue Mechanism Irrespective of tumour type or oncogenic originIrrespective of tumour type or oncogenic origin Cancers arise from many different mutagenic originsCancers arise from many different mutagenic origins

Induction tightly regulatedInduction tightly regulated Induced by various cellular damaging effectsInduced by various cellular damaging effects

G.A. Potter, British Journal of CancerG.A. Potter, British Journal of Cancer, , 8686 (Suppl 1), S12, (Suppl 1), S12, 20022002

Designed Prodrugs Designed Prodrugs Activated by a Tumour Activated by a Tumour

Specific EnzymeSpecific Enzyme Synthetic Prodrugs DesignedSynthetic Prodrugs Designed

Shows very exciting tumour selective activityShows very exciting tumour selective activity No toxic effectsNo toxic effects Development to clinical use taking many yearsDevelopment to clinical use taking many years

Realised molecular relationship to natural compoundsRealised molecular relationship to natural compoundsthat have cancer preventative propertiesthat have cancer preventative properties Could have a natural version of this drugCould have a natural version of this drug Could explain link between diet and cancerCould explain link between diet and cancer

Potter et al, British Journal of CancerPotter et al, British Journal of Cancer, , 8686 (Suppl 1), (Suppl 1), S117, 2002S117, 2002

Targeting Growth Factor Targeting Growth Factor PathwaysPathways

Designed Prodrugs Designed Prodrugs Activated by a Tumour Activated by a Tumour

Specific EnzymeSpecific Enzyme Synthetic Prodrugs DesignedSynthetic Prodrugs Designed

Shows very exciting tumour selective activityShows very exciting tumour selective activity(10,000-fold selective)(10,000-fold selective) No toxic effects observedNo toxic effects observed Currently Undergoing Pre-clinical development at the Currently Undergoing Pre-clinical development at the

Gray Cancer Institute, LondonGray Cancer Institute, London Phase I Clinical Studies being planned in the USPhase I Clinical Studies being planned in the US Results look very promisingResults look very promising Drug has real potential as a non-toxic tumour selective Drug has real potential as a non-toxic tumour selective

anticancer agentanticancer agent

Potter et al, British Journal of CancerPotter et al, British Journal of Cancer, , 8686 (Suppl 1), S117, (Suppl 1), S117, 20022002

Classic Chemotherapeutic Classic Chemotherapeutic AgentsAgents

Methotrexate

0

25

50

75

100

125

10 -3 10 -2 10 -1 100 101 102

control concentration (M)

Normal Breast

Breast Tumour

IC50 =0.06M

IC50 =0.04M

surv

ival

(%

)

sem

•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)

Tumour Selective Tumour Selective Activation of DMU-212 Activation of DMU-212

(Stilserene(StilsereneTMTM))DMU212 cytotoxicity

0

25

50

75

100

125

10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2

control

Normal breastIC50=4.3 M

Breast tumourIC50=0.001 M

concentration (M)

surv

ival

(%

)

sem

Tumour Selective Bioactivation of the Tumour Selective Bioactivation of the Prodrug DMU212 (Stilserene) by Human Prodrug DMU212 (Stilserene) by Human

Breast TissueBreast Tissue

0

1

2

3

4

5

6

7

8

9

10

HBM016 HBM017 HBM018 HBM019 HBM020 HBM021 HBM022 HBM023 HBM024 HBM025 HBM026 HBM027

DM

U21

2 m

etab

oli

te f

orm

atio

n [

pm

ol/

min

/mg

prt

]

DMU281

DMU214

DMU291

normal breast tissue samples

tumour breast tissue samples

Discovery of Natural Discovery of Natural Dietary Prodrugs Dietary Prodrugs

(Salvestrols)(Salvestrols) Realised molecular relationship to natural Realised molecular relationship to natural

compoundscompounds Some of these have known cancer preventative Some of these have known cancer preventative

propertiesproperties Explains the link between diet and cancer Explains the link between diet and cancer

preventionprevention Generic name for natural dietary prodrugs termed Generic name for natural dietary prodrugs termed

as salvestrolsas salvestrols

G.A. Potter, British Journal of CancerG.A. Potter, British Journal of Cancer, , 8686 (Suppl 1), (Suppl 1), S12, 2002S12, 2002

