Targeted Tumor Therapy Remixed-An Update on the Use of Small-Molecule Drugs in Combination Therapies

Abstract

Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies. Depending on the mutational status, BRAF and MEK inhibitor combinations or immune checkpoint inhibitors are current first-line treatments for metastatic melanoma. However, despite great improvements of survival rates limitations due to tumor heterogeneity, primary and acquired therapy resistance, immune evasion, and economical considerations will need to be overcome. Accordingly, ongoing clinical trials explore the individualized use of small-molecule drugs in new targeted therapy combinations based on patient parameters and tumor biopsies. With focus on melanoma therapy this review aims at providing a comprehensive overview of such novel alternative and combinational therapy strategies currently emerging from basic research. The molecular principles and drug classes that may hold promise for improved tumor therapy combination regimens including kinase inhibition, induction of apoptosis, DNA-damage response inhibition, epigenetic reprogramming, telomerase inhibition, redox modulation, metabolic reprogramming, proteasome inhibition, cancer stem cell transdifferentiation, immune cell signaling modulation, and others, are explained in brief. In addition, relevant targeted therapy combinations in current clinical trials and individualized treatment strategies are highlighted.

Keywords: DNA-damage response; apoptosis; clinical trial; epigenetics; kinase inhibitor; melanoma; metabolomics; small-molecule; targeted therapy; tumor.

Figure 1

The principles of targeted cancer therapy. A number of physiological processes are potentially altered in a cancer cell (light blue) and can be targeted by small-molecules and other drugs (1–9, strongly simplified). In addition, immune cells (purple) can be targeted (10) as well as other cells of the tumor micro-environment (not shown). A more detailed description of each cellular process and the therapeutic ways to interfere with it is provided in the text.

Figure 2

Algorithm suggestion for therapy decisions based on the assessment of the tumor genetic and immunologic status and patient parameters for the example of metastatic melanoma.