Targeting Tumor Hypoxia with Prodrugs: Challenges and Opportunities

Abstract

Th e widespread occurrence of hypoxia in human tumors, and its importance in tumor progression and resistance to therapy, is now well established. Th us hypoxia is a well validated therapeutic target in oncology. Prodrugs that are selectively activated by enzymatic reduction in hypoxic cells (hypoxia-activated prodrugs, HAP) can potentially exploit tumor hypoxia, but have not yet provided useful clinical activity. A fundamental challenge is that hypoxia represents a qualitative rather than quantitative target, with many normal tissues also contain regions of physiological hypoxia. Th is problem may be compounded by low expression of the activating enzymes (oxidoreductases) in some tumors relative to normal tissues, and by ineffi cient penetration of HAP into hypoxic tissue because of excessively rapid kinetics of metabolic consumption relative to diff usion. Th ese challenges have led to design of a new generation of HAP which are now in clinical development (banoxantrone, PR-104, TH-302). We illustrate ways in which these HAP seek to exploit tumor hypoxia with greater selectivity, focusing on PR-104 which is a hypoxia-activated nitrogen mustard developed in our lab.

Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials

“…Each HAP candidate is a bespoke invention [42] , [43] , [62] . The diversity of pharmacophores and their mechanism of action indicate every HAP candidate will have tailored requirements as design criteria for optimal activity are stringent [63] . It is notable that several HAPs were identified through in vitro screening campaigns that selected for the pharmacodynamic (PD) endpoint of maximal individual cell kill under low cell density conditions [64] , [65] .…”

“…For example, the clinical failure of TPZ is likely due, in part, to poor tissue penetration [66] , [67] and inadequate oxygen inhibition (K O 2 = 1.3 ± 0.28 µM) [28] , with toxicity preventing schedule/dose intensification [68] . HAPs such as PR-104 [30] possess several optimal properties, including good extravascular transport (tissue penetration) [21] , [63] , strict oxygen inhibition (K O 2 = ∼0.126 ± 0.021 µM) [28] and adequate cytotoxic metabolite redistribution (‘bystander effect’) [29] , [69] . However, several unforeseen problems led to the subsequent clinical failure of PR-104, most notably the aerobic activation of PR-104A by human aldo-keto reductase 1C3 (AKR1C3) [38] and high levels of circulating cytotoxic metabolites [70] .…”