Hypoxia: The Cornerstone of Glioblastoma Domènech, Marta; Hernández, Ainhoa; Plaja, Andrea ...
International journal of molecular sciences,
11/2021, Letnik:
22, Številka:
22
Journal Article
Recenzirano
Odprti dostop
Glioblastoma is the most aggressive form of brain tumor in adults and is characterized by the presence of hypervascularization and necrosis, both caused by a hypoxic microenvironment. In this review, ...we highlight that hypoxia-induced factor 1 (HIF-1), the main factor activated by hypoxia, is an important driver of tumor progression in GB patients. HIF-1α is a transcription factor regulated by the presence or absence of O
. The expression of HIF-1 has been related to high-grade gliomas and aggressive tumor behavior. HIF-1 promotes tumor progression via the activation of angiogenesis, immunosuppression, and metabolic reprogramming, promoting cell invasion and survival. Moreover, in GB, HIF-1 is not solely modulated by oxygen but also by oncogenic signaling pathways, such as MAPK/ERK, p53, and PI3K/PTEN. Therefore, the inhibition of the hypoxia pathway could represent an important treatment alternative in a disease with very few therapy options. Here, we review the roles of HIF-1 in GB progression and the inhibitors that have been studied thus far, with the aim of shedding light on this devastating disease.
Small-cell lung cancer (SCLC) is an aggressive malignancy characterized by a rapid progression and a high resistance to treatments. Unlike other solid tumors, there has been a scarce improvement in ...emerging treatments and survival during the last years. A better understanding of SCLC biology has allowed for the establishment of a molecular classification based on four transcription factors, and certain therapeutic vulnerabilities have been proposed. The universal inactivation of
and
, along with the absence of mutations in known targetable oncogenes, has hampered the development of targeted therapies. On the other hand, the immunosuppressive microenvironment makes the success of immune checkpoint inhibitors (ICIs), which have achieved a modest improvement in overall survival in patients with extensive disease, difficult. Currently, atezolizumab or durvalumab, in combination with platinum-etoposide chemotherapy, is the standard of care in first-line setting. However, the magnitude of the benefit is scarce and no predictive biomarkers of response have yet been established. In this review, we describe SCLC biology and molecular classification, examine the SCLC tumor microenvironment and the challenges of predictive biomarkers of response to new treatments, and, finally, assess clinical and molecular characteristics of long-term survivor patients in order to identify possible prognostic factors and treatment vulnerabilities.
Patients with solid tumors have been a risk group since the beginning of the SARS‐CoV‐2 pandemic due to more significant complications, hospitalizations or deaths. The immunosuppressive state of ...cancer treatments or the tumor itself could influence the development of post‐vaccination antibodies. This study prospectively analyzed 89 patients under chemotherapy and/or immunotherapy, who received two doses of the mRNA‐1237 vaccine, and were compared with a group of 26 non‐cancer individuals. Information on adverse events and neutralizing antibodies against the ancestral strain of SARS‐CoV‐2 (WH1) have been analyzed. Local reactions accounted for 65%, while systemic reactions accounted for 46% of oncologic individuals/cancer patients. Regarding the response to vaccination, 6.7% of cancer patients developed low neutralizing antibody levels. Lower levels of neutralizing antibodies between cancer and non‐cancer groups were significant in individuals without previous SARS‐CoV‐2 infection, but not in previously infected individuals. We also observed that patients receiving chemotherapy or chemoimmunotherapy have significantly lower levels of neutralizing antibodies than non‐cancer individuals. In conclusion, our study confirms the importance of prioritizing cancer patients receiving anticancer treatment in SARS‐CoV‐2 vaccination programs.
Cancer patients are a risk group for SARS‐CoV‐2 infection. We determined the levels of anti‐SARS‐CoV‐2 plasma neutralizing antibodies post mRNA‐1273 vaccination and observed that cancer patients exhibit lower titers compared to non‐cancer individuals, particularly in individuals not previously infected by SARS‐CoV‐2. Additionally, we found an association between low levels of neutralizing antibodies and chemotherapy‐containing treatments, highlighting their prioritization in SARS‐CoV‐2 vaccination programs.
