9.3

History of Integration of Reverse Translational Research

and Biomarkers in Drug Discovery

Reverse translational approach can be utilised to improve biomarker discovery,

study of its validation parameters, utilisation and practical application. It is expected

that the application of biomarkers would be helpful even for predicting the drug

development in the early stages, which can further ensure that the drug candidates

have requisite safety and toxicity profiles that can be considered effective before

administering and starting the trials in humans (Strimbu and Tavel 2010).

A biomarker, as defined by Wikipedia, ‘is an indicator of a biological state

(i.e. cellular, biochemical, molecular, genetic, protein, metabolite, specific post-

translational modification or physiological or physical sign) that is objectively

measured and evaluated as an indicator of normal biological processes, pathogenic

processes, or pharmacologic responses to a therapeutic intervention’ (Aronson and

Ferner 2017).

Earlier in the fourteenth century, the clinicians used the techniques of uroscopy

for identifying and diagnosing disease via examining the features such as colour and

sediment of patient’s urine, e.g. presence of sugar in urine for diagnosing diabetes,

was a biomarker (Eknoyan 2007). The history of biomarker was observed and

known to have an early intervention of Philadelphia chromosome in the year 1960

wherein a biomarker was used for indicating the right patient for a drug. In the

experimental phase, the drug such as imatinib, ‘Gleevec’, has been observed to

decrease the proliferation of Philadelphia chromosomal cells which ultimately

slowed the disease progression. Considering the consequences of the landmark of

the observed specific mutations, as in the case of BCR-ABL wherein genes had been

identified as biomarker for predicting resistance to imatinib, further leads to the

pathway for the development of novel tyrosine kinase inhibitors (Kang et al. 2016).

Similarly, human epidermal growth factor receptor (HER-2) gene and other

receptors are known to be the most promising biomarkers during mid-1980s wherein

it has been reported that about 20–30% of breast cancer patients showed an

upregulation of HER-2 receptor in cancer cells by these drug discoveries. Besides

being known for a high risk of adverse outcomes, the research provided a clear idea

and suggested attention of researchers towards a targeted therapy (Reynolds et al.

2014). Subsequently, in late 1980s, further discovery of HIV viral load as a marker

provided an indication of disease progression rate for effectively measuring the

antiretroviral treatment efficacy. The method of assessing viral load in patients

while receiving combination therapy had been observed along with a higher reduc-

tion compared to those patients who are on monotherapy and showed effectiveness

in slowing the progression of the said disease (Mayeux 2004; Kagan et al. 2015).

Generally, two types of biomarkers are known to be effective as being the

personalised medicine which includes the predictive and prognostic biomarkers.

The predictive biomarker is considered as a pretreatment or provides baseline

measurement, which in turn can result in predicting whether the benefit can be

obtained from a specific treatment. A predictive biomarker is known to be designated

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R. K. Goyal and G. Aggarwal