The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

Abstract

It is a time of great promise and expectation for the applications of knowledge about mechanisms of cancer toward more effective and enduring therapies for human disease. Conceptualizations such as the hallmarks of cancer are providing an organizing principle with which to distill and rationalize the abject complexities of cancer phenotypes and genotypes across the spectrum of the human disease. A countervailing reality, however, involves the variable and often transitory responses to most mechanism‐based targeted therapies, returning full circle to the complexity, arguing that the unique biology and genetics of a patient's tumor will in the future necessarily need to be incorporated into the decisions about optimal treatment strategies, the frontier of personalized cancer medicine. This perspective highlights considerations, metrics, and methods that may prove instrumental in charting the landscape of evaluating individual tumors so to better inform diagnosis, prognosis, and therapy. Integral to the consideration is remarkable heterogeneity and variability, evidently embedded in cancer cells, but likely also in the cell types composing the supportive and interactive stroma of the tumor microenvironment (e.g., leukocytes and fibroblasts), whose diversity in form, regulation, function, and abundance may prove to rival that of the cancer cells themselves. By comprehensively interrogating both parenchyma and stroma of patients' cancers with a suite of parametric tools, the promise of mechanism‐based therapy may truly be realized.

Microenvironment-Derived HGF Overcomes Genetically Determined Sensitivity to Anti-MET Drugs

“…Alternatively, combination with anti-HGF antibodies could be envisioned to enhance the pharmacologic effect of a MET-selective drug, thus accomplishing a more favorable therapeutic response at the highest tolerated dose. With respect to the latter possibility, it should be kept in mind that only a minor fraction of patients eligible for a targeted therapy based on genetic testing respond clinically to pharmacologic blockade of the corresponding target (45). Considering the high levels of HGF frequently found in the tumor microenvironment, innate resistance to MET inhibitors in a significant percentage of these nonresponders could probably be overcome by HGF neutralization using agents like ficlatuzumab, thereby contributing to increasing the overall response rate.…”

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

“…Due to the vast heterogeneity of fibroblasts, as well as their different origins, much of the accumulating knowledge on the functional roles and activation pathways of fibroblasts may be tumour typeand tumour stage-specific. Nevertheless, clinical oncology is progressing increasingly towards a new era of integrative cancer therapy, based on personalized diagnostics that takes into account the individual complexities of tumours, including cells, pathways, and molecular mediators in the tumour microenvironment [118]. As a result, cancer therapeutics is moving progressively towards combinatorial approaches that act synergistically by targeting intrinsic pathways in neoplastic cells, as well as extrinsic tumour-enabling pathways in the tumour microenvironment.…”

Compensatory Pathways in Oncogenic Kinase Signaling and Resistance to Targeted Therapies: Six Degrees of Separation

“…Non-small cell lung cancers that exhibit mutational activation of the EGF receptor (EGFR) tyrosine kinase respond to EGFR inhibitors, whereas those with an intrachromosomal translocation of anaplastic lymphoma kinase ( ALK ) express constitutively active ALK fusion proteins that confer hypersensitivity to ALK inhibitors. Melanomas displaying a mutationally active BRAF kinase undergo massive regression following treatment with specifi c BRAF inhibitors ( 1 ).…”