Any type of disease condition will likely be associated with several abnormal molecular entities and pathological events. For discovering and developing molecular-targeted therapeutics against a disease condition, it will be important to determine which of those altered molecular entities and biological events are essential to the disease onset and to the underlying pathological mechanism(s) that initiate, support, and maintain the disease condition, and also promote its progression. The knowledge of this information is crucial for determining the suitability of the biological entity as a target and for defining the significance of the target to the disease. Target identification thus represents the key first step in the target-based discovery approach. A cancer drug target represents a biological entity with molecular and biochemical functions that are critical to the key biological processes underlying the existence of cancer. The altered biological entity may be a genetic material, a gene or gene product, or a molecular or biological mechanism present within cancer. The identity or the knowledge of the critical target also provides a basis for defining some aspects of the biological and molecular underpinnings of the disease. A defined target may be distinctive to the particular cancer type, representing part of the properties that define the cancer phenotype, as well as distinguish the cancer from other cancer types or subtypes, or the cancer cells from their normal counterparts from which the tumorigenesis events may have originated. It provides a means of characterization of the cancer in terms of differences in specific molecular and biological properties that are the foundation of the disease and for which the target is critically important. Identifying and defining a target is also an important step toward setting priorities regarding the specific aspects of the target that need to be focused on that might be relevant to function. Selecting the target influences the decision on what approach to take in order to maximize the potential to achieve the highest level of selectivity and specificity of effects for the candidate drug. The knowledge of the target is also useful for making predictions about the potential to regulate specific tumor types with minimal toxicity to the patient. It could be said that a defined target for a tumor type provides the platform for predicting the potential clinical outcome when the new drug is used in a patient against the target, which is aberrantly regulated in some fashion, although it needs to be stressed that this prediction is no guarantee of the clinical success of the candidate drug. Other important considerations in determining target identity that impacts significance are the cellular location and the expression profile of the target, molecular status in normal versus tumor cells, the functional status in relation to the tumor phenotype, as well as other physical/biochemical and biological properties of the target.

The functional status of the candidate target should be considered relative to the mechanism of carcinogenesis and the development of the cancer phenotype. The important questions to address here are what role the target has and in what manner, as well as how important the target’s role is to the disease phenotype. Determining the answers to these key questions provides the framework for making the critical decision on whether to focus on the target for drug discovery purposes. These questions are addressed experimentally to ensure that the selected candidate target sufficiently meets certain minimum conditions or set guidelines. Information from those studies becomes the basis for making critical decisions on moving forward. Other important issues include druggability and how well drugs can be designed and developed against the target, as well as the tractability of the target or the difficulty of inhibiting the target. It is proposed that of the genes in the human genome, only a small percentage is druggable and is associated with diseases. This is even more important when the disease phenotype is linked to several similar targets, and the question becomes which one of these possible targets should be pursue in the discovery program. It is worth stating that what constitutes a good target may be regarded as an ongoing debate and this debate and the evaluation of the target should continue throughout the drug discovery process to ensure suitability. In that regard, what is now emerging is a sense of value that the potential target presents and this influences the “go-no-go” decision. Moreover, emphasis is placed on target value for the sake of patentability and intellectual property matters, which are important considerations from financial standpoint, given how much of resources would need to be invested and how much efforts would be allocated for pursuing the target in the discovery program, and the overall cost associated. It is a common practice for one target to be pursued by many organizations, particularly if it is highly relevant to the cancer type and its druggability is high. Overall, the concept of target is generally accepted as one of the most critical factors to consider in the anticancer drug discovery process [10–14].

The concept of target represents one of the most important issues i n anticancer drug discovery. Granted the multiple genetic alterations, which are associated with the cancer type, lead to a myriad of functional aberrations in the gene products with altered biological outcome, it is reasonable to expect many factors to become associated with any particular cancer phenotype. While such associations are significant and may suggest some level of importance for the altered entities in relation to the carcinogenesis and the tumor formation processes, rigorous investigative studies are required before any major conclusions can be made regarding target validity. The point needs to be made that an observation that a biological molecule is altered in some fashion in cancer cells, while suggesting an association with the cancer phenotype, should not necessarily be taken as an indication the altered entity is essential for the events that led to the cancer phenotype or that it is important within the underlying mechanisms leading to carcinogenesis, tumor formation, and tumor progression. Ideally, to be considered as potential targets, altered proteins, or biological molecules and their functions should have critical roles in the underlying events leading to the cancer formation. Adopting this viewpoint is to safeguard against selecting and focusing on spurious biological entities that may not be essential to the basis of the disease phenotype, but may be readily available for targeting for reasons other than a requirement for the cancer formation. This brings us to the issue of the cause and effect. This is an important consideration, which indicates the need to establish the causal relationship between the altered molecular entity (and its function), as a potential target, and the biological or pathological events underlying the cancer phenotype. It will be ideal to envision that the altered molecular entity will have a causal role in the induction of the cancer phenotype in order to represent a validated and credible target for drug discovery and development.

