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Mirit Aladjem John Weinstein Kurt Kohn Decision for Clinical Development of Oxaliplatin Platinum cmpds (clustered by activity pattern)

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Presentation on theme: "Mirit Aladjem John Weinstein Kurt Kohn Decision for Clinical Development of Oxaliplatin Platinum cmpds (clustered by activity pattern)"— Presentation transcript:

1 Mirit Aladjem John Weinstein Kurt Kohn Decision for Clinical Development of Oxaliplatin Platinum cmpds (clustered by activity pattern) http://discover.nci.nih.gov

2 Edward R. Tufte on visual representation of evidence, quoted by Michael Shermer in Sci. Amer. April 2005: “Good displays of data help to reveal knowledge relevant to understanding mechanism, process … cause and effect” “Clear and precise seeing becomes as one with clear and precise thinking.” “Simple design, intense content.” Aim for minimum number of different symbols. maximum mechanistic detail. On the importance of clear and precise diagrams: http://discover.nci.nih.gov

3 Diagrams can be a tremendous aid in thinking clearly about a model, in predicting possible experimental outcomes, and in conveying the model to others. Ideker, Galitski & Hood (2001) Annu Rev Genomics Hum Genet, 2: 343-372 Without consistent and unambiguous rules for representation, not only is information lost, but misinformation could be disseminated. Kurata, Matoba & Shimizu (2003) Nucleic Acids Res, 31:4071-4084. The diagrams commonly used to show bioregulatory schemes are often incomplete and ambiguous. Pirson et al. (2000) Trends Cell Biol, 10: 404-408 http://discover.nci.nih.gov

4 MARMOR, SKARIA, & YARDEN (2004) Int. J. Radiation Oncology Biol. Phys. 58: 903–913 ErbB-induced signaling pathways.

5 Molecular Interaction Map (MIM) notation Kohn et al. Molec. Biology Cell 17: 1-13 (2006). http://discover.nci.nih.gov

6 A B x x = A : B C yy = x : C = (A : B) : C Kohn et al. Molec. Biology Cell 17: 1-13 (2006). http://discover.nci.nih.gov

7 A x x = phosphorylated A P B P Kohn et al. Molec. Biology Cell 17: 1-13 (2006). http://discover.nci.nih.gov

8 Heuristic Heuristic Explicit Explicit Combinatorial Combinatorial http://discover.nci.nih.gov Three types of MIMs:

9 They show the interactions that can occur when molecules are in the same place at the same time. Cell type independent Process independent Cell compartment independent Heuristic MIMs are “canonical” Heuristic = “helping to discover or learn”

10 http://discover.nci.nih.gov/mim Click “Chk2” eMIM = electronic Interactive MIM Pommier 2006 Clin. Cancer Res. Chk2 MIM (Molecular Interaction Map)

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19 Kohn, Aladjem, Kim, Weinstein & Pommier Molecular Systems Biology 10.1038 (2006) ATM activates p53 by at least 4 coherent pathways

20 They can be used for computer simulation. Explicit MIMs are unambiguous

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22 Properties of switch-like bioregulatory networks studied by simulation of the hypoxia response control system *Laboratory of Molecular Pharmacology and t Laboratory of Biosystems, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland Kurt W. Kohn* ‡, Joseph Riss t, Olga Aprelikova t, John N. Weinstein*, Yves Pommier*, and J. Carl Barrett t ‡ Corresponding author: 301-496-2769. Email: kohnk@dc37a.nci.nih.govkohnk@dc37a.nci.nih.gov Mol. Biol. Cell, (2004) 15: 3042

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26 Switch-like HRE response to low oxygen levels Mol. Biol. Cell, (2004) 15: 3042

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28 As ARNT varies, transition occurs within a similar oxygen level. HRE occupancy is independent of ARNT levels at high oxygen levels Mol. Biol. Cell, (2004) 15: 3042

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30 As VHL varies, transition occurs within a similar oxygen level. HRE occupancy is independent of VHL at low oxygen levels Mol. Biol. Cell, (2004) 15: 3042

31 Oxygen transition varies as proline hydroxylase (PH3,3) varies Mol. Biol. Cell, (2004) 15: 3042

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33 mRNA kinetics in response to various oxygen levels No feedback from HRE elements in the proline hydroxylase genes PHD2 and 3 Low feedback set at k32=0.04 High feedback set at k32=0.40 As above, except with proline hydroxylase degradation added (k33=0.04) Mol. Biol. Cell, (2004) 15: 3042

34 combinatorial interpretation assumes that all interactions can occur simultaneously in any combination (‘transitive’ property), while heuristic interpretation is non-committal in this regard. In both interpretations, contingency symbols can be used to assert particular dependencies. Both can be used for simulation. Combinatorial MIMs Kohn et al (2006) Molec. Systems Biol. 10.1038

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36 plasma membrane PYPY GRB2 SH2 SH3 SOS Ras slow GDP GTP slow RasGAP RBD kinase Raf-1 Sur-8 Signaling from receptor tyrosine kinases via Ras MIM corresponding to Lodish et al. figs. 20-22,23,28 and Kolch et al. 2000 Biochem. J. 351:289 Ligand RTK MEK PSPS ERK P TxY Heuristic = “helping to discover or learn”

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40 ErbB-inhibitors used for cancer treatment.

