Drugs that target intracellular signalling pathways have markedly improved progression-free survival of patients with cancers who were previously regarded as untreatable. However, the rapid emergence ...of therapeutic resistance, as a result of bypass signalling or downstream mutation within kinase-mediated signalling cascades, has curtailed the benefit gained from these therapies. Such resistance mechanisms are facilitated by the linearity and redundancy of kinase signalling pathways. We argue that, in each cancer, the dysregulation of key transcriptional regulators not only defines the cancer phenotype but is essential for its development and maintenance. Furthermore, we propose that, as therapeutic targets, these transcriptional regulators are less prone to bypass by alternative mutational events or clonal heterogeneity, and therefore we must rekindle our efforts to directly target transcriptional regulation across a broad range of cancers.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Patients with colorectal cancer with peritoneal metastases (CRPMs) have limited treatment options and the lowest colorectal cancer survival rates. We aimed to determine whether organoid testing could ...help guide precision treatment for patients with CRPMs, as the clinical utility of prospective, functional drug screening including nonstandard agents is unknown.
CRPM organoids (peritonoids) isolated from patients underwent parallel next-generation sequencing and medium-throughput drug panel testing
to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing.
Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for two patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications.
Our approach is feasible, reproducible, and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.
BACKGROUND:Currently there is no reliable test to predict pathological complete response following neoadjuvant chemoradiotherapy for rectal cancer. However, there is increasing interest in using ...clinical complete response as a surrogate marker, allowing a subset of patients with locally advanced rectal cancer to be allocated into a “watch and wait” pathway. Little is known about the oncological safety of the “watch and wait” approach or the rate of salvage surgery in cases of tumor regrowth. This information is critical for the implementation of this approach.
OBJECTIVE:The aim of this study is to assess the rate of salvage surgery and associated oncological outcomes for patients who develop a tumor regrowth with the “watch and wait” approach.
DATA SOURCES:Relevant studies were identified through PubMed, Embase, and Google Scholar search.
STUDY SELECTION:A systematic review was undertaken of studies assessing patients selected for the “watch and wait” approach according to PRISMA guidelines.
MAIN OUTCOME MEASURES:The associated tumor regrowth, salvage surgery, and disease-free and overall survival rates were assessed.
RESULTS:Five retrospective and 4 prospective observational studies were included into the analysis, with a total of 370 patients in the “watch and wait” group, of which 256 (69.2%) had persistent clinical complete response. Of those who had tumor regrowth, salvage surgery was possible in 83.8%. There was no difference in overall survival and disease-free survival between patients who received immediate surgery and the “watch and wait” group.
LIMITATIONS:The limitations of this study include its retrospective nature and small sample size. Furthermore, there is significant heterogeneity between study protocols, including the short median follow-up, given that tumor regrowth and distant metastasis may manifest at a later time point.
CONCLUSION:The majority of patients with tumor regrowth can be salvaged with definite surgery after “watch and wait.” However, there is insufficient evidence to draw firm conclusions on the oncological safety of this approach; therefore, it is currently not the standard of care for locally advanced rectal cancer.
Colorectal peritoneal metastases (CRPM) can be resistant to the chemotherapy agent (oxaliplatin) most employed, up until recently, as hyperthermic intraperitoneal chemotherapy (HIPEC). ...Glutathione-mediated inactivation of oxaliplatin can be substantially reduced by genomic deletion of the gene or pharmacological inhibition of glutamate-cysteine ligase in CRPM tumouroids. These discoveries may rekindle the enthusiasm for HIPEC in concert with cytoreductive surgery, which has been employed to manage patients with this once-nihilistic form of stage-IV disease.
RAD21 Mutations Cause a Human Cohesinopathy Deardorff, Matthew A.; Wilde, Jonathan J.; Albrecht, Melanie ...
American journal of human genetics,
06/2012, Letnik:
90, Številka:
6
Journal Article
Recenzirano
Odprti dostop
The evolutionarily conserved cohesin complex was originally described for its role in regulating sister-chromatid cohesion during mitosis and meiosis. Cohesin and its regulatory proteins have been ...implicated in several human developmental disorders, including Cornelia de Lange (CdLS) and Roberts syndromes. Here we show that human mutations in the integral cohesin structural protein RAD21 result in a congenital phenotype consistent with a “cohesinopathy.” Children with RAD21 mutations display growth retardation, minor skeletal anomalies, and facial features that overlap findings in individuals with CdLS. Notably, unlike children with mutations in NIPBL, SMC1A, or SMC3, these individuals have much milder cognitive impairment than those with classical CdLS. Mechanistically, these mutations act at the RAD21 interface with the other cohesin proteins STAG2 and SMC1A, impair cellular DNA damage response, and disrupt transcription in a zebrafish model. Our data suggest that, compared to loss-of-function mutations, dominant missense mutations result in more severe functional defects and cause worse structural and cognitive clinical findings. These results underscore the essential role of RAD21 in eukaryotes and emphasize the need for further understanding of the role of cohesin in human development.
