Editorial: Novel Combination Therapies for the Treatment of Solid Cancers

Abstract

The concept of combination therapy was first introduced in 1965 when Emil Frei et al. launched the first-ever combination chemotherapy in pediatric patients with acute leukemia (1). The success of this combination therapeutic approach had remarkably changed the landscape of clinical oncology ever since (2). Consequently, much emphasis in cancer research was directed to investigating combination therapies that target different pathways to generate a favorable anticancer activity (3). In line with this, advancements in cancer cell genomics, epigenomics, transcriptomics, and proteomics have paved the way to identifying new molecular targets and the development of selective targeted anticancer therapies (4). Targeted therapies have substantially expanded the options for combinational anticancer treatments that can be combined with other targeted therapies or chemotherapeutic drugs (5). The combination of anticancer therapies is clinically appealing for several reasons. Firstly, combination therapy improves treatment outcomes and results in superior therapeutic effects, especially when a synergistic anticancer activity is achieved (6). Secondly, the combinational approach overcomes clonal heterogeneity which is further associated with improved response rates (7). Thirdly, combined drug regimens reduce the toxicity of the regimen as it allows using individual drugs at reduced dosages at maintained therapeutic efficacy (6). Another advantage of combination therapies is reducing the emergence of drug resistance (6). In this context, combination therapy enables concurrent targeting of several molecular pathways essential for cancer cell survival and abolish cellular mechanisms associated with adaptive resistance (8). Despite the advantages of combination cancer treatments, several challenges accompany the development and utilization of combined therapies. A challenging aspect of combination therapies is the potential drug interactions and the pharmacokinetics of co-administered agents that could influence the therapeutic activity of the regimen (2, 9). Besides, the administration of suboptimal doses of drugs in the combination may be necessary to avoid toxicity (9). The definition of synergism is inconclusive, particularly in clinical studies, and its prediction is challenging (10). Historically, the development of most drug combinations was conducted using empirical experimental or clinical settings (7, 8). In such a case, a detailed mechanistic analysis is rarely performed for the prediction of effective combinations (7). Therefore, the development of strategies