Tumour Selective Tumour Selective ActivationActivation

of Salvestrolsof Salvestrols

M

Ez

Normal Cell Cancer Cell

Tumour Selective Tumour Selective BioactivationBioactivation

Ez

Ez

Ez

EzEz

M

Salvestrol(Non-toxic)

Actived Salvestrol(Highly Toxic)

Ez

SalvestrolActivase

Cancer Cells

Cancer Cells

Normal Cells

ResveratrolResveratrolThe First Salvestrol to be The First Salvestrol to be

DiscoveredDiscovered Resveratrol is a natural molecule found in Resveratrol is a natural molecule found in

grapesgrapes

(a phytoestrogen, polyphenol, and antioxidant)(a phytoestrogen, polyphenol, and antioxidant) Cancer preventative (unknown mechanism)Cancer preventative (unknown mechanism)

Tumour CYP enzyme catalyses the Tumour CYP enzyme catalyses the bioactivation of resveratrol to generate bioactivation of resveratrol to generate piceatannolpiceatannol

PiceatannolPiceatannol Known anticancer activityKnown anticancer activity TK Inhibitor (src, MAPK, tubulin)TK Inhibitor (src, MAPK, tubulin)Potter et al, British Journal of Cancer, 86, 774, 2002

HO

OH

OH

Resveratrol

HO

OH

OH

OH

Piceatannol

CYP1B1

HO

HO

OH

OH

OH

HO

OH

HO

OH

Estradiol 4-Hydroxyestradiol

OH

a

b

c

CYP1B1

Bioactivation of Resveratrol by CYP1B1

SalvestrolsSalvestrols New class of molecule with very important New class of molecule with very important

activity in removing diseased cells from the activity in removing diseased cells from the human bodyhuman body((salvesalve = to save) = to save)

Defined as natural dietary prodrugs that are Defined as natural dietary prodrugs that are bioactivated in diseased cellsbioactivated in diseased cells

Present in cancer preventative foods and dietsPresent in cancer preventative foods and diets

Higher levels found in traditional medicinal Higher levels found in traditional medicinal plantsplants

Anti-salvestrols also identifiedAnti-salvestrols also identified- inhibit the positive action of salvestrols- inhibit the positive action of salvestrols

Relationship of Salvestrols to Relationship of Salvestrols to Antioxidants, Polyphenols & Antioxidants, Polyphenols &

PhytoestrogensPhytoestrogens

Antioxidants

PolyphenolsSalvestrols

Salvestrols are a new class of natural productSome are antioxidantsSome are polyphenolsSome are phyoestrogens

- others are not

However…Some Anti-salvestrols are alsoantioxidants, polyphenols and phytoestrogens

A model of CYP1B1 A model of CYP1B1 Activation Activation

of a Salvestrol in a of a Salvestrol in a Tumour Tumour

Classic Chemotherapeutic Classic Chemotherapeutic AgentsAgents

Methotrexate

0

25

50

75

100

125

10 -3 10 -2 10 -1 100 101 102

control concentration (M)

Normal Breast

Breast Tumour

IC50 =0.06M

IC50 =0.04M

surv

ival

(%

)

sem

•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)

Tumour Specific ActivationTumour Specific Activationof Salvestrol Q40of Salvestrol Q40

Salvestrols in Natural Salvestrols in Natural FoodsFoods

(Fruits & Vegetables)(Fruits & Vegetables)

Natures Way of Eliminating Cancer Cells as they form

– Disease Prevention

Hippocrates “Let food be your medicine

and medicine be your food”

- referring to foods rich in salvestrol Q40

Salvestrol Q40

0

25

50

75

100

125

10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2control

Breast cancerIC50=2 M

Normal breastIC50=21 M

concentration (M)

surv

ival

(%

)

sem

Resveratrol Bioactivation

0

25

50

75

100

125

10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2

control

Normal BreastIC50=60 MIC25=30 M

Breast TumourIC50=60 MIC25=0.003 M

concentration (M)

surv

ival

(%

)

sem

Salvestrols in Medicinal Salvestrols in Medicinal HerbsHerbs

Salvestrol P52

0

25

50

75

100

125

10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2control

Breast cancerIC50=0.5 M

Normal breastIC50=16 M

concentration (M)

surv

ival

(%

)

sem

Salvestrol P54

0

25

50

75

100

125

10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2control

Breast cancerIC50=0.08 M

Normal breastIC50>100 M

concentration (M)

surv

ival

(%

)

sem

Ancient Cancer Cures used herbs rich in Salvestrols

Culpeper (1653) - This herb is under the celestial sign of Cancer

“It healeth tough tumours of the breast, and for this I hold it inferior to but few herbs that grow”

