Systems Biology, Cancer Therapeutics, and Personalized Medicine

1. Systems Biology,Cancer Therapeutics,andPersonalized Medicine Timothy Kinsella, M.D.

2. Towards Understanding Cancer Biology: Organized Complexity Systemsbiology is the analysis of the interactions among components of a biological system in response to genetic or environmental perturbations, with the goal of understanding the emergent properties of the system and its behavior. Cancer results from aberrations in the normal interactions of the component elements in the body in response to genetic or environmental perturbations. Understanding the disease requires understanding the emergent properties of the system.

3. Cancer: A Systems Biology Disease • Genes and genetics • Complex signaling networks • Multiple cellular processes • Micro-environment • Host systems • Environmental factors • Population dynamics HistologyVariation Initiation Progression Metastasis Recurrence Time - Progression

4. Goals of the ICBP • Develop an integrative approach to the understanding of cancer through the development of multidisciplinary research teams • Create predictive in-silico models to aid with the understanding and management of the disease • Integrate and explore the multi-dimensionality of large “omic” datasets as well as quantitative and descriptive data. • Enrich the community and the developing field through shared resources and a vibrant educational/outreach effort.

5. ICBP Integrative Cancer Biology Program Cancer Cell Initiation Progression Metastasis Huang(OSU) - epigenetics, gene silencing Golub (DFCI) - kinase, signaling, high throughput biology Kinsella (CWRU/UHC) - DNA repair, drug/radiation effects, therapy Lauffenburger (MIT) – signaling, mouse models, mitogenesis, DNA repair, progression Nevins (Duke) – signaling networks, cell fate, proliferation, mouse models Plevritis (Stanford) – progression, lymphoma, gene expression, clinical data Gray (LBNL)– signaling, progression, microenvironment, targeted therapies Quaranta(Vanderbilt) - invasion, metastasis, angiogenesis, microenvironment Deisboeck (MGH) - angiogenesis,invasion, 3D tumor modeling, repository

6. Disciplinesof ICBP Investigators

7. Why Study DNA Damage Response (DDR) and Repair Pathways? • DNA damage, if not accurately repaired, can cause cancer (e.g. Atomic Bomb survivor; chronic environmental exposures; treatment related second(ary) cancers). • Certain genetic (familial) defects in either the DNA damage response or DNA repair pathways are associated with increased incidence of human cancers. • These pathways are involved in the cellular response of ionizing radiation (IR) and several classes of chemotherapeutic (CT) drugs in both malignant and normal tissues.

8. Harper, J.W., Elledge, S.J. Molecular Cell, 2007;28:739-745.

10. General Principles Linking DDR and Cancer Therapeutics • Ionizing radiation (IR) and several different CT groups directly cause DNA damage and the subsequent DNA repair pathways determine cytotoxicity (via death pathways in both tumor and normal tissue/cells). These CT groups include: monofunctional alkylators (e.g. Temozolomide), bifunctional alkylators (e.g. Cisplatin, MMC), antimetabolites (e.g. fluoropyrimidines and thiopurines), topoisomerase inhibitors (e.g. camptothecins, Etoposide), and replication inhibitors (e.g. HU). • In human cancers with defective (deficient) DNA repair processing, there is a potential therapeutic window as dose-limiting normal cells/tissues are DNA-repair competent (proficient). This concept does not apply to germline mutations with cancer susceptibility but does apply to genetic and epigenetic alterations in DNA repair in sporadic cancers.

11. General Principles Linking DDR and Cancer Therapeutics (cont’d) • Small molecule inhibitors of the DDR and DNA repair may be combined with IR and/or DNA-damaging CT with encouraging results in pre-clinical models and early clinical trials in human cancers. • The concept of “synthetic lethality” can be applied to some human cancers where small molecule DNA repair inhibitors can be used as monotherapy. The principle example involves the use of poly (ADP-ribose) polymerase (PARP) inhibitors in BRCA1- and/or BRCA2- cancers.

12. ManyChallenges Exist in Applying Our Current Understanding of DDR/DNA Repair to Targeted Cancer Therapeutics • Some of these challenges include: • Cancers are very complex diseases characterized by persistent genomic instability. • Our current technologies yield immense amounts of data requiring sophisticated amounts of mathematical modeling and bioinformatics. • How should we analyze and integrate experimental/clinical data using genomics, proteinomics, and metabolomics? • Can pre-clinical models of DDR/DNA Repair targets be translated to the clinic? • How do we design clinical trials for targeted therapy of DDR/DNA repair pathways?

13. NCI Cancer Bulletin, 2008;5:17.

14. Steeg, P. S. Clin Cancer Res 2008;14:3643-3645

15. Crucial Relevance to Understanding and Treatment of Cancer Identification of cancer-associated genes needs to be followed by determination of consequent mechanisms to target for intervention – and of the contexts permitting success

16. Models of Cancer Drug Development: Present and Future a N = 300 FDA N = 3000 N = 30 Phase I Phase III Phase II FDA b Supporting assays in model systems N = 5-10x N = 50-100x FDA N = x Target developmentphase 0 Target assessmentphase I/II Target validationphase III

17. TheIterative Nature of Systems Biology and Modeling

18. The ICBP Approach Data & Information - Clinical, Biological, Epidemiological IntegrativeCancerBiology(ICBP) Computational Modeling Experimental Hypothesis Testing Discovery and Knowledge- Basic and translational