Molecular Targets and Developmental Therapeutics
SCIENTIFIC ACCOMPLISHMENTS
The scientific accomplishments and achievements of MTDT are organized into the following areas of research focus:
Antisense/Gene Therapy
Key Accomplishments:
- Bcl-2 (bench to bedside within MTDT)
- G3139 (AS Bcl-2 ODN) in combination with chemotherapy in animals resulted in regression of breast xenograft tumors that overexpress Bcl-2
- Phase I clinical trial of G3139 plus docetaxel demonstrated safety, clinical activity
- Intermediate biomarker analysis of PBLs negative
- Program member discovers that Gossypol targets Bcl-2 family, Phase I trial planned, related compounds patented - Raf-1 (basic science within Radiation Biology Program and translated to trial in MTDT)
- Therapeutic ODN developed by Radiation Biology Program members
- AS raf-1 ODN radiosensitizes radiation resistant cancer cells
- Liposome encapsulated AS raf-1 ODN inhibited tumor growth and enhanced radiation sensitivity of tumors in animal models
- First in humans Phase I clinical trials of both single agent and with radiation underway
- p53 (bench to bedside within MTDT)
- Ligand-liposome-p53 complex can be systemically delivered and shown to be tumor-targeted
- In established xenograft tumor mouse models, intravenous administration in combination with radiation or chemotherapy resulted in long term (6-18 month) tumor regression
- Tumor growth inhibition also evident in a syngeneic mouse melanoma lung metastasis model
- Developed through Rapid Access to Intervention Development (RAID) and the NCI Decision Network for Clinical Trials
- IND for Phase I trial has been filed
Table 1. Summary of Clinical Trials in Antisense and Gene Therapy
| Target |
Agent |
Trial |
First Trials in Humans |
| Protein Kinase C |
ISIS 3521 |
Phase II |
|
| bcl-2 |
G3139 + docetaxel |
Phase I |
|
| Protein Kinase A |
GEM 231 |
Phase I |
|
| raf |
LErafAON |
Phase I |
|
| raf |
(LErafAON) +XRT |
Phase I |
|
Anti-Angiogenesis
Key Accomplishments:
- TNP-470 (basic science within Angiogenesis, Invasion, Metastasis Program and Breast Cancer Program, translated to trial in MTDT)
- Development and use of a bioassay to determine an effective and intermediate end-point for TNP-470 treatment in patients
- Phase I clinical trial of TNP-470 and docetaxel - Matrix metalloproteinase inhibitors (basic science within the Breast Cancer Program and translated to trial in MTDT)
- MMPIs are safe, differ in toxicity profiles, limited in vivo effects on MMPs in humans (Batimastat- BB-94, Marimastat- BB-2516, BMS 275291)
- A new cancer membrane-associated serine protease (matriptase) identified and trials planned
Collaboration with the Angiogenesis, Invasion, Metastasis Program has generated
significant translational research over the past several years to
include the testing of a series of matrix metalloproteinase inhibitors
and antiangiogenic agents (batimastat, marimastat, BMS275291, TNP-470,
pentosan polysulfate, and squalamine).
Table 2. Summary of Trials of Anti-Angiogenic and MMPI Agents
| Agent |
Trial |
First Trial in Humans |
| TNP-470/ Paclitaxel |
Phase I |
|
| Bryostatin + Cisplatin |
Phase I |
|
Marimastat
NSCL
Colon
Small Cell |
Phase II
Phase II
Phase II | |
| BMS-275291 |
Phase I
Phase II Lung Ca |
|
| Anti-matriptase |
|
|
| Squalamine |
Phase I
Phase II Lung Ca |
|
Tumor Vaccines as Therapy
Key accomplishments:
- Papilloma vaccines (basic research within Growth Regulation of Cancer Program, trial within MTDT)
- Vaccine induces protective systemic neutralizing antibodies
- Phase I trials demonstrate safety
- Second generation vaccine development supported by NIH RAPID Award - CEA-based vaccines
- CEA-based vaccines are safe, generate CEA-specific immune responses reliably, objective anticancer activity is seen
- Using two vaccine constructs (vaccinia CEA and ALVAC CEA) increases T-cell response
- Correlation between T-cell immunologic endpoint and patient survival
- Addition of cytokines plays a significant role in the T-cell immune response
Table 3. Summary of Vaccine Trials
| Agent |
Trial |
First Trials in Humans |
| Papilloma Virus Vaccine |
Phase II |
|
| ALVAC-CEA Vaccine |
Phase I |
|
| ALVAC + Vaccinia CEA Vaccines |
Phase I/II |
|
| TRICOM CEA Vaccines |
Phase I |
|
| Hyb2055 |
Phase I |
|
| TRICOM CEA-MUC I |
Phase I |
|
| TRICOM CEA + docetaxel |
Phase I |
|
Signal Transduction
Key Accomplishments:
- Validation of Protein Kinase B/AKT as a target for drug development, beginning of drug discovery efforts
- Completion of Phase I trials with novel retinoids, Phase II trial underway
- Completion of trials and translational efforts targeting PKC
Table 4. Summary of Signal Transduction Trials
| Agent |
Target |
Trial |
First Trial in Humans |
| ISIS 3521 |
PKC alpha |
Phase II |
|
| Bryostatin/Cisplatin |
PKC |
Phase I |
|
| Targretin + Chemo |
RAR |
Phase II Lung |
|
| TAC-101 |
RXR, RAR |
Phase I |
|
| Retinoid + PPAR gamma agonist | PPAR, RXR |
Phase I |
|
| SU101 | PDGF |
Phase I |
|
| AKT antisense | AKT |
Phase I |
|
| Anti-BCL-2 family small molecule | BCL-2 |
Phase I |
|
| EGFR/HER2 small molecule | EGFR/HER2 |
Phase I |
|
Drug Discovery
Key Accomplishments:
- Using a structure-based virtual screen strategy screening approach, three potent inhibitors for Bcl-2 and inhibitors of matriptase represent promising leads for the development of entirely new classes of anticancer drugs
- NMR determination of three-dimensional structures of potential molecular targets, Fibroblast Growth Factor (FGF)-Binding Proteins, and prostate-specific homeoprotein NKX3.1, has begun moving basic studies developed in other Lombardi programs closer to translational objectives of drug discovery
Table 5. Summary of Drug Discovery at Lombardi
| Targets Under Study |
Agents Developed |
| Bcl-2/Bcl-XL |
|
| FGF-BP |
|
| NKX3.1 |
|
| AKT |
|
| EWS/FLI1 |
|
| PPAR |
|
| PI3 kinase |
|
| AKT, PTEN |
|
| P53 |
|
| Matriptase |
|
An important goal of MTDT is the discovery and/or synthesis of novel
anti-cancer agents. Most prominently, the recruitment of Dr. Milton Brown in the role of drug discovery and translational research has been our most significant recruitment for the MTDT program. However, in addition, Dr. Steve Soldin and Dr. Al Fornace (Radiation Biology and DNA Repair Program) will contribute greatly to the MTDT program with an emphasis on pharmacokinetics, metabolomics, peptodomics and proteomics. |
