In this publication of Cancer Highlights, BioSeeker Group analyzes the latest progress made for 25 drug candidates targeting the cell death pathway, apoptosis. Additionally, more early stage candidates are also under investigation, which brings the total number of companies interested in this field to around 40.
The five major targets in apoptosis, p53, Bcl-2, TRAIL, IAP and Caspases, are the corner stones for further analysis in study to address whether they are successful cancer therapeutic targets or not and what level of competition is present. Only p53 and Bcl-2 are apoptotic targets with drug candidates that have reached Phase III clinical testing, although death receptors "TRAIL" are closing the gap. BioSeeker projects that the competition targeting the IAP family of molecules will be intense and Caspase inhibitor will take a year or two to reach clinical tests.
Apoptosis is central to the development of cancer and resistance to apoptosis has been attributed as a reason to why cancer therapies fail. A contributing factor for investing R&D in the cell death pathway is that apoptotic drugs add sensitization to chemotherapy and radiotherapy. Novel treatments have been designed to modulate apoptosis, using traditional small molecular drugs as well as modern biotechnology tools such as gene therapy, monoclonal antibodies, antisense, biological drugs and peptide/non-peptide mimetics.
In a relative short time more than 40 therapeutic companies have taken up the cell death pathway as an important target to kill cancer cells. Some have already candidate drugs in clinical trials, but the gross majority is still in a very early stage of development and has not yet presented any further information. To include these new entrants BioSeeker has relied on available patent information to further understand what the future holds in store, and what kind of research the pharmaceutical industry is interested in.
Because the mechanism of apoptosis started to be unraveled quite recently even the most advanced novel therapies are still only at the clinical trial stage. This including new approaches on the tumor-suppressor protein p53, a target that attracted many investigators years ago.
Although attempts to counteract defective p53 with gene therapy and oncolytic virus have met mixed result, BioSeeker Group has listed no less than 16 companies that conduct R&D on p53. One of the newer approaches that is about to revive the view on p53 are small molecular drugs that act as scaffold for p53/DNA and Mdm2/p53 interaction.
Genasense (Genta Inc, USA), the first oncology drug of its kind to directly target the biochemical pathway of apoptosis, has also experienced difficulties after completing Phase III trial in several indications. Its NDA was rejected by FDA for the treatment of patients with metastatic melanoma. However, this incidence has not stopped other investigators from applying and pursuing similar strategy. No less than nine companies are today actively working on to improve the antisense line of attack on apoptotic targets.
TRAIL, IAP and Caspases as molecular targets have taken a step forward. Positive news includes antisense drugs that offer a way around drug resistance. Monoclonal antibodies against TRAIL receptor have reached Phase II. Several candidate drugs targeting members of the IAP family of molecules are now in Phase I trial. BioSeeker list additional drugs involving Caspase which are expected to advance to clinical trials within a year or two.
Companies included: Abbott laboratories, Aegera, Amgen, Antisoma, Apoxis, Aprea AB ArQule, AVI BioPharma, Biomeasure, Bristol-Myers Squibb, Cambridge Antibody Tech, CEREP, Chroma Therapeutics, Cyclacel, Cyclis, De Novo, Eli Lilly and Company, Exelixis, Gemin X Biotechnologies, Genentech, Genta, Hoffmann-La Roche, Human Genome Sciences, Hybridon, Idun Pharmaceuticals, Incyte Genomics, Introgen Therapeutics, ISIS Pharmaceuticals, Kirin Brewery, Maxim Pharmaceuticals, Millennium Pharmaceuticals, Molecular Engines Laboratories
Table of Contents
Apoptosis: Promise or deception?
Table of Contents
BSG General Working Model & Methodology
Key findings
Introduction
- Figure 1. Generalized illustration, depicting the key elements involved in the apoptotic pathways.
- Table 1. Common gene/protein defects in apoptotic pathways and associated mechanism
Multipathway Regulators
- Table 2 Overview of Apoptosis Targets Under Development
Projects on the p53 Pathway Increasing Again
- Box 1. The Agreement Between Sanofi-Aventis and Introgen Therapeutics
- Table 3. Overview of p53 Based Therapies in Clinical Trial
- New Attention to p53 Gene Therapy
- Activating p53 with Small-Molecule Drugs
- Are p53-MDM2 interacting peptides the future?
- Will 2nd generation of antisense that targets mdm2 deliver?
- Drug discovery to develop inhibitors of the p53-MDM2 interaction
- The importance of Aurora Kinase inhibitors
The Bcl-2 Pathway: Antisense versus New Approaches
- Table 4. Overview of Bcl-2 and Bcl-XL Based Therapies in Clinical Trial
- Has Genasense Lost its Sting?
- Box 2 The Collaboration Between Genta and Aventis
- Improved Bcl-2 Antisense Takes Off
- Peptides and Small Molecules Mimics: Option to Bcl-2 Antisense
- Other Drugs Mediating a Bcl-2 Pathway-Induced Cell Death
Death Receptors a Powerful Way To Apoptosis
- Table 5. Overview of Death Receptor Based Therapies in Clinical Trial
- Monoclonal Antibodies Towards TRAIL Receptor: Expanded Clinical Trials
- A Soluble Form of TRAIL Finally in Phase I trial
- Attempts Made for Fas Ligand System
Time Ripe for Inhibitors of Apoptosis Proteins
- Table 6. Overview of IAP Based Therapies in Clinical Trial
- Way Around Drug Resistance
- Survivin: Cell Death Inhibitor Or Not? Still an Excellent Target
- Smac/Diablo: Peptides and Small Molecule Mimetics
Modulators of the Caspase Pathway on Way
- Table 7. Overview of Caspase Based Therapies in Clinical Trial
- Companies with Focus on Caspase
- Newly Discovered Compound Affecting the Activity of Caspases
Appendix A Company Profiles
Abbreviation List
