R.G.C.C. International GmbH PERSONALIZE MEDICINE IN ONCOLOGY HOW - - PowerPoint PPT Presentation

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R.G.C.C. International GmbH PERSONALIZE MEDICINE IN ONCOLOGY HOW - - PowerPoint PPT Presentation

Feb 04, 2024 26 likes •1.29k views

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

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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

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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

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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

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How reliable the biomarkers can be?

  • Example
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How reliable the biomarkers can be?

  • Assumption

(The cascade is linear)

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How reliable the biomarkers can be?

  • In reality

(cross talking)

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DOGMA OF BIOLOGY

DNA RNA PROTEINS MUTATIONS REVERSE TRANSCRIPTION & Retrotransposition MISSFOLDING RNAi

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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.

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What we need to consider for applied true personalized approach

  • Precise information with downstream reflect
  • r outcome
  • Multimodal data not only in a genomic level

but also in :

  • 1. Epigenetic (gene expression)
  • 2. Proteomics
  • 3. Glucoproteomics
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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

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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)

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Who we are and what we are offering

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New lab facilities

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SOT: Supportive Oligonucleotide Therapy Gene silencing selectively

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Antisense (modified) siRNA (modified)

This technology that RGCC

  • ffers is use modified

ODNs (phosphothioates) so that genes that

  • verexpressed on cancer

cells will be “silenced” and lead selectively cancer cell to apoptosis

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How SOT sequence is selected?

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MICRO-ARRAY ANALYSIS OF CTCs & CSCs (ONCOSTAT, ONCOSTAT PLUS) CLASISIFICATION OF GENES THAT RELATED WITH REGULATION OF CELLS CYCLE REGULATION OF APOPTOSIS REGULATION OF MIGRATION VALIDATION OF ALL GENE EXPRESSION BY KNOCKING DOWN SELECTION OF TARGET

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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

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SOT: Synthesis

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Synthesis is take place in a synthesizer by a chemical pathway

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SOT: Problems with life span

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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

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SOT: Side effects-adverse reactions

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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.
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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)

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SOT: DIAGRAMMS IN CLINICAL PRACTICE

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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/ Oncotrail Clinical Action Equilibrium Change of SOT target TLS Continue Tumor progression Change of strategy

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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).
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Example from Antisense (SOT)

Debulked resistant Tumor after 2nd application of SOT

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Development of substances as Drug-”Whanabe”

Sunday 27th January 2013

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Drug R&D pipeline development

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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.

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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)

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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)

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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.

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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.

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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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Drug R&D pipeline development

1. Clinical trials Phase I (MTD) 2. Clinical trials Phase II (toxicities of the drug , MTD, theraputic index) 3. Clinical trial phase III (comparative study or double blind study either with placebo or with a “gold standard” therapy)

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Drug R&D pipeline development

1. FDA or EMEA registration of data and outcome 2. Authorities approval 3. Marketing of the drug (optimal situation is a discovery of an “orphan” drug

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  • R.G.C.C. expertise
  • 1. Choice of project
  • 2. Target identification
  • 3. Target validation
  • 4. HTS or Drug Design
  • 5. Optimization
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R.G.C.C. PIPELINES

  • MoAbs

1. New technology for selective target. 2. Humanization of MoAbs

  • SMW molecules with selective inhibition

1. Combining HTS and drug design we have better outcome 2. Selective docking allow better design and predict of the best adducts and groups to add 3. Extensive ADMET allow better bioavailability of the product.

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MICRO-ARRAYS

  • By analyzing multiple clinical samples and

test the epigenetic profile, the expression footprint is generated

  • Repeatable patterns may related with the

development of the disease become drugable target

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PIPELINE I (Moab)

DENDRITIC CELLS EPITOPE OF OUR WISH NAÏVE B-CELLS PLASMA CELLS MYELOMA CELLS HYBRIDOMAS MoAb of our wish

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Ligands-Receptors as targets

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CSC in clinical reality

Extrinsic support of stemmness???

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Experiments I

Gene siRNA Sequence (5'-3') Notch-1 Sense UAGUAGGGGAAGAUCAUCUUU Antisense AGAUGAUCUUCCCCUACUAUU Notch-2 Sense UAAAUUUGGAUAGGACUGAUU Antisense UCAGUCCUAUCCAAAUUUAUU Notch-3 Sense UUAUUGGCUCCAUUUUUGAUU Antisense UCAAAAAUGGAGCCAAUAAUU Notch-4 Sense UAAAUAGCGAUAGCAGUGGUU Antisense CCACUGCUAUCGCUAUUUAUU

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PIPELINE II (SMW)

TARGET PROTEIN LIGAND ANALYSIS ACTIVE POCKET IN. RETRO- SYNTHESIS ANALOGUE QSAR OPTIMIZE ALLOSTERIC SITE NON COMP. SITE

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PIPELINE IIa (Signal transduction pathway)SMW)

RAS RAF MEK ERK 1/2 AP1 RGCCP 07/11-2 RGCCP 02/11-1 RGCCP 12/11-3 RGCCP-09/11-1

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PIPELINE IIb (Stemness-SMW)

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Experiments II (Sox-2 or 17 & Oct-4)

