The Challenges in Personalized Cancer Medicine by chenmeixiu

VIEWS: 15 PAGES: 23

									       The Challenges in Personalized
             Cancer Medicine
Bridging the knowledge gab between pathophysiology and
              the drug mechanism of action

             Merging Knowledge - the 5th Anniversary of CoSBi
  The Microsoft Research - University of Trento Centre for Computational and
             Systems Biology, November 30 – December 3, 2010.

                        Jan Trøst Jørgensen, M.Sc.Pharm., Ph.D.
                                     Dx-Rx Institute
                                 Fredensborg, Denmark
                               E-mail: jan.trost@dx-rx.dk




Jan Trøst Jørgensen           Merging Knowledge, December 1, 2010              1
                                         Personalized Medicine1,2,3




    1.   Robert Langreth & Michael Waldholz. Wall Street Journal, 6. April 1999 & The Oncologist 1999; 4: 426-427
    2.   Jørgensen JT, Winther H. The New Era of Personalized Medicine: 10 Years Later. Per Med 2009; 6: 423-428.
    3.   Jørgensen JT. New Era of Personalized Medicine – A Ten Year Anniversary. Oncologist 2009; 14: 557-558.

Jan Trøst Jørgensen                                              Merging Knowledge, December 1, 2010                2
                                     Personalized Medicine1,2
                                                                        Oncology


                   1960                        Estrogen receptor



                   1970                        Tamoxifen (Nolvadex®, AstraZeneca)
                                               Breast Cancer



                   1980                        HER2/HER2


                   1990                        Trastuzumab (Herceptin®, Genentech/Roche)
                                               Breast Cancer


          1.   Jørgensen JT, Nielsen KV, Ejlertsen B. Pharmacodiagnostics and Targeted Therapies – A rational approach for individualizing medical anti-cancer
               therapy in breast cancer. Oncologist 2007; 12, 397-405.
          2.   Jørgensen JT, Winther H. The Development of the HercepTest™ - From Bench to Bedside in: Molecular Diagnostics – The Key Driver of Personalized
               Medicine. Jørgensen JT and Winther H eds. Pan Stanford Publishing , Singapore 2010.


Jan Trøst Jørgensen                                         Merging Knowledge, December 1, 2010                                                                  3
                        Personalized Cancer Medicine
                               Drug-Diagnostics Combinations

       • The current efficacy of medical anti-cancer therapy
         is still not optimal
       • Rational use of drugs
              –       The right drug
              –       For the right patient
              –       In the right amount
              –       At the right time
       • The key elements in pharmacotherapy
              – Pathophysiology
              – Mechanism of action of the drug



Jan Trøst Jørgensen                    Merging Knowledge, December 1, 2010   4
           Drugs Work at the Molecular Level
                      Companion Diagnostic Testing



                          Individual Level


                            Organ Level

                                                                      HercepTest™
                        Tissue/Cellular Level


                        Protein/Enzyme Level
Molecular                                                        TOP2A FISH pharmDx™

 Level
                           RNA/DNA Level


                           Merging Knowledge, December 1, 2010     AmpliChip® CYP450
Jan Trøst Jørgensen                                                                    5
                                   Companion Diagnostics1,2


            Companion Diagnostics/
            Pharmacodiagnostics
            A pre-treatment test performed in
            order to determine whether or not a
            patient is likely to respond to a
            given therapy. This type of test is
            classified as a predictive test and a
            prerequisite for the implementation
            of stratified and personalized
            medicine.                                                                                 Adenocarcinoma of the stomach stained with HER2 FISH
                                                                                                      pharmDx™ Kit




       1.   Jørgensen JT. Are we approaching the post-blockbuster era? – Pharmacodiagnostics and rational drug development. Expert Rev Mol Diagn 2008;
            8: 689-695.
       2.   Jørgensen JT . Developing Pharmacodiagnostics for HER2 Positive Gastric Cancer. Connection 2010 (in press)




Jan Trøst Jørgensen                                          Merging Knowledge, December 1, 2010                                                             6
           Stratified and Personalized Medicine1

    Personalized Medicine
    Management of the patient’s disease
    by using molecular diagnostic testing
    to tailor the therapy in order to achieve
    the best possible medicinal outcome
    for that individual.

