R.G.C.C. International GmbH CTCs & CSCs Analysis: Practical model AUTHOR-PRESENTER: DR. IOANNIS PAPASOTIRIOU THIS PRESENTATION CONSIDERED RGCC LTD INTELECTUAL PROPERTY AND THE USE OF A PART OR ALL RESENTATION FOR GENERATION OF ANOTHER MATERIAL OR ADVERTISEMENT PRIOR RGCC’s CONCENT, WILL BE A VIOLATION OF A LAW
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PROPOSED DIAGRAMM OF TREATMENT INDUCTION CONSOLIDATION MAINTENANCE ???? : TIMING OF FOLLOW-UP :ONCOSTAT ( former TUP)
Primary assessment 1. Spread of the disease 2. Aggressiveness of the disease ONCOTRACE 3. Risk of relapse 4. Response to therapeutic agents (PharmakokinetIcs) ONCOSTAT -PLUS 5. Ability of the body to metabolize the agents (Pharmacodynamics) SNiP 6. Status of patients immune system IMMUNOSTAT 7. Performance status SCORE ECOG
Algorithm steps PERFORMANCE SCORE ECOG GOOD PERFORMANCE ECOG POOR PERFORMANCE ECOG 0-2 3-4 REASSESS PERFORMANCE ONCOSTAT EXTRACT STAGE OF THE DISEASE SUPPORT THERAPY (ONCOTRACE) ADVANCE MRD PD (ONCOSTAT PLUS) PK (SNiP) IMMUNOSTAT+METASTAT FOLLOW UP ONCOTRAIL HYPERTHERMIA ONCOCOUNT CHEMICAL AGENTS CONSIDER THE OPTION FOR NATURAL SUBSTANCES IMMUNOTHERAPY (DCs & MOAB) IN HIGH RISK RADIOTHERAPY IN LOW RISK OR TARGETED THERAPIES REASSESMENT CONTINUE METRONOMIC THERAPY
FIRST APPROACH ALGORITHM FOR PATIENTS WITH THE PRESENCE OF THE DISEASE HOW EFFICIENTLY THE WHICH AGENTS BODY TRANSPORMS THE ARE EFFECTIVE TO AGENTS TO THEIR ACTIVE CANCER CELLS? FORM? (Pharmacodynamic-PD) (Pharmacokinetic-PK) • • ONCOSTAT (former TUP) CHEMOSNiP • ONCOSTAT EXTRACTS • ONCOSTAT TLUS TREATMENT PLAN
How we could design the therapy protocols for each patient?
Algorithm for therapy plan design Pharmacodynamic analysis Pharmakinetic analysis Therapy options for clinical use Oncostat plus ChemoSNiP Conventional agents Conventional agents Conventional agents • • X X (Normal metabolizer) • X • • Y Y (Normal metabolizer) • Y • • Z Z (Rapid metabolizer) Natural substances Natural substances Natural substances 1. Class I (cytotoxic affect) 1. Class I (cytotoxic affect) 1. Class I (cytotoxic affect) • • F F (Normal metabolizer) • F • • G G (Normal metabolizer) • G • • H H (Rapid metabolizer) 2. Class II (growth factor inh.) 2. Class II (growth factor inh.) 2. Class II (growth factor inh.) • • R R (Normal metabolizer) • R • • M M (Accumulator) 3. Class III (immunomodulators) 3. Class III (immunomodulators) 3. Class III (immunomodulators) • • Q Q (Normal metabolizer) • Q • • N N (Rapid metabolizer)
Choice of the agents Conventional Natural substances agents One agent from each class is 1. chosen for application for one The agents are chosen one 1. month (the one with the most from each group in order to high efficacy) achieve synchronization and Shift to the next more efficient 2. maximum effect. agent from each class in order Besides the alkyliating 2. to avoid secondary resistance) agents all the rest are active • Targeted Therapies in specific point of the cells cycle. The TKI or the Moab are 1. S phase: nucleotide antagonists, chosen by the markers topoisomerase I & II inhibitors Metaphases: Vinca, Taxanes, epothilones
Choice of the agents S phase Antimetabolites G0 phase Topoisomerase I Topoisomerase II G2 phase G1 phase Antibiotics prophase telophase metaphase Alcaloid of anaphase vinca taxanes
MARKERS THAT ARE HELFUL FUNCTION CLINICAL MARKERS RESULTS OUTCOME RISK Migration- MMPs 0>= LOW RISK invasion HIGH RISK KISS-1-r 0<= LOW RISK Nm23 0> HIGH RISK Angiogenesis VEGFr LOW RISK FGFr PDGFr MECHANISM CLINICAL MARKERS RESULTS OUTCOME RISK Signal HIGH Ras/raf/MEK/Erk >0 HIGH transduction PROLIFERATI 1-2 pathways VE SIGNAL mTOR =<0 LOW Growth factor LOW EGFr TGF- β1/2 receptors PROLIFERATI VE SIGNAL c-erb-B2 Hormone Estrogen receptors Receptor HORMONE Progesterone DEPENDED Receptor NC3R4 NC3R4 Cell cycle rate P27 >0 SLOW RAPID P16 >0 RAPID P53 >0 RAPID
MARKERS THAT ARE HELFUL MARKERS RESULTS OUTCOME PHENOTYPE Dnmt1 >0 RESISTANT DNA demethylase RESISTANT O6 akyltransferase PHENOTYPE HAT Histone deacetylase Marker Result (%) Clinical outcome per Clinical marker outcome HSP90 -20 SENSITIVE HSP72 0 NOT SENSITIVE SENSITIVE HSP27 15 NOT SENSITIVE
Theoretical Model of usage Patients with present macroscopic disease 1. In order to identify active substances and drug against the disease the following test are recommended • ONCOSTAT (TUP) or • ONCOSTAT extracts (TUP extracts) or • ONCOSTAT PLUS (TUP PLUS) 2. In order to identify whether each patient is able to metabolize normaly each agent and receive the biological benefit from it the following test is recommended • CHEMOSNiP 3. For following up and monitor the patient the following test are recommended • Oncocount or • Oncotrace or • Oncotrails only for known and specific types of malignancies 4. Time interval for the follow-up tools • For the first year every trimester and then every half year
Theoretical Model of usage Patients with minimal residual disease As first step an Oncotrace test is recommended – If the patient is low risk of relapse then one of the follow-up tests is recommended – If the patient is high risk the more extensive analysis may required in order to have more information to schedule more effective approach. In that case TUP platform (ONCOSTAT) of test is recommended.
