Genotype- or Phenotype-Targeting Anticancer Therapies? Lessons from Tumor Evolutionary Biology

Abstract

Despite the efficacy of most cancer therapies, drug resistance remains a major problem in the clinic. The eradication of the entire tumor and the cure of the patient by chemotherapy alone are rare, in particular for advanced disease. From an evolutionary perspective, the selective pressure exerted by chemotherapy leads to the emergence of resistant clones where resistance can be associated with many different functional mechanisms at the single cell level or can involve changes in the tumor micro-environment. In the last decade, tumor genomics has contributed to the improvement of our understanding of tumorigenesis and has led to the identification of numerous cellular targets for the development of novel therapies. However, since tumors are by nature extremely heterogeneous, the drug efficacy and economical sustainability of this approach is now debatable. Importantly, tumor cell heterogeneity depends not only on genetic modifications but also on non-genetic processes involving either stochastic events or epigenetic modifications making genetic biomarkers of uncertain utility. In this review, we wish to highlight how evolutionary biology can impact our understanding of carcinogenesis and resistance to therapies. We will discuss new approaches based on applied ecology and evolution dynamics that can be used to convert the cancer into a chronic disease where the drugs would control tumor growth. Finally, we will discuss the way metabolic dysfunction or phenotypic changes can help developing new delivery systems or phenotypetargeted drugs and how exploring new sources of active compounds can conduct to the development of drugs with original mechanisms of action.

Secondary Metabolites from the Culture of the Marine-derived Fungus Paradendryphiella salina PC 362H and Evaluation of the Anticancer Activity of Its Metabolite Hyalodendrin

“…The relative stereochemistry of 1 was also deduced from the NOESY correlations from H 3 In addition to 1, the previously described glycocholic acid methyl ester (2, Figure 2) [24], (-)-(3R, 6R) hyalodendrin (3, Figure 2) [25] and (-)-(3R, 6R) bisdethiodi(methylthio)hyalodendrin (4, Figure 2), also known as gliovictin [26], were isolated from the crude extract of P. salina PC 362H strain. The absolute configuration of 3 was deduced from its optical rotation sign and from structural consideration.…”

“…Carcinogenesis is an evolutionary disease driven by somatic cell mutations and subclonal selection [1][2][3]. During the course of the disease, the ability of the tumor cells to adapt to a wide range of environmental conditions leads to the selection of phenotypes whose aggressiveness usually increases with the stage of cancer [3].…”

“…Carcinogenesis is an evolutionary disease driven by somatic cell mutations and subclonal selection [1][2][3]. During the course of the disease, the ability of the tumor cells to adapt to a wide range of environmental conditions leads to the selection of phenotypes whose aggressiveness usually increases with the stage of cancer [3]. As an example, breast cancer progresses through defined pathological and clinical stages, starting from ductal hyperproliferation with possible evolution towards in situ and invasive carcinoma and eventually metastatic disease [4,5].…”

Expression Pattern of Purinergic Signaling Components in Colorectal Cancer Cells and Differential Cellular Outcomes Induced by Extracellular ATP and Adenosine

“…Interestingly, our gene expression data show that both P2RX7 and PANX1 coding genes whose products are known to participate to the release of ATP in the extracellular compartment [ 64 ] were both downregulated in CRC cells compared to the normal-like HCEC-1CT cell line ( Figure 2 B,D). This observation, combined with the fact that pro-inflammatory signaling pathways were overexpressed in all our CRC cells when structured in 3D ( Figure 1 B), suggest that microenvironment-driven cancer cell selection might drive CRC cells, at least initially, to downregulate pathways capable of releasing additional pro-inflammatory molecules, including ATP [ 67 ]. This assumption is of particular interest if we consider the differential function of acute and chronic inflammation in tumor progression [ 68 ].…”

Perspective: plasticity, the enemy of the good

“…In that model, oncogenes and tumor suppressor genes are particularly important because they can be thought as highly connected nodes in the genetic network capable of integrating signals controlling cell cycle and cell death [ 4 , 5 ] . Tumor formation then requires the accumulation of additional mutations determining the biological features of the tumor [ 1 ] . In the “epigenetic progenitor model of cancer”, it has been suggested that tumorigenesis first relies on an abnormality of the epigenetic network of progenitor cells that precedes mutations in tumor suppressor genes and oncogenes [ 6 ] .…”