4. Combinatorial biomedicine has obvious advantages
Totally, combinatorial biomedicine has a lot of obvious advantages, in particular screening, diagnosis, and treatments of both mNCDs (such as CVD, diabetes, and cancer) as well as mIDs (such as AIDS, Helicobacter pylori infection, and COVID-19). For example, combination therapy with intravenous doxycycline and azithromycin is a better option for severe infection [21], a combination treatment (Cabozantinib plus Nivolumab and Ipilimumab) of cancer has significantly longer progression-free survival [22], and venetoclax-obinutuzumab with or without ibrutinib is better than chemoimmunotherapy as first-line treatment in chronic lymphocytic leukemia [23]. Recent studies in Nature Cancersupported that combinatorial treatment led to a significant increase in survival and could further improve the therapeutic outcome in a syngeneic model of pancreatic ductal adenocarcinoma [24].
Of course, we should know the concept of the right combination of drugs or agents and therapeutic programs, for example, combined PD-1, BRAF and MEK inhibition in colorectal cancer [25], and the optimal sequence of several combination therapies is indeed pivotal to improve the outcomes in the treatment of cancer [26]. For example, combination chemotherapy for cancer cases by integrating the clinical and molecular features of the cancer is helpful to precise medicine and personalized and targeting treatment. Since there are multi-pathways of mechanisms and multi-factors of etiology, both mNCDs and mIDs need combinatorial treatment. Moreover, combinatorial biomedicine has resulted in newer concepts and better solutions, such as CDCs, OOHS, SEEDi1.0-3.0 technologies, and the iRT-ABCDEFG strategy, as well higher efficacy (1+1>2, 1+1+1>3) and less adverse events.
As we know, combinatorial immunotherapy for cancer is a promising approach [27]. Previous study showed that the chemotherapeutic effects of EGCG in combination with p53siRNA therapy induced a synergic pro-apoptotic effect [28], in fact, combinatorial treatments [29] in cancer are common, for example, triple-combination nanovesicles for cancer [30], Atezolizumab plus nab-Paclitaxel for metastatic triple-negative breast cancer [31]. Triple-drug combination against cervical cancer is a promising antineoplastic therapy since it inhibits the mTOR pathway leading to cell death by apoptosis [32]. Obviously, optimal patient-specific cancer targeted treatments need possible combinations, and there is a large drug combination dataset in AstraZeneca [33]. However, tumors’ resistance may reduce or combat some drug combinations. Hence, we need an effective platform for combinatorial drug screening [34]. Moreover, we need to know how combination therapies may become the preferable approach over monotherapy for cancer [35]. Moreover, combining a machine-learning molecular method with biomarkers may help predict early recurrence of some cancers [36]. As new personalized combinatorial treatments [37], combination of microfluidic experiments and mathematical model can be a novel tool toward cancer precision medicine. Therefore, as a new strategy, a fresh combination of therapeutic agents is efficacy for cancer in preclinical and clinical investigation [38].
In addition, there are combinatorial drug screening, diagnosis, and prediction of clinical outcomes and analysis of biological structure and molecular mechanisms. Herein, just as synthetic biology is popular, it is believed that combinatorial biomedicine, like click chemistry [39-41], will become a new discipline with great prospect and potential growth in the future. All in all, combination is always present and ubiquitous. As is well known, a house is composed of several building materials, and a car is composed of several parts. The classic biological example is that the double helix structure of deoxypentose nucleic acids (DNA) molecules [42-44] is composed of four complementary pairs of A, C, G, and T bases. Currently, synergistic molecular targeting therapy with the combination of all-trans-retinoic acid and arsenic trioxide for acute promyelocytic leukaemia is a valuable translational model [45]. Adeno-associated virus-delivered gene therapy of hemophilia A with a human/rat hybrid FVIII has an enhanced therapeutic effect [46]. In addition, a combination of elexacaftor/tezacaftor/ivacaftor may restore renal transmembrane conductance regulator function in patients with cystic fibrosis [47], and decrease risk for electrolyte disorders and metabolic alkalosis. No doubt, these are also classical examples of combinatorial biomedicine.