Example PERFORMANCE STATUS • FEMALE PATIENT • PRETREATED • BREAST CARCINOMA • STAGE III • ECOG SCORE 2 • 0-Normal activity • 1-Symptoms, ambulatory • 2-50% of time in bed • 3-more than 50% of time in bed • 4-Unable to go out from bed
Algorithm steps PERFORMANCE SCORE ECOG GOOD PERFORMANCE ECOG POOR PERFORMANCE ECOG 0-2 3-4 REASSESS PERFORMANCE ONCOSTAT EXTRACT STAGE OF THE DISEASE SUPPORT THERAPY (ONCOTRACE) ADVANCE MRD PD (ONCOSTAT PLUS) PK (SNiP) IMMUNOSTAT+METASTAT FOLLOW UP ONCOTRAIL HYPERTHERMIA ONCOCOUNT CHEMICAL AGENTS CONSIDER THE OPTION FOR NATURAL SUBSTANCES IMMUNOTHERAPY (DCs & MOAB) IN HIGH RISK RADIOTHERAPY IN LOW RISK OR TARGETED THERAPIES REASSESMENT CONTINUE METRONOMIC THERAPY
Example (ONCOSTAT PLUS) Non cell cycle S phase of cell cycle Metaphases depended Alkyliating Inhibitors of Inhibitors of antimetabolites Inhibitors of tubulin Spindle agents topoisomerase I topoisomerase II polymerization poisoning agents GEMCITABINE VINORELBIN ABRAXAN Moab (Monoclonal Antibodies) SMW (Small Molecular Weight molecule) ANASTROZOL TEMSIROLIMUS ERLOTINIB Class I Class II Class III (cytotoxic agents) (growth factors inhibitors) (immuno-modulatory effect) ARTEMISININ QUERCETINE MISTELTOE VITAMIN C GENISTEIN VITAMIN D Marker Result (%) Clinical outcome per Clinical marker outcome HSP90 -20 SENSITIVE HSP72 0 NOT SENSITIVE SENSITIVE HSP27 15 NOT SENSITIVE
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Simplified usage of the viability diagrams Sensitive-effective area Partial sensitive area No sensitive area
Chemosensitivity testing Apoptosis activation Natural-biological substances They include all natural extract from plants or cells which may have direct on 1. indirect therapeutic (anticancer) activity. Mainly in cancer therapy almost the majority of natural substances they have an 2. unknown mechanism of action or they have multiple interference in many point and pathways. Additionally they composed from a large number of substance with potent 3. anticancer activity. Generally their anticancer activity can be categorized as follows Direct anticancer-cytotoxic effect (without a known mechanism of action) 1. Block of growth factors 2. Stimulation of immune system and activation of immune cells. 3.
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Simplified usage of natural substances test data Sensitive-effective area
Example (ONCOSTAT PLUS)+(CHEMO-SNIPS) Non cell cycle S phase of cell cycle Metaphases depended Alkyliating Inhibitors of Inhibitors of antimetabolites Inhibitors of tubulin Spindle agents topoisomerase I topoisomerase II polymerization poisoning agents GEMCITABINE VINORELBIN ABRAXAN Moab (Monoclonal Antibodies) SMW (Small Molecular Weight molecule) ANASTROZOL RAPID TEMSIROLIMUS METABOLIZER ERLOTINIB Class I Class II Class III (cytotoxic agents) (growth factors inhibitors) (immuno-modulatory effect) RADIATION ARTEMISININ QUERCETINE MISTELTOE HYPERTHERMIA VITAMIN C GENISTEIN SENSITIVE VITAMIN D Marker Result (%) Clinical outcome per Clinical marker outcome HSP90 -20 SENSITIVE HSP72 0 NOT SENSITIVE SENSITIVE HSP27 15 NOT SENSITIVE
Algorithm steps PERFORMANCE SCORE ECOG GOOD PERFORMANCE ECOG POOR PERFORMANCE ECOG 0-2 3-4 REASSESS PERFORMANCE ONCOSTAT EXTRACT STAGE OF THE DISEASE SUPPORT THERAPY (ONCOTRACE) ADVANCE MRD PD (ONCOSTAT PLUS) PK (SNiP) IMMUNOSTAT+METASTAT FOLLOW UP ONCOTRAIL HYPERTHERMIA ONCOCOUNT CHEMICAL AGENTS CONSIDER THE OPTION FOR NATURAL SUBSTANCES IMMUNOTHERAPY (DCs & MOAB) IN HIGH RISK RADIOTHERAPY IN LOW RISK OR TARGETED THERAPIES REASSESMENT CONTINUE METRONOMIC THERAPY
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