Cancer research as a continuum
We view cancer research as a continuum, where basic research, translational approaches, clinical studies, and outcomes research are intercalated to achieve optimal results for cancer diagnostics, treatment and care. The Policy Paper by Ringborg, Berns, Celis, Heitor et al. crystallise the latest discussions on European Cancer Research Policy and provide a coherent view of this cancer research continuum and how it can be further structured to immediately benefit patients and the society.
Basic cancer research feeding back to drug development and treatment combinations
Progress often comes from disruptive thinking in the context of basic research. In their review article, Matheus Henrique Dias and René Bernards have put forward the counter-intuitive hypothesis that activation of mitogenic signaling in cancer cells might hold therapeutic potential through selective sensitization to drugs targeting stress response pathways. Stress responses often include the activation of a cellular senescence programme, a cellular state involving proliferation arrest, and Daniel Muñoz-Espín and colleagues have reviewed senescence under the prism of early detection of cancer and/or therapy responses.
Naturally, targeting of cancer-associated signalling pathways should not be overlooked as an approach for cancer diagnostics and treatment. Antonia Schubert and Michael Boutros have reviewed how extracellular vesicles (EVs) are involved in cancer-associated signalling and can be potentially harnessed to treat cancer. Moreover, diverse research articles published in Molecular Oncology last year shed light onto various aspects of cancer signalling and metabolic pathways and their targeting for cancer treatment:
- Julia Krushkal et al. characterized genomic profiles underlying responses of cancer cell lines to plant, marine and microbial compounds, highlighting potential pathways involved in reactivity to new chemotherapeutic drug candidates.
- Two studies investigated the consequences of targeting inflammatory signalling in cancer: inhibition of pyroptotic function of TGF-beta or targeting of WBP2-driven inflammatory signalling were shown to hold therapeutic potential in triple negative breast cancer.
- HDAC inhibitors, targeting aberrant protein acetylation, were shown to affect immune gene expression. Moreover, MAPK inhibitors were reported to potentially influence the tumor microenvironment through a compensatory p38 MAPK signaling activation leading to the upregulation of immunosuppressive protein CD73. Both studies indicated that targeted therapy approaches may be combined well with immunotherapies.
- Several research groups reported new molecules and metabolic pathways as potential targets in cancer. Indicatively, VprBP was identified as a histone kinase contributing to the development and progression of colon cancer. The pro-apoptotic protein SMAC/Diablo was shown to have a targetable non-canonical function, namely in the regulation of lipid synthesis in cancer. Moreover, targeting amino-acid uptake in KRAS-mutant cancer cells could inhibit tumor growth.
Zooming out to get the patient picture
Moving further away from basic research, Davide Cirillo et al. have reviewed the applications of artificial intelligence over a landscape of heterogeneously granular cancer research data, combining the results from large-scale omics studies, imaging data and healthcare registries.
Moreover, large-scale analyses have revealed actionable profiles in cancer patients:
- Exosome analyses in a primary malignant melanoma-derived cell line identified significant metabolomic differences between cancer stem cells and differentiated melanoma cells.
- Aggressive gliomas showed widespread expression of sense and antisense HOX transcripts despite DNA hypermethylation in the four HOX clusters, as a result of alternative promoter use, providing a comprehensive description of the epigenetic and transcriptional regulation of HOX gene clusters.
- Analyses of whole-genome sequences from primary and metastatic colorectal tumors for viral, phage and bacterial species have identified potential microbial risk factors.
- Targeted next generation sequencing of small-cell lung cancers from non-smokers indicated a distinct and rare disease entity of carcinomas with driver mutations that only clinically mimic SCLC.
- Gene expression profiles of breast cancer metastases suggested unique biological features of metastatic tumors depending on organ site.
- Romero et al. assessed in a prospective study with 72 non-small cell lung cancer (NSCLC) patients entering a first-line tyrosine kinase inhibitors (TKI) treatment various liquid biopsy approaches for noninvasive EGFR testing and indicated the need to systematically report mutant allele frequencies so that false-positive results are excluded. Moreover, Pasine et al. have introduced a new rapid EV-RNA test for profiling the dynamics of EGFR mutations in NSCLC patients receiving TKI.
- Comprehensive HLA benchmarking in TCGA cohorts was performed to predict the impact of HLA alleles on tumor prognosis.
- Single-cell transcriptomics of tumour-infiltrating T cells in oral squamous cell carcinoma revealed populations of exhausted CD8 T cells and regulatory CD4 T cells and identified genes potentially contributing to T-cell dysfunction.
- A pilot study verified the efficacy of multiplexed digital spatial profiling technology in metastatic breast cancer and revealed potentially relevant differences in the tumor microenvironment of racially diverse female patients.
- Whole-exome sequencing and transcriptomic data of NSCLC patients receiving immune checkpoint inhibitor (ICI) immunotherapy revealed an association of long-term ICI benefit with tumor mutational burden, somatic copy number alterations and PD-L1 expression.
Finally, in a Systematic Review, Raymond Henderson et al. stress the importance of health economics data for translating cancer research into clinical practice; while indicating that precision diagnostic testing for precision medicine approaches holds economic value for the care of patients with NSCLC, the authors recommend more robust health economics evaluation in the routine of clinical trial planning, as such analyses may further reveal a benefit of the otherwise costly precision medicine approaches.
You may access our collection of highlighted articles also here: https://febs.onlinelibrary.wiley.com/doi/toc/10.1002/(ISSN)1878-0261.2021-Highlights.
Would your own research fit well within this collection? Then we encourage you to submit your manuscript to our journal.
Cover image from Pixabay: https://pixabay.com/de/illustrations/dna-wendel-kurve-wissenschaft-869110/
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