Dioscorides – “this is marvellous good for the joints, and for Cancers which cannot be healed by any other meanes”

Depletion of SalvestrolsDepletion of Salvestrolsin the Modern Dietin the Modern Diet

Depleted by Modern Agricultural MethodsDepleted by Modern Agricultural Methods- Use of fungicides depletes plants - Use of fungicides depletes plants salvestrolssalvestrols- Much Higher levels in Organic produce- Much Higher levels in Organic produce

Removed by Food ProcessingRemoved by Food Processing- Fruit Juice Extraction- Fruit Juice Extraction- Filtering- Filtering

Only really present in wholefoodsOnly really present in wholefoods Modern processed foods have no Modern processed foods have no

salvestrolssalvestrols

P450 Salvestrol P450 Salvestrol ActivationActivation

Catalytic heme group

Need for a SalvestrolNeed for a SalvestrolFood SupplementFood Supplement

Specialist knowledge of SalvestrolsSpecialist knowledge of Salvestrols Modern diet seriously depleted in Modern diet seriously depleted in

SalvestrolsSalvestrols Dietary intake randomDietary intake random

-food source, growing conditions-food source, growing conditions No need for exotic foods or specialist dietNo need for exotic foods or specialist diet Guaranteed intake of essential SalvestrolsGuaranteed intake of essential Salvestrols Convenient source of SalvestrolsConvenient source of Salvestrols

Formation of Natures Formation of Natures Defence LtdDefence Ltd

Linked up with The Herbal ApothecaryBased in Syston, Leicestershire

Natures Defence Ltd Established January 2004

Salvestrol Natural Products Ltd

Produce Salvestrol Rich Food Supplements

Salvestrols in ActionSalvestrols in Action

Tumour Selective Action

Rich in the most potent salvestrols

Non-toxic even at high doses

www.IJOPT.org

Salvestrol SupportingSalvestrol SupportingVitamins & MineralsVitamins & Minerals

Biotin (Vitamin H)Biotin (Vitamin H) 0.2 – 1.0 0.2 – 1.0 mgmg

Niacin (Vitamin B3)Niacin (Vitamin B3) 50 mg50 mg MagnesiumMagnesium

IronIron OxygenOxygen

Cancer Cure Cases & Cancer Cure Cases & ResponsesResponses

using Salvestrol Therapyusing Salvestrol TherapyTerminally Ill people with Advanced Metastatic DiseaseTerminally Ill people with Advanced Metastatic Disease(relapsed after chemotherapy and radiotherapy failed)(relapsed after chemotherapy and radiotherapy failed)

Have made truly remarkable recoveries after taking salvestrol food Have made truly remarkable recoveries after taking salvestrol food supplementssupplements

Salvestrol supplements have exciting anticancer activity against:Salvestrol supplements have exciting anticancer activity against:

•Breast CancerBreast Cancer•Prostate CancerProstate Cancer•Ovarian CancerOvarian Cancer•Testicular CancerTesticular Cancer

•Bladder Bladder CancerCancer•Liver Liver CancerCancer•Lung CancerLung Cancer•Colon Colon CancerCancer

Google search on “Salvestrol Case Studies"Google search on “Salvestrol Case Studies"

* * experience since 2004 with practitioners & patients. experience since 2004 with practitioners & patients. max 120,000 pointsmax 120,000 points

Observer MagazineObserver MagazineBest & BrightestBest & Brightest

Innovation Award 2005Innovation Award 2005

AcknowledgementsAcknowledgements

Cancer Drug Discovery GroupCancer Drug Discovery Group

Danny BurkeDanny BurkePaul ButlerPaul ButlerNicola WilsherNicola WilsherElugba WanogoeElugba WanogoeKetan RupareliaKetan RupareliaHoon TanHoon TanAsma PatelAsma PatelDyan AnkrettDyan AnkrettSomchaiya SurichanSomchaiya SurichanVasilios AndroutsopoulosVasilios AndroutsopoulosSaba LodhiSaba LodhiKen BeresfordKen BeresfordEllen GaoEllen GaoRandolf ArrooRandolf ArrooMeng WangMeng WangToks TaiwoToks Taiwo