Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T ...cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis–specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.
In BRAF(V600)-mutant tumours, most mechanisms of resistance to drugs that target the BRAF and/or MEK kinases rely on reactivation of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal ...transduction pathway, on activation of the alternative, PI(3)K-AKT-mTOR, pathway (which is ERK independent) or on modulation of the caspase-dependent apoptotic cascade. All three pathways converge to regulate the formation of the eIF4F eukaryotic translation initiation complex, which binds to the 7-methylguanylate cap (m(7)G) at the 5' end of messenger RNA, thereby modulating the translation of specific mRNAs. Here we show that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, is associated with resistance to anti-BRAF, anti-MEK and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with one of three mechanisms: reactivation of MAPK signalling, persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 or increased pro-apoptotic BCL-2-modifying factor (BMF)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions shows that eIF4F complex formation is decreased in tumours that respond to anti-BRAF therapy and increased in resistant metastases compared to tumours before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergizes with inhibiting BRAF(V600) to kill the cancer cells. eIF4F not only appears to be an indicator of both innate and acquired resistance but also is a promising therapeutic target. Combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms arising in BRAF(V600)-mutant cancers.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Patients treated with systemic anticancer drugs often show changes to their nails, which are usually well tolerated and disappear on cessation of treatment. However, some nail toxicities can ...cause pain and functional impairment and thus substantially affect a patient's quality of life, especially if they are given taxanes or EGFR inhibitors. These nail toxicities can affect both the nail plate and bed, and might present as melanonychia, leukonychia, onycholysis, onychomadesis, Beau's lines, or onychorrhexis, as frequently noted with conventional chemotherapies. Additionally, the periungual area (perionychium) of the nail might be affected by paronychia or pyogenic granuloma, especially in patients treated with drugs targeting EGFR or MEK. We review the nail changes induced by conventional chemotherapies and those associated with the use of targeted anticancer drugs and discuss preventive or curative options.
Background The multikinase inhibitor sorafenib (Nexavar) is associated with a relatively high incidence of dermatologic symptoms. Objective We sought to evaluate and provide guidance on the diagnosis ...and clinical management of dermatologic symptoms associated with sorafenib in patients with advanced solid tumors. Methods English-language studies representative of a patient population with a variety of tumor types, who received single-agent sorafenib, were selected. Particular emphasis was placed on the phase III Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGETs). Results Frequently observed dermatologic side effects (any grade in TARGETs) of sorafenib include rash/desquamation (40%), hand–foot skin reaction (30%), alopecia (27%), and pruritus (19%). Generally, dermatologic symptoms resolve with appropriate management, including topical treatments, dose interruptions, dose reductions, or a combination of these. Limitations The results presented here are based on a limited number of studies. Conclusion Although sorafenib is associated with dermatologic symptoms, these are usually resolved with appropriate intervention, patient-led practical treatment, and preventative measures.
Treatment of BRAF(V600E) mutant melanoma by small molecule drugs that target the BRAF or MEK kinases can be effective, but resistance develops invariably. In contrast, colon cancers that harbour the ...same BRAF(V600E) mutation are intrinsically resistant to BRAF inhibitors, due to feedback activation of the epidermal growth factor receptor (EGFR). Here we show that 6 out of 16 melanoma tumours analysed acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Using a chromatin-regulator-focused short hairpin RNA (shRNA) library, we find that suppression of sex determining region Y-box 10 (SOX10) in melanoma causes activation of TGF-β signalling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-β (PDGFRB), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-β results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-β becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells having varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug, but this is reversed when the drug treatment is discontinued. We find evidence for SOX10 loss and/or activation of TGF-β signalling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Our findings provide a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identify patients with EGFR-positive melanoma as a group that may benefit from re-treatment after a drug holiday.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Management of patients with metastatic melanoma has improved radically in recent years with the development of new drugs capable of signifcantly prolonging life expectancy. Two strategies have been ...implemented: targeted anti-BRAF therapy for BRAF-mutated melanomas, and non specific immunotherapies based on anti-CTLA-4 (ipilimumab) and, more recently, anti-PD-1 monoclonal antibodies. These antibodies, by blocking physiological brakes on immune activation, induce an indirect immune response. Ipilimumab, a drug approved in 2011 is of benefit to 20 % of patients but can also trigger significant immune-mediated toxicity. Anti-PD-1 antibodies presently in development seem to have a better therapeutic index, with higher response rates and less toxicity than ipilimumab. Combination therapy with anti-CTLA-4 and anti-PD-1 v is also giving encouraging preliminary results. In future, these new drugs will probably be used in combination, either concurrently or sequentially.
Sarcoid-like granulomatosis (SLG) reaction caused by immunotherapy remains poorly understood. This study aims to investigate the outcome of patients with cancer and SLG associated with immunotherapy.
...Between April 2016 and June 2020, 434 patients with immunological adverse events were screened from the ImmunoTOX assessment board of Gustave Roussy, an academic cancer centre in France. Among them, 28 patients had SLG associated with immunotherapy (SLG cohort) and 406 patients had other immunological adverse events (control cohort). Clinical characteristics and outcome of patients were compared from SLG and control cohort.
The SLG cohort consisted of 28 patients, 14 women and 14 men, with the median (range) age of 56.5 (28.7–75.3) years. Patients in the SLG cohort with sarcoidosis were asymptomatic (only radiographical finding) in 13 (46.4%) cases; otherwise, the most frequent symptoms were dyspnoea in 8 (28.6%) patients and cough in 5 (17.8%) patients. The computerised tomography scan found sarcoidosis localisations in mediastinal or peri-hilar thoracic lymph nodes in 26 (92.9%) patients, and lung parenchymal involvement was found in 14 (50.0%) patients. The radiographic Scadding stages for sarcoidosis classification were distributed in stages 0, I, II, III and IV in 2 patients (7.1%), 13 patients (46.4%), 11 patients (39.3%), 1 patient (3.6%) and 1 patient (3.6%), respectively. Compared with patients with other immunological toxicities (cohort control), patients with sarcoidosis presented most frequently with melanoma (75.0% versus 21.9% of patients; p < 0.001) and more often received combined therapies of anti–programmed cell death 1 plus anti–cytotoxic T-lymphocyte antigen 4 protein (46.4% versus 12.6% of patients; p = 0.002). Patients with sarcoidosis had an improved overall survival (OS); the median OS was not reached in the SLG cohort and 40.4 months in the control cohort, hazard ratio = 0.232 (95% confidence interval: 0.086–0.630) (p = 0.002).
Sarcoidosis-like reactions in patients receiving immunotherapy were reported as non-severe immunological reactions in most cases and were correlated with improved OS. SLG should not be misdiagnosed as tumour progression in patients receiving immunotherapy treatment for cancer.
•Sarcoidosis associated with immunotherapy correlated with improved overall survival.•Sarcoidosis associated with anticancer immunotherapy was generally of mild severity.•Sarcoidosis seems more related to the combination of anti–programmed cell death 1 plus anti–cytotoxic T-lymphocyte antigen 4 protein.
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