Although the validation of a putative target may be viewed as a complex and long process, when successfully done, it authenticates the drug discovery process and has the potential to improve the chances of success in terms of the clinical outcome in patients for the drug candidate that emerges from targeting the altered biological entity. The question of what makes a good target for anticancer drug design and development may not be answered in one study. The attempt to address this question may take the form of a number of observations made from a series of studies throughout the drug discovery and development process. The significance of these studies is primarily in terms of establishing the nature of the relationship between the candidate target and the disease. The type of relationship will have a strong influence on the potential response of the drug candidate in the treatment of the disease based on the effect of the drug on the target. Thus, a high importance should be placed on defining the importance of the altered biological entity, as a target, in relation to the cancer. In that regard, there ought to be a set of criteria with minimum requirements that need to be fulfilled by the putative target in regard to its consideration as the target of choice for the cancer phenotype, and to the justification to develop agents that modulate its activity or function. The validation does not only make certain that the target is critical to the cancer type in terms of the viability and the survival of the cancer cells, but also serves to minimize the chances of toxicity by ensuring that the potential drug candidate would exert specific effect preferentially on tumor cells without indiscriminate effect on normal cells. Overall, target validation is an important consideration in the drug discovery process, and establishing the causal role for a target in the disease phenotype is a good beginning of a potentially viable anticancer drug discovery process. However, target validation should be perceived as an ongoing process pursued at all stages of the drug discovery and development process. By its very nature, the validation therefore represents a complex process that will require diverse experimental approaches and important decision-making steps in order to accomplish and establish a tractable and viable drug target [10, 14].

An important issue in considering a candidate target for drug discovery is whether an entity hypothetically associated with a disease necessarily represents an appropriate point for new drug intervention. It is vital to establish the credibility of the hypothetical target as it relates to its activity in the context of the disease and the target’s mechanism(s) of action, and to establish a cause and effect relationship between the disease and the candidate target. There are no standard processes for validating and establishing the credibility of a target, and different organizations may consider different approaches for accomplishing this goal. Notwithstanding, the main goal is to present a clear definition of the position of the target in relation to the disease phenotype and the molecular and biological events leading to cancer. Achieving this goal will require using various experimental models of the disease and diverse approaches. It should be pointed out that disease-relevant systems that are available for experimental use outside of humans may not be accurately reflective, but nonetheless serve the purpose at this stage of the discovery process. While the establishment and the use of appropriate disease models for target validation present some challenges, the lack thereof for evaluating a potential target for credibility will only compromise the pharmacological usefulness of the emerging drug candidate. Given the objective, which is to verify the credibility of the potential target in relation to its role in the cancer phenotype, one could propose some minimum conditions and lay out a set of criteria that need to be fulfilled by a molecular entity that is being considered or evaluated as a potential target for cancer drug discovery:

These target-focused requirements are important considerations in determining the validity of a target for developing novel anticancer drugs for therapeutic purposes. The ultimate test of the validity of the target in relation to the cancer type is the clinical outcome in the appropriate cancer patients who are given the drug. An example is seen in the good clinical activity of Bevacizumab, the humanized anti-VEGF monoclonal antibody as standalone or used in drug combination. Various genetic, molecular, biological, and pharmacological approaches are frequently used to evaluate and validate a putative target and its relevance to cancer. While the experimental approaches to evaluate the potential for a molecular entity or biological event to make a good target may vary from one organization to the next, the basic premise remains the same and that is to establish the credibility of the putative target for the disease phenotype. The emphasis is on ensuring that a particular biological entity has all the necessary properties and fulfills the criteria for its consideration as a valid drug target. It suffices to mention that even when a target is validated, its credibility as a good target continues to be evaluated at every stage throughout the drug discovery process and finally at the level of clinical response when the drug is administered to patients [8, 10, 11, 14–18].