Systems medicine in colorectal cancer: from a mathematical model toward a new type of clinical trial

Abstract

Current colorectal cancer (CRC) treatment guidelines are primarily based on clinical features, such as cancer stage and grade. However, outcomes may be improved using molecular treatment guidelines. Potentially useful biomarkers include driver mutations and somatically inherited alterations, signaling proteins (their expression levels and (post) translational modifications), mRNAs, micro-RNAs and long noncoding RNAs. Moving to an integrated system is potentially very relevant. To implement such an integrated system: we focus on an important region of the signaling network, immediately above the G1-S restriction point, and discuss the reconstruction of a Molecular Interaction Map and interrogating it with a dynamic mathematical model. Extensive model pretraining achieved satisfactory, validated, performance. The model helps to propose future target combination priorities, and restricts drastically the number of drugs to be finally tested at a cellular, in vivo, and clinical-trial level. Our model allows for the inclusion of the unique molecular profiles of each individual patient's tumor. While existing clinical guidelines are well established, dynamic modeling may be used for future targeted combination therapies, which may progressively become part of clinical practice within the near future.

Precision wildlife medicine: applications of the human‐centred precision medicine revolution to species conservation

“…The emergence of precision medicine has been driven by an unprecedented ability to generate and analyse big data, and by the convergence of omic technologies (Table 1), the computational revolution, medical and research knowledge bases, and advances in bioinformatics and mathematical modelling (Committee on a Framework for Developing a New Taxonomy of Disease, 2011;Hood & Friend, 2011;Robinson, 2012;Flores et al, 2013;Vandamme et al, 2013;CASyM Consortium, 2014;Tortolina et al, 2015;Castagnino et al, 2016;Duffy, 2016;Parodi et al, 2016). While every one of these factors is not necessarily required for each precision medicine project, the interchangeable combination of these factors is facilitating our most in-depth understanding of human health and disease to date.…”

Transcription Factors Synergistically Activated at the Crossing of the Restriction Point between G1 and S Cell Cycle Phases. Pathologic Gate Opening during Multi-Hit Malignant Transformation

“…Additional gene target of E2F1-3 is also the S-phase kinase-associated protein -SKP2, a protein involved in an ubiquitin ligase pathway degrading E2F1-3. This represents an additional component of the negative feedback loop [26,29].…”

“…Recently we have enlarged our MIM, including the ALK, the MET and the Extracellular Matrix Integrin receptors pathways (see Fig. 5 and Table 1) [29]. The signals downstream of them propagate through a complex network, involving cross talks among interacting pathways, and strong feedback loops on different levels.…”

“…Chromosomal instability can give origin to specific decreased copy numbers of gatekeeper repressor genes, or specific increased copy numbers of gatekeeper dominant oncogenes, or can generate chimeric oncogenes. The caretaker level will facilitate/accelerate the appearance of errors at the gatekeeper level [29,38,40].…”

“…As of the end of 2014, the model involved 447 reactants (basic species, modified species, complexes and inhibitors), 348 reversible reactions and 174 catalytic reactions: (348•2 + 174 = 870 reactions) [12]. Their number increased by about 50% as of June 2015 [29].…”