title: Glufosfamide: can we improve the process of anticancer agent development?
abstract: BACKGROUND
  Drug development is a complex and risky enterprise. Clinical development must be a thoroughly paced process sequenced by clinical and developmental questions logically ordered. Drug development parameters are changing due to better insights in system biology and mechanisms of actions. Therefore, there is a need to revisit how clinical trials are designed and sequenced.
  
  
  METHODS
  In the context of this paper, the development of glufosfamide is placed in perspective of possible new trends for more optimal drug development. Glufosfamide is an alkylating agent with a favorable safety profile as its metabolic activation does not lead to the release of toxic metabolites such as acrolein. In addition, its cellular uptake mediated through the transmembrane receptors of glucose makes it an attractive agent for the treatment of highly proliferative tumors cells. These observations have served the rationale to bring this agent to the clinic from Phase I up to Phase III with a focus on pancreatic cancer. The pathways for its development have been challenging due in part to the fact that there is no proof of mechanism-based study for any alkylating agent, even those used in the clinic.
  
  
  CONCLUSIONS
  Solid mechanism and translational research-based clinical trials providing evidence on the mechanism of action and how the agent interacts with the biology of the targeted disease are today an absolute requirement for the development of new agents. Optimal clinical trial design must complement system biology understanding so that 'trials designed to learn' may give robust grounds to 'clinical trials designed to conclude'.
authors.affiliation: Headquarters, European Organization for Research and Treatment of Cancer, Ave. E Mounier 83, Brussels, Belgium. denis.lacombe@eortc.be
authors.forename: Denis
authors.initials: D
authors.lastname: Lacombe
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D055808:Drug Discovery; D005947:Glucose / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007069:Ifosfamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; C092028:beta-D-glucosylisophosphoramide mustard; D005947:Glucose; D007069:Ifosfamide