Biomarkers of cell death applicable to early clinical trials

Abstract

The development of biomarkers of cell death to reflect tumor biology and drug-induced response has garnered interest with the development of several classes of drugs aimed at decreasing the cellular threshold for apoptosis and exploiting pre-existing oncogenic stresses. These novel anticancer drugs, directly targeted to the apoptosis regulatory machinery and aimed at abrogating survival signaling pathways, are entering early clinical trials provoking the question of how to monitor their impact on cancer patients. The parallel development of drugs with predictive biomarkers and their incorporation into early clinical trials are anticipated to support the pharmacological audit trail, to speed the development and reduce the attrition rate of novel drugs whose objective is to provoke tumor cell death. Tumor biopsies are an ideal matrix to measure apoptosis, but surrogate less invasive biomarkers such as blood samples and functional imaging are less challenging to acquire clinically. Archetypal and exploratory examples illustrating the importance of biomarkers to drug development are given. This review explores the substantive challenges associated with the validation, deployment, interpretation and utility of biomarkers of cell death and reviews recent advances in their incorporation in preclinical and early clinical trial contexts.

Introduction

A biomarker is “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [1]. Biomarkers are increasingly being incorporated into early clinical trials [2] with the expectation that they can help document the pharmacological audit trail (described in [3]) which briefly involves:

• Identification of patients most likely to benefit from a specific drug treatment (a predictive biomarker)

• Demonstration that potentially active drug concentrations are achieved in the patient (a pharmacokinetic biomarker)

• Demonstration that a drug hits its desired target (proof of mechanism pharmacodynamic biomarker, a POM PD biomarker)

• Achievement of appropriate drug-induced biological effect (proof of concept pharmacodynamic biomarker, POC PD biomarker)

• Monitoring clinical response to therapy (a surrogate response biomarker).

The importance of biomarkers in drug development is illustrated by the development of trastuzumab, a monoclonal antibody targeting the HER-2 protein, whose development may have failed had a companion diagnostic (a predictive biomarker) not been used to restrict the trial to patients over-expressing the drug target [4]. Similarly bortezomib, a proteosome inhibitor, achieved its initial license in the treatment of myeloma on the basis of changes in a surrogate response biomarker [5]. The parallel development of drugs with predictive biomarkers that allow patient stratification and PD POM and POC biomarkers to facilitate dose and schedule selection is anticipated to speed up the development and reduce the attrition rate of new drugs in clinical development.

While debate continues about when such biomarkers should be deployed during drug development [6], [7], defining the dose of drug that hits its molecular target and elicits an appropriate tumor response is a key goal prior to embarking on expensive late stage trials. In this review, we examine the challenges and recent advances in the implementation of POC PD biomarkers to assess the optimal drug-induced tumor cell endpoint: cell death.