Abstract
Traditional anticancer chemotherapeutics targeting DNA replication and cell division have severe side effects, but they have proved to be highly successful in treating some cancers. Drugs targeting signalling oncoproteins that have gained tumour-driving functions through mutations or overexpression were subsequently developed to increase specificity and thus reduce side effects, but have limitations such as the development of resistance. Now, a new wave of small-molecule anticancer agents is emerging, targeting complex multicomponent cellular machineries — including chromatin modifiers, heat shock protein chaperones and the proteasome — which thus interfere with those support systems that are more essential for cancer cells than for normal cells. Here, we provide our perspective on the advantages and limitations of agents that target tumour-supportive cellular machineries (other than those involving DNA replication), comparing them with agents that target signalling intermediates.
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Acknowledgements
We are indebted to H. Bastians, Y. Begus-Nahrmann, A. P. Kudelka, N. Malek, A. Stolz and G. Wulf for critically reading the manuscript. We apologize to all colleagues whose important work could not be cited owing to space limitations. Our work was funded by the German Research Foundation (DFG), the German Cancer Aid, the German José Carreras Leukemia Foundation, the Wilhelm Sander foundation and the European Union (the GANNET53 project).
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Glossary
- Antibody–drug conjugates
-
Therapeutics consisting of a tumour surface-targeting antibody (a whole monoclonal antibody or a single-chain variable fragment) linked via a chemical linker to a cytotoxic molecule with anticancer activity.
- Biomarkers
-
Parameters that can be measured in patients — for example, to indicate the expression levels of a gene in tumour cells. In cancer treatment, biomarkers serve to indicate the likelihood of cancer progression, death, remission or a cure (these are known as prognostic biomarkers), or to assess how well a particular therapeutic regimen will work for a given patient (these are known as predictive biomarkers).
- Hallmarks of cancer
-
The general phenotypic traits of cancers. The original article by Hanahan and Weinberg defines six such hallmarks: self-sufficiency in growth signals; insensitivity to anti-growth signals; evasion of apoptosis; limitless reproductive potential; sustained angiogenesis; and tissue invasion and metastasis. This list has since been expanded.
- Kinobead technologies
-
The use of beads that are linked to kinase inhibitor molecules. These molecules bind to a subset of kinases from a cell lysate, allowing their subsequent identification and quantification by mass spectrometry.
- Monoclonal antibodies
-
Antibodies generated by a clonal B cell population (traditionally fusion hybrids of individual B cells with a myeloma cell). For cancer therapy, monoclonal antibodies are used to target tumour-associated molecules on the surface of cancer and/or stromal cells or secreted factors.
- Non-oncogene addiction
-
The phenomenon whereby cancer cells critically depend on a particular adaptive mechanism to a greater extent than normal cells, although the corresponding genes do not fulfil the criteria of oncogenes; this mechanism is typically composed of a complex multicomponent machinery.
- Oncogene addiction
-
The phenomenon whereby cancer cells depend on the continuous hyperactivation of one or more oncogenes and their products for their survival.
- Philadelphia chromosome
-
A reciprocal translocation of the chromosomes 9 and 22, designated t(9;22)(q34;q11), found in more than 90% of chronic myeloid leukaemias.
- REMARK guidelines
-
Guidelines entitled 'Reporting recommendations for tumour marker prognostic studies', which recommend standards for the evaluation of, and reporting on, biomarkers in clinical studies on cancer, including “study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods”.
- Small molecules
-
Organic compounds with a low molecular mass (the usual upper limit is 500–1,000 Da) that bind to specific macromolecules (such as proteins), thus altering their activity or function. Traditionally, small molecules with anticancer effects inhibit enzymatic activities, but more recently protein–protein interactions have also been successfully targeted.
- Synthetic lethality
-
Originally defined as a combination of two genes that, when individually mutated, can be tolerated by an organism, but when mutated simultaneously, result in death. This concept was extended to cancer therapy; if a gene is synthetically lethal to a cancer-associated mutation of another gene, targeting (that is, inhibiting) the product of the first gene using drugs will also result in synthetic lethality.
- Therapeutic window
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The range of a drug dose that both confers the desired effect (such as a reduction in tumour growth) and can also be tolerated by the patient without causing prohibitively severe side effects as a result of damage to normal tissues.
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Dobbelstein, M., Moll, U. Targeting tumour-supportive cellular machineries in anticancer drug development. Nat Rev Drug Discov 13, 179–196 (2014). https://doi.org/10.1038/nrd4201
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DOI: https://doi.org/10.1038/nrd4201
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