Glioblastoma (GBM) is the most aggressive brain tumor in adults and is characterized by an immunosuppressive microenvironment. Different factors shaping this tumor microenvironment (TME) regulate ...tumor initiation, progression, and treatment response. Genetic alterations and metabolism pathways are two main elements that influence tumor immune cells and TME. In this manuscript, we review how both factors can contribute to an immunosuppressive state and overview the strategies being tested.
Phosphorus (P) is an essential element for plant growth and development. Finding new P sources and ways to improve crop P utilization are necessary due to the depletion of phosphate reserves. Five ...crop species, buckwheat (Fagopyrum esculentum L.), maize (Zea mays L.), oilseed rape (Brassica napus L. ssp. oleifera (Moench) Metzg.), spelt wheat (Triticum spelta L.), and white lupine (Lupinus albus L.), were grown in pots containing sandy soil with chemical nutrients, digestate, and meat bone meal (MBM) without added nutrients. Thirty days after the seeding plants were harvested, the growth stage, soil-plant analysis development (SPAD) value, biomass, P content of the plants, colonization of the roots with endomycorrhiza, and soil pH were analyzed, and the number of fungal spores in the soil was counted. All species showed interaction with the P sources for measured traits, except for the rhizosphere pH. A high biomass was recorded in all species fertilized with various P sources compared to the unfertilized treatment. Buckwheat and spelt wheat showed a higher P uptake with MBM, and the mycorrhizal symbiosis improved with digestate or MBM compared to synthetic P. The results indicate that different species have adaptative mechanisms to various P sources which could improve the resilience and sustainability of cropping systems.
Gliomas are a heterogenous group of central nervous system tumors with different outcomes and different therapeutic needs. Glioblastoma, the most common subtype in adults, has a very poor prognosis ...and disabling consequences. The World Health Organization (WHO) classification specifies that the typing and grading of gliomas should include molecular markers. The molecular characterization of gliomas has implications for prognosis, treatment planning, and prediction of treatment response. At present, gliomas are diagnosed via tumor resection or biopsy, which are always invasive and frequently risky methods. In recent years, however, substantial advances have been made in developing different methods for the molecular characterization of tumors through the analysis of products shed in body fluids. Known as liquid biopsies, these analyses can potentially provide diagnostic and prognostic information, guidance on choice of treatment, and real-time information on tumor status. In addition, magnetic resonance imaging (MRI) is another good source of tumor data; radiomics and radiogenomics can link the imaging phenotypes to gene expression patterns and provide insights to tumor biology and underlying molecular signatures. Machine and deep learning and computational techniques can also use quantitative imaging features to non-invasively detect genetic mutations. The key molecular information obtained with liquid biopsies and radiogenomics can be useful not only in the diagnosis of gliomas but can also help predict response to specific treatments and provide guidelines for personalized medicine. In this article, we review the available data on the molecular characterization of gliomas using the non-invasive methods of liquid biopsy and MRI and suggest that these tools could be used in the future for the preoperative diagnosis of gliomas.
Approximately 20% of lung adenocarcinomas harbor activating mutations at
KRAS
, an oncogene with the ability to alter the tumor immune microenvironment. In this retrospective study, we examined 103 ...patients with
KRAS
-mutant lung adenocarcinoma who were treated with immunotherapy-based regimens and we evaluated the clinical outcomes according to PD-L1 expression and the type of
KRAS
mutation. Among all patients included, 47% carried
KRAS G12C
mutation whereas 53% harbored
KRAS
non-G12C mutations. PD-L1 status was available for 77% of cases, with higher expression among KRAS G12C tumors (p = 0.01). Better overall survival and progression-free survival were observed in high PD-L1 expression tumors, regardless of
KRAS
mutation type. The heterogeneous nature of KRAS-mutant tumors and the presence of other co-mutations may contribute to different outcomes to immunotherapy-based strategies.