41 Kohn et al (2006) Molec. Systems Biol. 10.1038

42 Kohn et al (2006) Molec. Systems Biol. 10.1038

43 Kohn et al (2006) Molec. Systems Biol. 10.1038

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48 Kohn et al. Molecular Systems Biology 10.1038 (2006) An explicit model of signaling from EGFR

49 Connection table & differential equations Kohn, Aladjem, Kim, Weinstein & Pommier Molec. Systems Biol. 10.1038 (2006)

50 Combinatorial model of Blinov et al. 2006, BioSystems 83:136-51

51 Kohn, Aladjem, Kim, Weinstein & Pommier Molecular Systems Biology 10.1038 (2006) Reaction classes defined in the combinatorial model of Blinov et al BioSystems 83: 136-151 (2006)

52 Summary -- Conclusions Molecular Interaction Maps (MIM) can be applied to various biological systems ():Molecular Interaction Maps (MIM) can be applied to various biological systems ( http://discover.nci.nih.gov/mim/ ): p53, cell cycle, DNA repair ( Kohn, KW.: Mol. Biol. Cell, 1999, 10: 2703 )p53, cell cycle, DNA repair ( Kohn, KW.: Mol. Biol. Cell, 1999, 10: 2703 ) Cell cycle ( Médecine & Sciences; Nature Encyclopedia of the Human Genome )Cell cycle ( Médecine & Sciences; Nature Encyclopedia of the Human Genome ) Replication initiation ( Science STKE, 2004, pe. 8 )Replication initiation ( Science STKE, 2004, pe. 8 ) Chk2/ATM pathway ( Current Topics Med. Chem. 2003, 3: 271 )Chk2/ATM pathway ( Current Topics Med. Chem. 2003, 3: 271 ) Apoptosis: Bcl-2, NFkB, Akt/PKB ( Oncogene 2004, 23: 2934 )Apoptosis: Bcl-2, NFkB, Akt/PKB ( Oncogene 2004, 23: 2934 ) Apoptosis: c-Abl ( Current Med Chem Anticancer Agents, 2003, 3: 271 )Apoptosis: c-Abl ( Current Med Chem Anticancer Agents, 2003, 3: 271 ) EGFR ( Mol Syst Biol. 2006, 10: 1038 )EGFR ( Mol Syst Biol. 2006, 10: 1038 ) Myc ()Myc ( http://discover.nci.nih.gov/mim/ ) MIMs allow compact and thorough compilation + organization of scientific knowledge.MIMs allow compact and thorough compilation + organization of scientific knowledge. MIMs can be applied to pharmacological targets to better understand and predict biological responses in normal and pathological tissues.MIMs can be applied to pharmacological targets to better understand and predict biological responses in normal and pathological tissues. MIM can be used as a first step for modeling and quantitative computer simulation of molecular pathways.MIM can be used as a first step for modeling and quantitative computer simulation of molecular pathways.

53 Kurt W. Kohn; Mirit I. Aladjem; John N. Weinstein; Yves Pommier Molec. Biology Cell 17: 1-13 (2006). MIM notation: definitions and rules. Can be used as reference or tutorial. Kurt W. Kohn; Mirit I. Aladjem; John N. Weinstein; Yves Pommier Molecular Systems Biology 10.1038 (2006). MIM compared to other notations. MIM can depict combinatorial complexity. MIM can depict both explicit and combinatorial models for simulation. http://discover.nci.nih.gov/mim/ Electronic MIMs (eMIMs). Links to other databases. Kurt W. Kohn; Joseph Riss; Olga Aprelikova; Yves Pommier; J. Carl Barrett Molec. Biology Cell 15: 3042-3052 (2004). MIM and simulation of network models. A switch-like model of the response to hypoxia. kohnk@mail.nih.gov

54 NCI Kurt Kohn Mirit Aladjem Sohyoung Kim John Weinstein Margo Sunshine Hong Cao David Kane Joseph Riss Yves Pommier Silvio Parodi Stefania Pasa Geoffrey McFadden Michael Blinov


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