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Experimental and Developmental Therapeutics

Experimental and Developmental Therapeutics. Program Leaders Jian-Ting Zhang, PhD Christopher Sweeney, MBBS. Program Overview Memberships.

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Experimental and Developmental Therapeutics

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  1. Experimental and Developmental Therapeutics Program Leaders Jian-Ting Zhang, PhD Christopher Sweeney, MBBS

  2. Program OverviewMemberships 41 full members and 7 associate members representing 15 Departments (8 Clinical / 7 Basic Science) from IU School of Medicine, IU Bloomington and IUPUI • Medicine, Radiology, Radiation Oncology, Pediatrics, Urology, Ob/Gyn, Surgery, Biochemistry & Mol Biol, Pharm & Tox, Anatomy & Cell Biol, Physiology, Micro & Immunology, Biology (IUSOM and Bloomington), Chemistry, Pathology

  3. Program OverviewMemberships, New Recruits Members Departments Chiorean, G. Medicine Long, E. Chemistry/IUPUI Matei, D. Medicine Sheng, H. Surgery Turchi, J. Medicine Xu, Y. Ob/Gyn Yan, C. Pathology Zhang, Z.Y. Biochemistry Red: co-recruits by IUCC

  4. Program OverviewPublications EDT publications since 2003: 477 Intra-programmatic: 59 (12%) Inter-programmatic: 87 (18%)

  5. Program OverviewPeer-Reviewed Funding

  6. Program OverviewAccrual to EDT Therapeutic Trials 2004 2005 2006

  7. Program OverviewActivities • EDT members invite and host significant numbers of speakers for the combined IUCC seminar series • Monthly noon EDT meetings • Presentations by EDT members and non-members to foster translational interactions • EDT members participate in IUCC Grand Rounds • EDT members actively participate and attract IUCC pilot funding • EDT members have formed various sub-groups • Ovarian cancer focus group resulting in DOD PPG • Specific disease working groups such as lung and GI cancer working groups for PPG’s are already in place

  8. Program OverviewResponsibilities of Co-Leaders • Foster interactions and collaborations within EDT and between EDT members and other IUCC program members • Organize monthly presentations for the EDT group by EDT and other program members • Participate on IUCC executive committee • Encourage invitation of outside seminar speakers related to EDT program • Mentor junior members of EDT

  9. Scientific Themes and Goals • Biomarker identification and novel prevention strategies • Goals: To identify markers and mechanisms of carcinogenesis. • Molecular targets and drug discovery • Goals: To facilitate the discovery of new targets and the development of new therapeutics. • Therapeutic optimization • Goals: To effectively design and perform basic and preclinical studies and facilitate novel and innovative clinical trials

  10. Scientific ThemesIntra-Programmatic Interactions • Nephew-Balch-Matei-Hahn • Investigation of methylation inhibitor Zebularine in antimitogenic and chemosensitizing effects on ovarian cancers and TCC • Kao-Gardner • Development of tools for gene therapy of prostate cancers • Sweeney-Mendonca • Development and use of parthenolide to overcome chemotherapy and radiation resistance in prostate cancer cell lines. • Zhang-Schmidt • Development of 14-3-3s inhibitors for treatment of pancreatic cancers. • Kelley- Georgiadis- Borch (Purdue) • Ape1 modulation and development of inhibitors of its redox activity

  11. Scientific Themes Inter-Programmatic Interactions • Sweeney (EDT)-DeGrado and Hutchins (BC) • In vivo imaging analysis of antiproliferative and antiangiogenic activity of parthenolide • Pollok (HM & I)- Smith (EDT) • Selenium-mediated bone marrow protection and platinum-induced toxicity • Kelley & Fishel (EDT)-Pollok (HM & I) • Combination therapy to enhance cell killing by inhibiting repair activity of Ape 1 • Carpenter (CP & C)-Sweeney (EDT) • Computerized symptom assessment • Robertson (EDT)-Clapp and Ingram (HM & I) • Phase I trial using Gleevec to target NF-1 signaling pathway to treat plexiform neurofibromas • Malkas (BC)- Zhang (EDT) • Development of small molecular inhibitors of csPCNA for breast cancer therapy

  12. VLP (~20,000 kD) L1 Capsomere (~280 kD) L1 Protein (55–57 kD) 72 Capsomeres 5 x L1 • Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine (Merck) • VLPs manufactured in Saccharomyces cerevisiae • Aluminum adjuvant 225 μg per dose • 0.5 mL injection volume • 3 doses within 6 months Scientific AccomplishmentsTheme 1: Biomarker and Prevention • Human papillomavirus L1 virus-like particle vaccine (Darron R. Brown) CIN = cervical intraepithelial neoplasia AIS = adenocarcinoma in situ GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

