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Problems in the development of target-based drugs
1Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan. nsaijo@gan2.ncc.go.jp
Abstract:
Numerous molecular targets of cancer chemotherapy have been identified based on progress made in molecular biology, and new categories of anticancer drugs have been developed. These include inhibitors for signal transduction, cyclin-dependent kinase, angiogenesis, and matrix metalloproteinase, gene therapy, etc. They are variously called target-based drugs, noncytotoxic drugs, or cytostatic drugs. Such drugs have interesting mechanisms of action and appear promising. However, preclinical and clinical evaluations are difficult. Some drugs have a direct antitumor effect, with demonstrated tumor shrinkage. Others show no direct cytotoxicity. The majority of recent phase I trials have evaluated the maximum tolerated dose, pharmacokinetics, adverse events, and antitumor effect. Unusual, unacceptable toxicities have been noted with some target-based drugs. Few phase I trials or preclinical studies have attempted to demonstrate target inhibition. So far very few studies has shown that there is a correlation between target inhibition and antitumor effect. In general, phase II studies are undertaken with compounds such as trastuzumab which have direct antitumor activity. Phase III trials of most target-based drugs are undertaken immediately after phase I studies since the design of appropriate phase II studies is difficult. The ultimate endpoint of phase III trials of target-based drugs is the same as that for cytotoxic drugs, such as improved cure and survival rates.
Insights
New anticancer drugs targeting specific molecules show promise but face evaluation challenges. Demonstrating target inhibition and its link to antitumor effects remains difficult in clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Advances in molecular biology have identified numerous cancer targets, leading to new drug categories like signal transduction inhibitors, cyclin-dependent kinase inhibitors, and anti-angiogenesis agents.
- These novel drugs, termed target-based, noncytotoxic, or cytostatic, offer unique mechanisms of action and therapeutic potential.
- Despite their promise, evaluating these drugs presents significant challenges in preclinical and clinical settings.
Purpose of the Study:
- To review the development and evaluation of novel molecularly targeted anticancer drugs.
- To discuss the challenges in preclinical and clinical assessment of these agents.
- To examine the correlation between target inhibition and antitumor efficacy.
Main Methods:
- Review of preclinical and clinical trial data for target-based anticancer drugs.
- Analysis of phase I, II, and III trial designs and endpoints.
- Examination of studies assessing target inhibition and its clinical relevance.
Main Results:
- Some target-based drugs exhibit direct antitumor effects, while others do not show direct cytotoxicity.
- Phase I trials commonly assess maximum tolerated dose, pharmacokinetics, and adverse events, with some target-based drugs showing unexpected toxicities.
- Few studies have successfully demonstrated target inhibition or established a clear correlation between target inhibition and antitumor effects.
Conclusions:
- Evaluating target-based anticancer drugs is complex, particularly in designing appropriate phase II studies.
- Compounds with demonstrated direct antitumor activity, like trastuzumab, are often advanced to phase II trials.
- The ultimate goal for target-based drugs in phase III trials remains consistent with cytotoxic drugs: improved cure and survival rates.