9.4

Development of Novel Biomarkers Through Reverse

Translational Research

Biomarkers are now considered as key to rational, precision medicine drug develop-

ment and successful clinical results. During forward and reverse translational

approach, the development process of biomarker can be divided into four stages,

which includes discovery, qualification, authentication and validation of biomarkers.

During the discovery and qualification stage, the biomarkers associated with interest

are identified from cell lines and animal models. Meanwhile, during verification and

validation stage, cell lines as well as primary human data are utilised to assess and

establish the sensitivity and specificity of biomarkers. As the research progresses

from discovery to validation of biomarkers, the validated biomarkers are utilised in

reverse translational research for drug discovery and precision medicine develop-

ment (Fall et al. 2014).

Novel biomarkers are beyond typical mutated genes (BRCA1/2) related to

increased risk of breast cancer and overexpressed proteins including HER2 or

programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) in breast

cancer, tumour mutational burden (TMB), minimal residual disease (MRD), micro-

satellite instability (MSI) and their spatiotemporal variations. Same biomarker

cannot work for every tissue, and changes apply throughout the duration of the

MOLECULAR

In vitro studies

In vivo studies

Pre-clinical

Pharmacology

MODELING

(Target

( Target Validation)

(Biomarker

(Biomarker

(Biomarker

Validation)

(Biomarker

Validation)

Authentication)

Phase - I

Phase - II

(Biomarker

Application)

(Validated

(Population

based

prognostic

studies)

Biomarkers)

Phase - III

Development)

identification)

(Molecular

Medicine)

Pathology

guided

genomics

Personalized

Medicine

Rx Dx

(Precision

Medicine)

Rx Dx

Drug Discovery

Diagnostics

and Development

Development

Reverse

Forward

Translation

Translation

Fig. 9.3 Biomarker-based drug discovery and precision medicine development through reverse

translational approach

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R. K. Goyal and G. Aggarwal