  13. DNA damage Selenium Protective Genes in Primary cells p53 NER XPC, XPE, Gadd45a Apoptosis Bax Cell cycle arrest p21 (Cip1/Waf1) Scientific AccomplishmentsTheme 1: Biomarker and Prevention • P53 and selenium (Smith, Pollok, Fishel, Kelley) Selenomethionine affects repair of UV-induced DNA damages in p53-dependent manner (MEF) Induction of DNA repair proteins of p53 pathway by selenomethionine (MEF)

  14. Scientific AccomplishmentsTheme 2: Targets and Drug Discovery NF kappa B and parthenolide analogues (Sweeney, Mendonca,Nakshatri) Drug / Biomarker Discovery Target ID In Vitro Data Animal Data & Prepare for IND Clinical Trials NF-kappa B relevance to prostate cancer carcinogenesis and angiogenesis (Clinical Cancer Res. 10:5501-5507; 2004) Inhibition of NF-kappa B with parthenolideenhances chemotherapy, hormonal therapy, XRT, and anti-angiogenesis (Mol Cancer Ther. 4:1004-1012; 2005, Prostate [in press]) Extending findings to: TCC: Upregulation of p21 in p53 mutant cells Anti-cancer activity in p53 mutant and intact TCC FAMRI grant, AACR presentation NSCLC: Kentucky Lung Cancer Foundation Grant In vitro activity in 4 cancer cell lines; In vivo activity in xenograft Pancreatic and Hepatocellular Cancer Yip-Schneider/Schmidt (Mol Cancer Ther. 4:587; 2005, Mol Cancer Res. 4:387;2006) Radiation Sensitizer (Mendonca) Phase 1 IU - 2007 Phase 2 IU/HOG Parthenolide and analogues one-step conversion process to water soluble analogue (LC-1) collaboration with Peter Crooks (Uni. Kentucky) NCI RAID Program (PI: Sweeney) Completion of 28 rat and dog tox GMP manufacturing at Uni Kentucky 2006 Preparing IND Long standing collaboration with Nakshatri and Breast Cancer Program

  15. Clinical Candidate Development Product Launch Preclinical Discovery Target ID - Target/Disease Validation Assay Development, Screening, Lead Generation/Selection, Drugability, Assay Validation Lead Optimization Candidate Selection Phase I, II, III, Launch, Life Cycle Idea/Target Hit Assess Lead Validation Lead Optimization Clinical Candidate Target ID Drug Discovery, In Vitro Data In Vivo Data Clinical Trials HDACI-42 ABCG2 PRL3 Transglutaminase 2 Scientific AccomplishmentsEDT Translational Portfolio By Stage PRL Phosphatase Parthenolide Eft. 2 SHP2 APE1/Redox XPA PDGFr APE1/Repair EDT C-FLIP RPA RPA/Cys Parthenolide Eft. 2 BG BRCA1 JNK Eft. 2 JNK (refractory AML) 14-3-3sigma Zebularine Metnase Enhance Radiation PTP1B MEK/PD325901

  16. Scientific AccomplishmentsTheme 2: Targets and Drug Discovery FIRST INTO HUMAN PHASE 1 CLINICAL TRIALS

  17. Scientific AccomplishmentsTheme 2: Targets and Drug Discovery Planned Clinical Trials of New Therapeutic Entities (based on EDT discoveries) • Parthenolide/DMAPT (Sweeney/Mendonca/Nakashatri) • Gemcitabine plus benzylguanine (Kelley/Fishel/Chiorean) • Cisplatin plus benzylguanine (Kelley/Chiorean) • Temozolomide plus methoxyamine (Kelley)

  18. Scientific AccomplishmentsTheme 3: Therapeutic Optimization PHASE 1 CLINICAL TRIALS OF NEW COMBINATIONS – IUCC Investigator Initiated Studies * Use of CPAC for PK

  19. Scientific AccomplishmentsTheme 3: Therapeutic Optimization Phase 2 studies incorporating emerging technologies (goal: right drug and dose for right patient)

  20. Scientific AccomplishmentsTheme 3: Therapeutic Optimization Pharmocogenetic-Pharmacokinetic Correlation Studies (basis for individualized therapies) *Use of CPAC for PK analysis

  21. Future Plans • Continue our effort in translational research activities and completion of clinical trials that arise from IUCC research. • Special focus on drug developments with the aid of the IUCC Translational Initiatives (ITI). • Expand the R21 Quick Trial-working group • Vehicle for translation of IUCC science to clinic • Match basic scientist with clinician to incorporate informative correlative studies • Encourage specific disease-oriented working groups • e.g. lung (led by a new recruit John Turchi) and GI cancer working groups • Recruit physicians experienced in clinical trials • Phase 1 trials to aid the basic science translation from the lab to the clinic • Disease based expertise to facilitate translational research • Continue collaborations with Purdue Cancer Center scientists to expand the scientific base for clinical trials

  22. END

  23. Cancer Prevention & Control Other Programs EDT themes Biomarker & Prevention Therapeutic Optimization Molecular Targets & Drug Discovery Breast HM & I Scientific Themes Intra- and Inter-Programmatic Interactions

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