R.G.C.C. International GmbH PERSONALIZE MEDICINE IN ONCOLOGY HOW PRERSONALIZED WE ARE? Future Perspectives AUTHOR-PRESENTER: DR. IOANNIS PAPASOTIRIOU THIS PRESENTATION CONSIDERED RGCC LTD INTELECTUAL PROPERTY AND ATHE USE OF A PART OR ALL RESENTATION FOR GENERATION OF ANOTHER MATERIAL OR ADVERTISEMENTPRIOR RGCC’s CONSENT, WILL BE AVIOLATION OF LAW
WHAT PERSONALIZED MEDICINE STAND FOR TODAY • The stratification of patients to different therapeutic protocols based on biomarkers. EXAMPLE K-ras Wild/mutated type selection of patients to be treated wit elrotinib (Terceva) or gefitinib (Iressa) when EGFr+ve
How many biomarkers are used in clinical practice ? • Haematology: 1. Brc-abl 2. Flit-3 3. CD33 4. CD52, CD20 • Solid Tumors: 1. ALK 2. K-ras, N-ras 3. BRCA1, BRCA2 4. EGF-r 5. VEGF
How reliable the biomarkers can be? • Example
How reliable the biomarkers can be? • Assumption (The cascade is linear)
How reliable the biomarkers can be? • In reality (cross talking)
DOGMA OF BIOLOGY MUTATIONS RNAi MISSFOLDING DNA RNA PROTEINS REVERSE TRANSCRIPTION & Retrotransposition
How we detect our biomarkers? 1. Mainly with Genetic techniques (NGS, PCR etc) ISSUES – We do not know whether the referred sequence is expressed – We do not know the influence of the genetic background to the cellular phenotype.
What we need to consider for applied true personalized approach • Precise information with downstream reflect or outcome • Multimodal data not only in a genomic level but also in : 1. Epigenetic (gene expression) 2. Proteomics 3. Glucoproteomics
What we need to consider for applied true personalized approach • Translational medicine (from bed to bed) • Multi-level of scientist and clinician with both fields background (scientist need to be trained in clinical issues and clinicians in scientific assays and methodologies) • Pharmacology methodologies and knowledge need to be very close to clinicians
What we need to consider for applied true personalized approach • Pharmacology – What the drug do to the disease (PD) – What the body do the drug (PK)
Who we are and what we are offering
New lab facilities
SOT: Supportive Oligonucleotide Therapy Gene silencing selectively
Antisense (modified) siRNA (modified) This technology that RGCC offers is use modified ODNs (phosphothioates) so that genes that overexpressed on cancer cells will be “silenced” and lead selectively cancer cell to apoptosis
How SOT sequence is selected?
MICRO-ARRAY ANALYSIS OF CTCs & CSCs (ONCOSTAT, ONCOSTAT PLUS) CLASISIFICATION OF GENES THAT RELATED WITH REGULATION OF REGULATION OF REGULATION OF APOPTOSIS CELLS CYCLE MIGRATION VALIDATION OF ALL GENE EXPRESSION BY KNOCKING DOWN SELECTION OF TARGET
Diagram of SOT validation • Methods of validation – Biochemical assessment (SPR) • Shows how strong the SOT bonds to the target sequence (rate-on, rate – off) • Shows that there is no random binding or dimmer formation – Cellular efficacy (killing rate of cancer cells) • Shows the biological activity of SOT to cancer cells directly
SOT: Synthesis
Synthesis is take place in a synthesizer by a chemical pathway
SOT: Problems with life span
Issues that we need and have resolve 1. Toxicities 2. Rapid degradation from endo & exonucleases SOLUTIONS • Olignucleotides are composed by nucleotide that are compatible and same with the nucleotides that we have inside our cells • Nucleotides are polymerized by substitute the phosphodiester bond with another that is not recognized by the nucleases
SOT: Side effects-adverse reactions
Short term adverse reaction during and after application Few cases they have report headaches the first day of application which is counter acted by the premedication before the application. How we may avoid the short term side effects? Premedication before application is required of: 1. 4mg IV dexamethasone bolus just before the application and 2. Paracetamol of 500mg qd for two days starting 1 hour before application.
Long term adverse reaction after application In cases with lung alveolar carcinoma mainly or with large volume of the disease a TLS (Tumor lysis syndrome) has been reported. (Fever, Local edema, accumulation of fluid in the area of the tumor etc) How we may avoid the long term side effects? A lab monitoring of the blood test for Na, K, pH, LDH is recommended to this type of malignancy. Support of the acidosis is required in serious stage of the TLS (rasburicase, saline, diuretic etc)
SOT: DIAGRAMMS IN CLINICAL PRACTICE
Application diagram & Control and monitor algorithm Application: The SOT has a life span of 6 months (half life of 10.5 months) Repeat of application is recommended every 6 months in full doses for an adult For individuals younger than 16 years old the dose need to be adjusted according to BSA Monitor is recommended: • In normal stages every 3 months: Oncocount or Oncotrail • In case of symptoms the following memorable table is recommended: Na, K, LDH Oncocount/ Clinical Action Oncotrail Equilibrium Change of SOT target TLS Continue Tumor progression Change of strategy
Preparation-Reconstitution Reconstruction in freeze-dry (lyophilized) formulation (a vial with a small crystal form of the ODNS as pellet) 1. Use 1ml of water for Injection (WFI ) and shake it in room temperature so that the final solution will be transparent and clear without any debri or visible particles. 2. Add to your solution 9ml water for injection (WFI or Saline) so that your final Solution must be 10ml total volume. 3. Apply your final solution iv. (do not exceed the final volume of 50ml and the appropriate solution will be WFI or isolyte or Saline) • After reconstruction (or in the formulation of 1ml vial) the final solution can be stored in -20 degrees if it does not applied immediately for 21 days . • In a freeze dry stages (lyophilized) it can be stored in long period (years).
Example from Antisense (SOT) Debulked resistant Tumor after 2 nd application of SOT
Development of substances as Drug- ” Whanabe ” Sunday 27 th January 2013
Drug R&D pipeline development
Drug R&D pipeline development 1. Decide the importance of a disease. 2. Evaluate the prevalence of a disease. 3. Evaluate the complexity of a disease. 4. Evaluate the taxonomy of a disease in a population or in the globe.
Drug R&D pipeline development 1. Understanding the mechanism of the disease 2. Identify patterns of genetic aberrations (CGH, IHC, blotting etc) 3. Identify patterns of altered gene expression (micro-arrays, Q-PCRs) 4. Identify biochemical abnormalities (spectometry, LMS etc)
Drug R&D pipeline development 1. Validate the importance of a gene or protein to a disease development 2. Validation through knocking down a gene (iRNA, antisense RNA etc) 3. Validation through protein(s) depletion or inactivation (MoAbs)
Drug R&D pipeline development 1. Using High Throughput Screening of substances libraries we can identify candidate drugs (whannabe). 2. Using molecular modeling it is possible to design a chemical compound with inhibitory or promotive features. 3. Using biochemical (in silico) tests a lead compound(s) is/are selected.
Drug R&D pipeline development 1. Either through HTS or drug design the lead compound will be evaluated via biochemical model in silico or in vitro for efficacy and potency. 2. Using synthetic chemistry the lead compound will receive modifications (methylations, acetylations, group chanches etc) in order to have a candidate drug.
Drug R&D pipeline development 1. In vitro preclinical development in cell lines (in vitro tests)-GI60. 2. Animal studies (in relevant species, in orthotopic model etc).
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