Abstract
Colorectal cancer (CRC) reflects the fourth most frequent etiology of brain metastasis (BM). Yet, molecular mechanisms supporting it are unknown. We aimed to explore drivers enabling ...adaptation of CRC cells to the brain and decipher mechanisms facilitating the process.
We analyzed the FoundationOne database, which contains genomic alterations data of cancer-related genes in over 16,000 human CRC primary and metastasis samples. Increased prevalence of IRS2 gene amplification was observed in 13% of BM, compared to only 3% of primary tumors or other metastatic sites. IRS2 is a cytoplasmic adaptor mediating effects of insulin and IGF-1 receptors and is involved in more aggressive behavior of different cancer types. In agreement with the genomic data, immunohistochemistry of human clinical samples showed increased expression of IRS2 protein in BM. We constructed an in-vitro system mimicking the brain microenvironment using cultured human astrocytes or their conditioned media. Under these conditions, IRS2-overexpressed CRC cells survived better and formed larger 3D spheres. IRS2-silenced CRC cells showed a mirror image. Moreover, in an intracranial CRC BM mouse model, IRS2-overexpressed cells generated larger brain lesions, while silencing IRS2 dramatically decreased tumor outgrowth and extended survival. Interestingly, transcriptomic analysis revealed enrichment of oxidative phosphorylation (OXPHOS) and Wnt/β-catenin pathways by IRS2. Indeed, IRS2-expressing cells showed increased mitochondrial activity and glycolysis-independent viability. Furthermore, IRS2-expressing cells had increased β-catenin transcriptional activity. Interestingly, β-catenin or IRS2 inhibition (using NT219) in IRS2-expressing cells decreased their viability, β-catenin transcriptional activity, and OXPHOS gene expression, suggesting involvement of IRS2 in modulating OXPHOS through β-catenin. β-catenin is known to confer 5-FU resistance; consequently, we showed that combination of 5-FU and NT219 worked in synergy, inhibited the formation of BM, and extended animal survival.
These data reveal the unique genomic profile of CRC BM and suggest IRS2 inhibition as a novel target for treatment of these patients.
Most stars generate winds and move through the interstellar medium that surrounds them. This movement creates a cocoon formed by the deflection of these winds that envelops and protects the stars. We ...call these “cocoons” astrospheres. The Sun has its own cocoon, the heliosphere. The heliosphere is an immense shield that protects the Solar System from harsh, galactic radiation. The radiation that enters the heliosphere affects life on Earth as well as human space exploration. Galactic cosmic rays are the dominant source of radiation and principal hazard affecting space missions within our Solar System. Current global heliosphere models do not successfully predict the radiation environment at all locations or under different solar conditions. To understand the heliosphere’s shielding properties, we need to understand its structure and large-scale dynamics. A fortunate confluence of missions has provided the scientific community with a treasury of heliospheric data. However, fundamental features remain unknown. The vision of the Solar wind with Hydrogen Ion charge Exchange and Large-Scale Dynamics (SHIELD) DRIVE Science Center is to understand the nature and structure of the heliosphere. Through four integrated research thrusts leading to the global model, SHIELD will: 1) determine the global nature of the heliosphere
;
2) determine how pickup ions evolve from “cradle to grave” and affect heliospheric processes; 3) establish how the heliosphere interacts with and influences the Local Interstellar Medium (LISM); and 4) establish how cosmic rays are filtered by and transported through the heliosphere. The key deliverable is a comprehensive, self-consistent, global model of the heliosphere that explains data from all relevant
in situ
and remote observations and predicts the radiation environment. SHIELD will develop a “digital twin” of the heliosphere capable of: (a) predicting how changing solar and LISM conditions affect life on Earth, (b) understanding the radiation environment to support long-duration space travel, and (c) contributing toward finding life elsewhere in the Galaxy. SHIELD also will train the next-generation of heliophysicists, a diverse community fluent in team science and skilled working in highly transdisciplinary collaborative environments.
Introduction: V600E BRAF mutation is an established driver mutation in a variety of tumors. Vemurafenib is a selective inhibitor of the BRAF V600E kinase, known to be highly effective in BRAF ...V600E-positive metastatic melanoma. As a single agent, vemurafenib is relatively ineffective in other V600E-positive malignancies.
Case 1: A 72 year old man with metastatic CRC who failed several previous lines of chemotherapy. Genetic analysis of 315 cancer-related genes (Foundation Medicine, FMI) revealed a BRAF V600E mutation. The patient was treated with vemurafenib resulting in a partial response of 18 months. Genetic analysis following development of resistance revealed a new mutation in KRAS-G12R.
Case 2: V600E mutation was identified in a 59 year old woman with metastatic PTC refractory to radioiodine therapy. The patient was treated with vemurafenib resulting in a partial response lasting 43 months. Genetic analysis following development of resistance revealed a new mutation in NRAS-Q61K.
The presented cases demonstrated the development of rare RAS mutations as a genetic mechanism of acquired BRAF inhibitor resistance. This observation is strongly supported by the analysis of a large database consisting of 712 BRAF V600E-positive melanoma samples showing higher rates of BRAF V600E and RAS mutations co-occurrence in metastatic lesions compared to local tumors (OR = 3.8, p = 0.035). This enrichment is likely a result of the development of RAS mutations following treatment with BRAF inhibitors.
Discussion: We report two cases showing extreme response to vemurafenib, which could not be predicted prior to treatment commencement. Genetic testing demonstrated a resistant mechanism not previously reported in CRC or PTC patients, namely an acquired mutation of RAS. This is supported by an analysis of a large cohort of BRAF V600E-positive melanomas.
Further studies are needed in order to identify predictive markers for response to vemurafenib and to explore novel strategies to overcome RAS-mediated resistance.
Immunotherapy has recently been incorporated into the treatment guidelines for metastatic urothelial carcinoma. Nevertheless, the role of prognostic and predictive biomarkers in this setting is not ...completely defined. To date, PD-L1 expression and a high tumour mutational burden (TMB) seem to predict better responses to immune checkpoint inhibitors, but patients without these biomarkers may still respond to immunotherapy. There are some caveats regarding these biomarkers, such as lack of standardisation of techniques, tumour heterogeneity and other factors influencing the tumour microenvironment. Genomic signatures are other promising emerging strategies. We hereby discuss the management of a 70-year-old man with a metastatic recurrence of urothelial carcinoma within 1 year after neoadjuvant chemotherapy and radical cystectomy. Tumour next-generation sequencing showed a high TMB and a CD274 (PD-L1) amplification. The patient was treated with pembrolizumab and achieved a complete response.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
PDF
