Challenges of PK/PD measurements in modern drug development
Section snippets
The need for PK and PD endpoints
Modern cancer drug development can be characterised by a number of important principles 1, 2, 3, 4. These include: (1) A focus on the genes and pathways that are driving the molecular pathology and progression of human cancers, providing an intellectual framework and a source of new molecular targets for improving drug efficacy and selectivity; (2) Application of new technologies, such as high throughput screening, combinatorial chemistry and gene expression microarrays, to accelerate the
Development of SR4554 as a hypoxia detection agent
Hypoxia is an extremely important factor in the malignant progression of human cancers 11, 12. Low oxygen levels are a major driving force for tumour angiogenesis and hypoxia is involved directly in resistance to radiation therapy and chemotherapy, as well in the selection for a more aggressive phenotype, including loss of p53. Furthermore, tumour hypoxia has been shown to be an independent prognostic factor in determining metastasis and survival in various types of cancer [13].
The
Development of PD endpoints for the Hsp90 molecular chaperone inhibitor 17AAG
The Hsp90 molecular chaperone is an exciting new molecular target for cancer treatment 20, 21. Of particular relevance is the fact that Hsp90 is responsible for the folding, stability and function of a range of oncogenic ‘client’ proteins, including Raf-1, erbB2, CDK4, oestrogen and androgen receptors and mutant p53. Inhibition of Hsp90 leads to degradation of the oncogenic client proteins by the ubiquitin proteasome pathway. Hence Hsp90 inhibitors may provide a one-step combinatorial attack on
Concluding remarks
PK and PD endpoints are an essential component of the rational development and evaluation of new cancer drugs. They provide enormously helpful information and inform the decision-making process. Particular emphasis should be focused on the development of PD endpoints. Biomarkers that indicate directly whether the molecular target has been modulated are extremely valuable. Endpoints that provide evidence for intervention in a biochemical pathway are also very useful, as are methods to confirm
Acknowledgments
Work carried out in the Cancer Research UK Centre for Cancer Therapeutics (http://www.icr.ac.uk/cctherap/index.html) is funded primarily by Cancer Research UK. Paul Workman is a Cancer Research UK Life Fellow. I thank my Centre colleagues and members of the Cancer Research UK Pharmacokinetic and Pharmacodynamic Advisory Committee for valuable discussions.
References (27)
- et al.
Discovering novel chemotherapeutic drugs for the third millennium
Eur. J. Cancer
(1999) Scoring a bull's-eye against cancer genome targets
Curr. Opin. Pharmacol.
(2001)- et al.
Gene expression microarray analysis in cancer biology, pharmacology and drug developmentprogress and potential
Biochem. Pharmacol.
(2001) Hsp90 inhibitors as novel cancer chemotherapeutic agents
Trends Mol. Med.
(2002)- Gibbs J B. Mechanism-based target identification and drug discovery in cancer research. Science 287,...
Initial sequencing and analysis of the human genome
Nature
(2001)- Ventor JC, Adams MD, Myers EW et al. The Sequence of the Human Genome. Science 291,...
- et al.
Cancer and genomics
Nature
(2001) - Workman P, Graham MA, guest eds. Pharmacokinetics of Cancer Chemotherapy. Cancer Surveys, vol. 17. New York, Cold...
Gene expression profiling of human colon cancer cells following inhibition of signal transduction by 17-allylamino-17-demethoxygeldanamycin, an inhibitor of the hsp90 molecular chaperone
Oncogene
Tumour hypoxiadefinitions and current clinical, biologic, and molecular aspects
J. Natl. Cancer Inst.
Cited by (65)
Optimization of bioanalysis of dried blood samples
2023, Journal of Pharmacological and Toxicological MethodsQuantitative analysis of ATM phosphorylation in lymphocytes
2019, DNA RepairCitation Excerpt :The use of PD biomarkers allows clinical outcome in patients to be evaluable in terms of both biological processes and clinical endpoint. Accordingly, a “pharmacological audit trail” would allow trial design to be modified and/or treatments repurposed as their efficacy is assessed in patients [1]. Since genotoxic chemotherapies target DNA, biomarkers that identify DNA damage signaling may prove particularly useful [2].
Modern Cancer Drug Discovery: Integrating Targets, Technologies, and Treatments for Personalized Medicine
2013, Cancer Drug Design and Discovery: Second EditionEORTC-related new drug discovery and development activities: Role of the Pharmacology and Molecular Mechanisms Group
2012, European Journal of Cancer, SupplementCitation Excerpt :This required a stringent quality assurance of assays, always a major aspect of PAMM activities. The initial studies faced a number of challenges,26 but various drugs were entered into the clinic and were developed according to this algorithm which still forms the basis for drug escalation in Phase I studies, albeit with several modifications. Examples of these drugs include several alkylating agents, anthracyclines, platinum analogs and antimetabolites,27 although it was assumed that the concept would be less accurate for antimetabolites.
Modern cancer drug discovery: Integrating targets, technologies and treatments
2008, Cancer Drug Design and Discovery