While AACR 2019 already seems like an age away, our Cancer Models Scout team has been hard at work sourcing models for all the researchers who visited the booth with their queries. But that hasn’t stopped us from keeping an eye on the latest publications across preclinical cancer research and drug development! Check out our picks below for some of the most interesting reads this Spring:
Prioritisation of cancer therapeutic targets using CRISPR–Cas9 screens
A team from the Wellcome Trust Sanger Institute has performed genome-wide CRISPR screens for essential genes in over 300 cancer cell lines. This study identified many new therapeutic targets, such as the WRN kinase in microsatellite instable tumours across multiple cancer types.
Even better, their work has been developed into an online database: Project Score. Part of the Cancer Dependency Map at the Sanger Institute, Behan and colleagues work has been integrated with previously published genomic information about the cancer models used in the paper. This is all part of the ongoing work to systematically identify genes that cancer cells depend on for survival or proliferation, with the aim of uncovering new therapeutic targets.
High-complexity shRNA libraries and PI3 kinase inhibition in cancer: High-fidelity synthetic lethality predictions
This study describes a database of synthetic lethal combinations with the PI3K inhibitor GDC0941 in T-cell leukemia, which were identified using high-throughput RNA screening techniques and specifically focused on evaluating deregulated signal transduction (one of the “hallmarks of cancer”). The authors argue that this high-throughput approach has enabled RNAi screening to become more accurate, reducing the rates of false positives and negatives previously associated with the technique at lower volumes.
Treatment with both GDC0941 and the microtubule inhibitor vincristine resulted in synergistic killing of the leukemia cells. However, in mouse studies, while the combination prolonged survival, the mice still succumbed to CNS metastasis, as the compounds were not able to cross the blood-brain barrier, showing the importance of confirming promising cellular results in animal models.
A compendium of mutational signatures of environmental agents
A team from the University of Cambridge and King’s College London treated human stem cells with a panel of 79 known and potential carcinogenic compounds. They then performed whole-genome sequencing on the cells and looked for patterns of mutations (mutational signatures). The signatures provide insight into how carcinogens induce DNA damage, as well as the DNA repair pathways that are activated. By mapping the signatures to patterns that are observed in cancer, scientists can begin to identify environmental factors that contribute to cancer progression in addition to those previously linked to primary human tumours, such as smoking or asbestos exposure.
Barcoding reveals complex clonal behavior in patient-derived xenografts of metastatic triple negative breast cancer
A team from the Walter & Eliza Hall Institute (Melbourne, Australia) carried out a study of metastasis in triple-negative breast cancer. They investigated the heterogeneity within drug-naïve patient-derived xenograft (PDX) models and their resulting metastases, and the effect of therapeutic intervention. Their findings highlight that while many cancer cells are shed from the primary tumour, only some tumour subclones have the ability to seed and develop in metastatic sites. Further, they observed that while the PDX model responded to chemotherapy, a majority of the subclones contributed to the tumour relapse, suggesting that most clones acquired resistance following exposure to the therapy.
You can read more about the key challenges faced by industry researchers modelling metastasis in our blog post: 4 factors hindering the development of new metastasis therapies in cancer
Multiple myeloma immunoglobulin lambda translocations portend poor prognosis
As part of the CoMMPass (Clinical Outcomes in Multiple Myeloma to Personal Assessment) study, researchers from Winship Cancer Institute, Emory University, studied whole-genome sequencing information from 795 newly diagnosed myeloma patients. They found that 10% of patients harboured a DNA translocation involving the immunoglobin lambda (IgL) locus (commonly IgL-MYC translocation), and this was associated with poor disease outcomes. Currently, many of these patients are misclassified as having standard risk myeloma, as IgL translocations aren’t tested for in the clinic. Further, these patients are resistant to immunomodulatory imide drugs, such as lenalidomide, leaving this patient subgroup with no targeted therapy option.
Thanks to this research, new avenues for therapeutic targets have been opened up, and the growing rise of genome sequencing as standard for cancer patients suggests that in the future, patients with IgL translocations might be identified earlier, sparing them the side effects of ineffective treatments.
That’s all for this round-up – check back in for more Cancer Model Scout picks soon!
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