There is a lack of useful diagnostic tools to identify EGFR mutated NSCLC patients with long-term survival. This study develops a prognostic model using real world data to assist clinicians to ...predict survival beyond 24 months.
EGFR mutated stage IIIB and IV NSCLC patients diagnosed between January 2009 and December 2017 included in the Spanish Lung Cancer Group (SLCG) thoracic tumor registry. Long-term survival was defined as being alive 24 months after diagnosis. A multivariable prognostic model was carried out using binary logistic regression and internal validation through bootstrapping. A nomogram was developed to facilitate the interpretation and applicability of the model.
505 of the 961 EGFR mutated patients identified in the registry were included, with a median survival of 27.73 months. Factors associated with overall survival longer than 24 months were: being a woman (OR 1.78); absence of the exon 20 insertion mutation (OR 2.77); functional status (ECOG 0-1) (OR 4.92); absence of central nervous system metastases (OR 2.22), absence of liver metastases (OR 1.90) or adrenal involvement (OR 2.35) and low number of metastatic sites (OR 1.22). The model had a good internal validation with a calibration slope equal to 0.781 and discrimination (optimism corrected C-index 0.680).
Survival greater than 24 months can be predicted from six pre-treatment clinicopathological variables. The model has a good discrimination ability. We hypothesized that this model could help the selection of the best treatment sequence in EGFR mutation NSCLC patients.
Virtually all glioblastomas treated in the first-line setting will recur in a short period of time, and the search for alternative effective treatments has so far been unsuccessful. Various obstacles ...remain unresolved, and no effective salvage therapy for recurrent glioblastoma can be envisaged in the short term. One of the main impediments to progress is the low incidence of the disease itself in comparison with other pathologies, which will be made even lower by the recent WHO classification of gliomas, which includes molecular alterations. This new classification helps refine patient prognosis but does not clarify the most appropriate treatment. Other impediments are related to clinical trials: glioblastoma patients are often excluded from trials due to their advanced age and limiting neurological symptoms; there is also the question of how best to measure treatment efficacy, which conditions the design of trials and can affect the acceptance of results by oncologists and medicine agencies. Other obstacles are related to the drugs themselves: most treatments cannot cross the blood-brain-barrier or the brain-to-tumor barrier to reach therapeutic drug levels in the tumor without producing toxicity; the drugs under study may have adverse metabolic interactions with those required for symptom control; identifying the target of the drug can be a complex issue. Additionally, the optimal method of treatment - local vs systemic therapy, the choice of chemotherapy, irradiation, targeted therapy, immunotherapy, or a combination thereof - is not yet clear in glioblastoma in comparison with other cancers. Finally, in addition to curing or stabilizing the disease, glioblastoma therapy should aim at maintaining the neurological status of the patients to enable them to return to their previous lifestyle. Here we review currently available treatments, obstacles in the search for new treatments, and novel lines of research that show promise for the future.
Abstract
RNA-Sequencing (RNA-Seq) can identify gene fusions in tumors, but not all these fusions have functional consequences. Using multiple data bases, we have performed an in silico analysis of ...fusions detected by RNA-Seq in tumor samples from 139 newly diagnosed glioblastoma patients to identify in-frame fusions with predictable oncogenic potential. Among 61 samples with fusions, there were 103 different fusions, involving 167 different genes, including 20 known oncogenes or tumor suppressor genes (TSGs), 16 associated with cancer but not oncogenes or TSGs, and 32 not associated with cancer but previously shown to be involved in fusions in gliomas. After selecting in-frame fusions able to produce a protein product and running Oncofuse, we identified 30 fusions with predictable oncogenic potential and classified them into four non-overlapping categories: six previously described in cancer; six involving an oncogene or TSG; four predicted by Oncofuse to have oncogenic potential; and 14 other in-frame fusions. Only 24 patients harbored one or more of these 30 fusions, and only two fusions were present in more than one patient:
FGFR3::TACC3
and
EGFR::SEPTIN14
. This in silico study provides a good starting point for the identification of gene fusions with functional consequences in the pathogenesis or treatment of glioblastoma.
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