The document summarizes the activities of the Experimental Therapeutics program at an annual retreat. It discusses the program's aims of identifying new drug targets and mechanisms of drug resistance. It provides an overview of clinical trials and preclinical research underway, including studies on cell cycle targets, drug sensitivity and resistance, and novel cancer therapeutics. The document also reviews funding, publications, and plans to renew the program's P30 grant.

1. Program Leader Douglas D. Ross, MD, PhD Clinical Program Leader Martin J. Edelman, MD Experimental Therapeutics Molecular & Structural Biology Hormone Responsive Cancers Viral Oncology (Developing) Tumor Immunology (Developing) X-Ray Crystallography Clinical Research Proteomics Flow Cytometry Experimental Therapeutics Biopolymer Tissue/ Biorepository Translational Biostatistics

2. Welcome to the 10 th annual ET retreat! Thanks to Bonita Chandler and Kimbrick Knox…and staff! Give Kent your presentations before session starts if possible…stay on schedule Please fill out the evaluations at the end of retreat – give them to Bonita Booklet of presentations pending…

3. ET Program Aims Identify mechanisms of drug action/resistance , and new targets/pathways for anticancer therapy using innovative basic and clinical research methods. Investigate treatment outcome disparities in cancer using innovative basic and clinical research methods. Discover and validate novel cancer therapeutics and innovative preclinical models for clinical trials and drug development

4. Members and Aims Clinical trials Badros, Baer, Bauer, Edelman, Garofalo, Gojo, Kleinberg, Greenwald, Hess, Ross, Zimrin, Tian, Suntha, Sausville, Regine Outcome disparities Baquet, Gordon, Edelman, Carter-Pokras, Tracy, Mullins, McGuire, Davidoff, Holt, Badros, Meiller, Baer AIM 2 Preclinical Models, Novel therapeutics Coop, Sadowska, Bryant, Fang/Tan, Ross, Gerratana, Seley, MacKerell, Edelman, Hosmane, Daniel AIM 3 Drug mechanisms/resistance HR Alexander, Varghese, Baer, Cullen, Fenselau, H. Wang, Nakanishi, Ross, Civin Targets / pathways Aurelian, Bauer, Black, Carey, Farber, Feldman, Yarowsky, J-Y Wang, J-B Wang, Stass, Sausville, Jiang AIM 1

5. ET Program Statistics 2009 (without TII and VO) Total Membership 56 40 Full Members, 16 Associate Members 19+ Full Members with peer-reviewed funding 50% Total annual cancer funding $6.6M Peer-reviewed NCI $2.6M Peer-reviewed NIH or other $1.9M Other cancer funding $2.1M Program focused publications 992 (past 5 yrs – 8.6 % are Intraprogrammatic)

6. Aim 1: New targets and pathways and drug resistance Targeting the cell cycle UCN-01, other cell cycle active agents (Sausville, Edelman, Gojo) Novel heat shock protein H11 protein (Aurelian) Eicosanoid pathway COX-2 (Edelman, Horiba, Fulton) Drug sensitivity and resistance Control of BCRP expression and clinical drug resistance (Ross) Mitochondrial basis for cisplatin activity (Cullen) mTOR and resistance in AML (Baer) Collaboration with TI program: Immunologic barriers (Strome, Rapoport, Ostrand-Rosenberg)

7. Aim 2: Epidemiological and Biological Basis for Disparities Genetic polymorphisms in AML (Baer) Racial differences in H&N outcomes (Cullen) Racial differences in esophageal cancer epidemiology (Mishra, Baquet) Different toxicities for bortezomib, zometa in myeloma (Badros)

8. Aim 3: Novel cancer therapeutics and Preclinical Development Hosmane: fat nucleosides MacKerell: cad design/screening Fang: SynStat drug interaction software (R01 submitted) Sadwoska/Lapidus/Edelman/Ross: preclinical modeling – testing novel agents Daniel: nanoparticles for drug delivery Gerratana: novel synthetic methods Edelman: anti-telomerase therapies

9. Clinical Trials (partial list) Aim 1: mTOR inhibition in AML- GCC 0706 (Baer) Radiotherapy to sensitize to chemotherapy (Regine) UCN-01/perifosine (Gojo) Phase I/II SNS025 Myeloma: (Badros) Phase 2 R-Roscovitine in lung (Edelman) Phase 1 AZD7762 / Gemcitabine in solid tumors (Sausville) Anticipated SCH727965 Phase I: Heme malignancies (Gojo) Planned SCH727965 Phase IIs Lung / Breast : Edelman / Tkaczuk Melanoma: Sausvillle Eicosanoids UMGCC 08XX: Apricoxib and MDSCs in NSCLC (Horiba) UMGCC 08XX: Randomized phase II trial of chemotherapy + apricoxib in recurrent NSCLC. Aim 2: Baltimore City Program (Garrett-Ray) COX-2 and race in aerodigestive tract malignancies (Horiba) Aim 3: KML-001/cisplatin phase I (Edelman), R21 S100 directed therapy with pentamidine (Sausville), R21

10. Multi-Investigator Grants U01 (with Wayne State) Gojo – Phase I trial of in AML N01 (with U. Chicago) Chumsri – Edelman – LOI – Topotecan + ABT-737 in SCLC P30 (Dorsey) SPORE (with TI, Cullen, Suntha) Nanotechnology – Swaan et. al.

11. Progam Meetings Third Tuesday of each month 4:00 PM-5:00 PM 9 th Floor Bressler Conference Room (BRB 9-031) Please mark your ca Calendars!

12. New Pilot Grant Competition P30 supplement – Funds for pilot grants 9-1-09 to 8-31-11; $100K from NIH to be matched by $100K from UMGCC $40,000 to each program over 2 years 1 award of $20,000 per year Pilot grant applications must utilize one of the UMGCC developing shared services: Flow Cytometry X-ray Crystallography High Throughput Screening Pathology Biorepository (Tissue Bank)

13. Time to Renew P30 – Already!! Timetable for ET: April 15, 2010 – first draft due for external review June 15, 2010 – revised draft due Sept 25, 2010 – final grant to NIH!!! How you can help – respond to requests to provide: Updated funding information Updated collaborative publications – with ET members and other programs Descriptions of your research and important recent findings Attend program meetings – make your voice heard!

14. Clinical Leader Dr. Edelman

16. New Recruitments Li Mao – New co-leader of ET program Curt Civin – Stem cell program

17. P30 Critique – Summary Broad programmatic effort without adequate focus on: Target Methodological approach Preclinical model assessment Drug discovery in clinical trials Need for increased investigator-initiated clinical trials that derive from the laboratories of the Program “… Program leaders [have not] guided the membership towards coordinated approaches that will lead to multi-investigator scientific initiatives and grants” “ It is not convincing that the Program will make significant progress in the near future or add considerably to the national effort in discovery and development of important anti-cancer drugs.”