    Stratified Medicine
    Management of a group of patients
    with shared biological characteristics
    by using molecular diagnostic testing
    to select the most optimal therapy in
    order to achieve the best possible
    medicinal outcome for that group.


      1.   Jørgensen JT. Are we approaching the post-blockbuster era? – Pharmacodiagnostics and rational drug development. Expert Rev Mol Diagn 2008; 8: 689-695.



Jan Trøst Jørgensen                                         Merging Knowledge, December 1, 2010                                                                     7
            Challenges in Personalized Medicine
                                                 Oncology

            • Scientific
                      – The molecular mechanisms of diseases
                      – The molecular mechanisms of the drug
            • Development of Companion Diagnostics
                      – Biomarker selection
            • Drug-Diagnostic Co-Development
                      – Clinical Research
            •     Commercial
            •     Regulatory
            •     Reimbursement
            •     Logistics
            •     Education
            •     Data Protection

Jan Trøst Jørgensen                     Merging Knowledge, December 1, 2010   8
                      FDA Drug Approvals 1996-20091
       New Molecular Entities and Biologic License Applications

                      60                                                                                           Cost
                      50


                      40


                      30


                      20


                      10


                      0
                                1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009




                           1.   Hughes B,. 2009 FDA drug approvals. Nature Reviews Drug Discovery 2010; 9: 89-92



Jan Trøst Jørgensen                                          Merging Knowledge, December 1, 2010                          9
  FDA Anticancer Drug Approvals 1997-20071




                                  “More than 800 drugs are now in clinical
                                  development for cancer indications yet
                                  rates in bringing drugs to market remain
                                  in the range of only 5%-8%”.
                                  Schilsky RL et al. .Oncologist 2010; 15: 484-487.




          1.   Hambley T W. Is Anticancer Drug Development Heading the Right Direction? Cancer Res 2009;69:1259-1262


Jan Trøst Jørgensen                                         Merging Knowledge, December 1, 2010                        10
        Low Success Rates in Anticancer Drug
                  Development1

   Factors that contribute to the low success rate:
   • Little scientific insight into the determinants of drug
     sensitivity and resistance
   • Poorly conceived and executed clinical development
     plans
   • Heterogeneous patient populations and lack of
     biomarkers to identify patients most likely to benefit from
     specific treatments
   • Unclear, conflicting, or burdensome regulatory
     requirements
          1.   Schilsky RL et al. Commentary: Tackling the Challenges of Developing Targeted Therapies for Cancer .Oncologist 2010; 15: 484-487.




Jan Trøst Jørgensen                                         Merging Knowledge, December 1, 2010                                                    11
             The Drug-Diagnostic Co-Development
                          Process1




1.   Drug-Diagnostic Co-Development Concept Paper . FDA, April 2005.




Jan Trøst Jørgensen                                           Merging Knowledge, December 1, 2010   12
        The Drug-Diagnostic Co-Development
                     Process1,2
    Discovery/                  Preclinical                                 Clinical Development                                                   Post
        Research                                                                                                                              Marketing

                                                                Phase I                    Phase II                  Phase III                  Phase IV

    Biomarker Selection


                                   Feasibility Studies


                                                                Prototype Assay


                                                                                       Analytical Validation


                                                                                                                 Clinical Validation


                                                                                                                                        Clinical Validated Assay

   1.    Jørgensen JT. Are we approaching the post-blockbuster era? – Pharmacodiagnostics And rational drug development. Expert Rev Mol Diagn 2008; 8: 689-695.
   2.    Winther H, Jørgensen JT. Drug-Diagnostic Co-Development in Cancer. Pharmaceutical Medicine 2010; 24:6 (in press)




