Recent advances in DNA sequencing and omics-based capabilities are revealing incredible therapeutic opportunities and quickly transforming drug discovery. Molecularly targeted drugs aim to exploit key tumor-specific vulnerabilities such as oncogenic or non-oncogenic addiction and synthetic lethality. The non-oncogenic addiction to tamoxifen creates the dependency on ribonucleotide reductase enzymes in Estrogen Receptor positive breast cancer cells. Moreover, targeting the host immune system with immunotherapies is proving to be another promising and complementary approach. Because of substantial genomic heterogeneity and immunologic complexities, combination strategies are required to interrupt intricate molecular signaling networks to achieve durable clinical responses in patients. The drug combinations have the potential to improve treatment response, minimize the development of resistance or minimize adverse events. Currently, designing combination trials relies mainly on clinical and experimental experience. While empirical experience has indeed crafted efficacious combination therapy clinical trials (combination trials), however, garnering experience with patients can take a lifetime. Therefore, to enhance the therapeutic success of combination therapies, we discovered that Ribonucleotide reductase inhibitors such as Didox, when combined with tamoxifen, created a novel combination therapeutics. Therefore, we proposed this most effective use of this combination should be directed towards eliminating polyclonal and heterogeneous cancer cells. Our results call to action a proactive paradigm aimed at preventing resistance rather than the current reactive paradigm of intercepting and treating drug resistance incrementally. Indeed, a paradigm shift is required from the traditional “drug-centric” model of clinical development to a “strategy-centric” model to provide personalized treatments in molecularly stratified subsets of patients or even in individual patients. Importantly, to battle the numerous challenges in combination drug development—including limited understanding of tumor biology, methodological and informatics limitations, regulatory challenges and ever-increasing monetary costs. This requires aligned goals and multidisciplinary collaboration to collectively harness knowledge and fuel continual innovation.
1. Defining the effective combination therapy
2. Identifying various challenges in designing the rational combination therapy
3. Current approaches to combination therapy in the clinic