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CANDIDATES

SCORE Macromolecules

EGFR Ras GTP Ras GDP c- Raf MEK1 MEK2 ERK1 ERK2

Known inhibitors

Erlotinib Salirasib Salirasib sorafenib selumetinib selumetinib ERK Inhibitor II, FR180204 CAY10561

  • 5,3
  • 4,2
  • 4,8
  • 6,2
  • 6,2
  • 7,2
  • 8
  • 9,2

Ligands

leading compound 19-08-2012-l-improved

  • 6,2
  • 4,3
  • 4,6
  • 7,3
  • 7,7
  • 8,8
  • 7,8
  • 8,8

leading compound 19-08-2012-l

  • 6,7
  • 5,3
  • 0,5
  • 6,8
  • 7,1
  • 8,6
  • 7,6
  • 8,6

Best score:

BINDING AFFINITY (kcal/mol) Macromolecules

c- Jun c- Fos c- Jun Homodimer c- Fos DNA binding site c- Jun, c- Fos Heterodimer

Best score: Ligands

leading compound 06-08-12

  • 5,8
  • 5,9
  • 6,9
  • 5,6
  • 7,3

c- Jun, c- Fos Heterodimer leading compound 06-08-12- b

  • 6,2
  • 6,3
  • 6,6
  • 6,2
  • 7,8

c- Jun, c- Fos Heterodimer leading compound 06-08-12- c

  • 6
  • 5,7
  • 6,4
  • 5,6
  • 7,4

c- Jun, c- Fos Heterodimer leading compound 06-08-12- d

  • 6,6
  • 5,9
  • 6
  • 8,1
  • 7,5

c- Fos DNA binding site leading compound 06-08-12- e

  • 6,4
  • 6
  • 5,9
  • 7,9
  • 8,3

c- Jun, c- Fos Heterodimer leading compound 06-08-12- g

  • 6,7
  • 6
  • 7,3
  • 9,4
  • 7,7

c- Fos DNA binding site leading compound 06-08-12- h

  • 5,1
  • 5,5
  • 5,7
  • 7
  • 6

c- Fos DNA binding site leading compound 06-08-12- i

  • 5,1
  • 5,9
  • 5,5
  • 6,1
  • 5,3

c- Fos DNA binding site leading compound 19-08-12- j

  • 5
  • 5,7
  • 5,4
  • 6,7
  • 6,7

c- Fos DNA binding site leading compound 19-08-12- k

  • 5
  • 5,1
  • 5,6
  • 7
  • 6,7

c- Fos DNA binding site leading compound 19-08-12- l

  • 4,9
  • 5,3
  • 6,1
  • 6,4
  • 6,5

c- Jun, c- Fos Heterodimer leading compound 19-08-12- m

  • 4,9
  • 5,3
  • 5,4
  • 6,3
  • 6,3

c- Fos DNA binding site leading compound 19-08-12- n

  • 5,3
  • 5,9
  • 5,3
  • 6,5
  • 6,7

c- Jun, c- Fos Heterodimer leading compound 19-08-12- o

* * * * *

SCORE Macromolecules

EGFR Ras GTP Ras GDP c- Raf MEK1 MEK2 ERK1 ERK2

Best score: Known inhibitors

Erlotinib Salirasib Salirasib sorafenib selumetinib selumetinib ERK Inhibitor II, FR180204 CAY10561

  • 5,3
  • 4,2
  • 4,8
  • 6,2
  • 6,2
  • 7,2
  • 8
  • 9,2

Ligands

leading compound 19-08-2012-p-jun-1

  • 6,5
  • 2,6
  • 4,7
  • 6,1
  • 7,5
  • 9,3
  • 8,9
  • 10

ERK2 leading compound 19-08-2012-p-jun-2

  • 7

1

  • 4,6
  • 5,3
  • 7,6
  • 10,1
  • 8,5
  • 9,9

MEK2

Best score:

p-jun-2

  • (p-jun-1)

(p-jun-1) p-jun-2 p-jun-2 p-jun-1 p-jun-1

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CANDIDATES

SMW

  • 1. Inhibitor of SOX-2
  • 2. Inhibitor of Erk-1/2-phosphorylated
  • 3. Inhibitor of c-Fos/AP-1
  • 4. Inhibitor of Transposase (Mariner)

Moab

  • 1. Anti c-Met (EMT)
  • 2. Anti TMX-2 (stemness)
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Thank you for your time

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QUESTIONS?

questions@rgcc-international.com

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THANK YOU FOR YOUR TIME. Visit our web site www.rgcc-international.com

THIS PRESENTATION CONSIDERED RGCC GROUP INTELECTUAL PROPERTY AND ATHE USE OF A PART OR ALL RESENTATION FOR GENERATION OF ANOTHER MATERIAL OR ADVERTISEMENTPRIOR RGCC’s CONCENT, WILL BE AVIOLATION OF A LAW.

Since the data and information is large and further questions and definition may generated, we strongly recommend to obtain the DVD presentation of RGCC International GmbH where more information and definition are there in order to help therapist to understand what is feasible in laboratory reality and what is applicable to clinical use. In case also of additional questions please do not hesitate to come in direct contact with RGCC International GmbH for any inquiry. The previous direct email address is specifically for this purpose.