Jan Trøst Jørgensen                                     Merging Knowledge, December 1, 2010                                                                        13
             Drug-Diagnostic Co-Development1
                                                Clinical Study Designs




                        Untargeted Design                                                                          Targeted Design




                      Stratified Design                                                                              Hybrid Design

   1.   Winther H, Jørgensen JT. Drug-Diagnostic Co-Development in Cancer. Pharmaceutical Medicine 2010; 24:6 (in press) .


Jan Trøst Jørgensen                                     Merging Knowledge, December 1, 2010                                          14
                      Tamoxifen - ER




                      Merging Knowledge, December 1, 2010
Jan Trøst Jørgensen                                         15
                      Trastuzumab - HER2
                             Breast Cancer




Jan Trøst Jørgensen      Merging Knowledge, December 1, 2010   16
                      Cetuximab & Panitumumab
                                  EGFR/K-ras




Jan Trøst Jørgensen        Merging Knowledge, December 1, 2010   17
                  Anti-Cancer Drug Development
                                    Simple versus Complex Systems

                                                                                         % Inhibition/Efficacy
”Simple System”                             ”Complex System”
                                                                                                    0%
      IN                                                IN




                                                                                                 100%
    OUT                                               OUT
                                                                                                                    0            1   2         3         4
                                                                                                                                         No . of inhibitions
              Inspired by :Lehar et al. High-order combination affects and biological robustness. Mol Sys Biol 2008; 215: 1-6.


 Jan Trøst Jørgensen                                     Merging Knowledge, December 1, 2010                                                             18
                Novel Agents for Cancer Therapy1
                           Cellular Signal Transductions Pathways




                  1.   Ma WW et al. Novel Agents on the Horizon for Cancer Therapy. CA Cancer J Clin 2009;59;111-137.



Jan Trøst Jørgensen                                      Merging Knowledge, December 1, 2010                            19
               1.   Butler D. Translational research: Crossing the Valley of Death. Nature 2008; 453: 840-842


Jan Trøst Jørgensen                                         Merging Knowledge, December 1, 2010                 20
                      Anti-Cancer Drug Development
                                  R&D Knowledge Gap




                                                   Clinical          Clinical    Clinical     Post
        Discovery      Research   Preclinical
                                                   Phase I           Phase II   Phase III   Marketing



                                     R&D Knowledge Gap
                                      ”Valley of Death”




Jan Trøst Jørgensen                 Merging Knowledge, December 1, 2010                                 21
Challenges in Personalized Cancer Medicine
                       Conclusion and Future Perspectives1,2,3

  •     Despite the advances in molecular medicine we have not yet been
        able to translate this into clinical medicine
  •     Understanding of the pathophysiology and drug mechanism of action is
        a prerequisite for the development of a more individualized anti-cancer
        pharmacotherapy
  •     The drug-diagnostic co-development model will be the preferred model
        for the development of new targeted drugs
  •     The use of companion diagnostics will pave the way for a more rational
        drug development process and the subsequent use of the drug in the
        clinic
  •     The development and implementation of personalized cancer
        medicine call for a multidisciplinary effort.
  •     “In 2020 most specialist therapies will include a companion diagnostic
        as a key component“
       1.   Jørgensen JT. From Blockbuster Medicine to Personalized Medicine. Per Med 2008; 5: 55-63
       2.   Jørgensen JT. Are we approaching the post-blockbuster era? – Pharmacodiagnostics And rational drug development. Expert Rev Mol Diagn 2008; 8: 689-695.
       3.    Diagnostic 2009 – Moving towards personalized medicine. PriceWaterhouseCoopers, June 2009


 Jan Trøst Jørgensen                                    Merging Knowledge, December 1, 2010                                                                          22
Jan Trøst Jørgensen   http://www.panstanford.com/books/nanosci/v024.html   23

								
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