Developmental Therapeutics Research Program

1
Developmental Therapeutics Research
Program Co-Program Leaders Yung-chi Cheng,
Ph.D. Edward Chu, M.D.
2
Mission/Scientific Goals

• Identify and characterize novel biological and/or
  molecular targets
• Develop novel agents and/or treatment regimens
  for clinical application

3
Leadership

• Leaders since 1996
• Expertise in cancer therapeutics with
  complementary interests in basic, translational,
  and clinical research
• Yung-chi Cheng, Ph.D. (Professor of Pharmacology)
• Antiviral and anticancer chemotherapy
• Pre-clinical design and development of novel
  agents and treatment regimens
• Chinese herbal medicine
• Edward Chu, M.D. (Professor of Medicine and
  Pharmacology)
• Fluoropyrimidine biochemistry
• Regulation of gene expression and mechanisms
  of cellular drug resistance
• Clinical development of novel drugs and drug
  regimens (colorectal cancer and solid tumors)

4
Membership

• 36 faculty
• 13 departments and 2 schools
• Recruitment new basic scientists (4)
• Hamilton (Chemistry)
• Saltzman (Biomedical Engineering)
• Ha (Pharmacology)
• Hodson (Laboratory Medicine)
• Recruitment new clinical investigators (12)
• Sznol, Foss, Kelly, Harris, Saif, Rose,
  Deshpande, Lee, Gettinger, Abu-Khalaf, Cha,
  Baehring
• Nucleus of Phase I, clinical investigations
  team

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Cancer-Related Funding
1
2
.
0
10.3
1
0
.
0
Dollars in Millions
8
.
0
Total Funding
6
.
0
NCI Funding
.
3.8
3.3
4
.
0
1.7
2
.
0
0
.
0
1997
2006
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Contribution of Program Members to Non-RO1 Grants

• P50 SPORE in Skin Cancer (M. Sznol, Co-P.I.)
• NCI RAID grant for the GGT inhibitor GGTI-2418
• (A. Hamilton, P.I.)
• NCI RAID grant for GFB-204 (A. Hamilton, P.I.)
• NCI Training Program in Cancer Pharmacology (Y.
  Cheng, P.I.)
• NCI/OCCAM grant for the development of Chinese
  herbal medicine in cancer therapy
• (Y. Cheng, E. Chu, W. Saif, J. Lee, M. Sznol,
  P.I.)
• NCCN grant for novel clinical study of Chinese
  herbal medicine plus chemotherapy in pancreatic
  cancer
• (W. Saif, P.I.)

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Scientific Accomplishments Molecules
Discovered/Developed

• 25 molecules discovered/developed by DT members
• 18 licensed to pharma
• 9 undergoing pre-clinical testing
• 6 anticancer agents in clinical testing - phase
  I, II, and III
• 3 antiviral agents in clinical testing - phase
  II, III , and market

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Molecules Discovered/Developed

• Clevudine (L-FMAU) - L-nucleoside
• Troxacitabine - L-nucleoside
• IPdR - thymidine analog
• 4-ED4T HIV RT inhibitor

• Small Organic Molecules
• Benzylacyclouridine nucleoside analog
• DB3505 tyloindocine analog
• Cloretazine - alkylating agent
• KS119 - alkylating agent
• Triapine - ribonucleotide reductase inhibitor
• Phenoxodiol isoflavenoid

• Natural Products
• Epoxomicin - proteasome inhibitor
• NF-?B inhibitor more potent than bortezomib
• Eriocalyxin B diterpenoid

• Nucleic Acids
• TS siRNA
• HIF-1? siRNA
• VEGF siRNA

• Peptides/Peptidomimetics
• Cavtratin - inhibits eNOS and VEGF signaling
• ISS610 - inhibits Stat3 dimerization
• GGTI-2418 - GGT inhibitor
• GFB-204 - calixarene derivative that blocks VEGF
  and PDGF signaling

• Chinese herbal medicine
• PHY-906

• Biologic Agents
• FVII/Fc icon - targets tissue factor
• TAPET

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Scientific Accomplishments Molecules
Discovered/Developed

• Phenoxodiol (G. Mor) - isoflavonoid
• Inhibits XIAP activity
• Restores chemosensitivity to taxanes and
  cisplatin
• Novel analogs NV-143 and NV-196 being developed
• GFB-204 (A. Hamilton) - calixarene derivative
• Binds to protein surfaces
• Binds with high affinity to VEGF and PDGF and
  inhibits their downstream signaling
• Epoxomicin (C. Crews) - epoxyketone peptide
• Inhibits 20S proteasome
• Prevents IkB degradation resulting in NF-kB
  inhibition
• More potent than bortezomib

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Phase I Clinical Trials
1998-2004 18 phase I studies 2005-2006 15
phase I studies Focus on YCC-based
discoveries/science

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DT - Phase I AccrualsImpact of 2005 Recruitments
120
100
80
Subject Enrollment
60
40
20
0
2005
2006 (Annualized)
Calendar Year
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Value Added of YCC to ProgramIntra- and
Inter-Programmatic Initiatives

• Targeted Areas of Research Excellence (TARE)
  projects
• DT members involved in 6 of 8 TARE
• Development of novel multitargeted molecules for
  cancer therapy
• Y. Cheng, E. Chu, A. Hamilton, J. Schlessinger,
• M. Saltzman
• Nanoparticles for cancer diagnosis and therapy
• M. Saltzman, J. Piepmeier, J. Costa, I. Mellman
• HPV Vaccination - Molecular Virology
• Breast Cancer - Signal Transduction
• Lymphoma - Immunobiology Immunotherapy
• DNA Repair - Radiation Biology Radiotherapy

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Value Added Program to Members

• Facilitate collaborations/interactions
• Intra-programmatic
• Inter-programmatic
• Basic scientists and clinical investigators
• Facilitate collaborations/interactions with
  academic centers and industry
• Facilitate collaborations/interactions with NCI
• Cancer Treatment Evaluation Program (CTEP)
• Office of Complementary and Alternative
  Medicine (OCCAM)
• Developmental Therapeutics Program (DTP)

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Interaction with YCC Research Programs
Radiobiology Radiotherapy
Developmental Therapeutics
15
Value Added Shared Resources
Genetic Counseling
Clinical Research Services
Developmental Therapeutics
Biostatistics
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Future Plans

• Develop new strategies for drug design,
  discovery, and formulation
• Expand collaborations with Signal Transduction
  Program and other YCC Research Programs
• Translate DT / YCC discoveries/science into
  clinical trials (e.g. Epoxomicin, GFB204,
  GGTI-2418)
• Design novel pilot clinical trials with
  biomarkers of response
• Enhance collaborative efforts with
  Clinical/Translational Research Programs