BACKGROUND:There is increasing literature emerging on the significance of tumor-infiltrating lymphocytes in colorectal cancer. However, there have been inconsistent findings, secondary to small ...patient numbers and varied methods for identifying these lymphocytes.
OBJECTIVE:The aim of this study was to determine the prognostic and predictive power of tumor-infiltrating lymphocytes in colon, rectal (in neoadjuvant setting), and metastatic colorectal cancer.
DATA SOURCES:A comprehensive search of PubMed and Embase was undertaken from January 2006 to December 2016.
STUDY SELECTION:The inclusion criteria included a description of the tumor-infiltrating lymphocyte subset(s) assessed with reporting of associated short- and long-term outcomes.
MAIN OUTCOME MEASURES:The main outcome measures, were disease-free and overall survival.
RESULTS:A total of 25 studies were included, 15 for primary colorectal cancer (4719 patients), 7 for locally advanced rectal cancer (727 patients), and 3 studies for metastatic colorectal cancer (418 patients). High CD3, CD8, FoxP3, and CD45RO densities were associated with improved overall survival for primary colorectal cancer, with pooled estimated HRs of 0.88, 0.81, 0.70, and 0.63 (all p < 0.001) respectively. Furthermore, in locally advanced rectal cancer, the levels of CD8 cells were a significant predictor of good tumor regression grade after chemoradiotherapy.
LIMITATIONS:The retrospective nature of included studies and the significant interstudy heterogeneity were limitations.
CONCLUSIONS:There is increasing evidence that tumor-infiltrating lymphocytes play an important role in predicting prognosis in colorectal cancer and tumor regression after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Clinical researchers are now in a unique position to build on this work to identify robust predictive markers to stratify patients not only to currently available therapies but also to immunotherapy, which has demonstrated success in improving patient outcomes.
Conflicting results regarding the impact of repeated vaccination on influenza vaccine effectiveness (VE) may cause confusion regarding the benefits of receiving the current season's vaccine.
We ...systematically searched MEDLINE, Embase, PubMed, and Cumulative Index to Nursing and Allied Health Literature from database inception to August 17, 2016, for observational studies published in English that reported VE against laboratory-confirmed influenza for the following four vaccination groups: current season only, prior season only, both seasons, and neither season. We pooled differences in VE (∆VE) between vaccination groups by influenza season and type/subtype using a random-effects model. The study protocol is registered with PROSPERO (registration number: CRD42016037241).
We identified 3435 unique articles, reviewed the full text of 634, and included 20 for meta-analysis. Compared to prior season vaccination only, vaccination in both seasons was associated with greater protection against influenza H1N1 (∆VE = 25%; 95% CI 14%, 35%) and B (∆VE = 18%; 95% CI 3%, 33%), but not H3N2 (∆VE = 7%; 95% CI - 7%, 21%). Compared to no vaccination for either season, individuals who received the current season's vaccine had greater protection against H1N1 (∆VE = 62%; 95% CI 51%, 70%), H3N2 (∆VE = 45%; 95% CI 35%, 53%), and B (∆VE = 64%; 95% CI 57%, 71%). We observed no differences in VE between vaccination in both seasons and the current season only for H1N1 (∆VE = 3%; 95% CI - 8%, 13%), but less protection against influenza H3N2 (∆VE = - 20%; 95% CI - 36%, - 4%), and B (∆VE = - 11%; 95% CI - 20%, - 2%).
Our results support current season vaccination regardless of prior season vaccination because VE for vaccination in the current season only is higher compared to no vaccination in either season for all types/subtypes, and for H1N1 and influenza B, vaccination in both seasons provides better VE than vaccination in the prior season only. Although VE was lower against H3N2 and B for individuals vaccinated in both seasons compared to those vaccinated in the current season only, it should be noted that past vaccination history cannot be altered and this comparison disregards susceptibility to influenza during the prior season among those vaccinated in the current season only. In addition, our results for H3N2 were particularly influenced by the 2014-2015 influenza season and the impact of repeated vaccination for all types/subtypes may vary from season to season. It is important that future VE studies include vaccination history over multiple seasons to evaluate repeated vaccination in more detail.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control of ...metastatic B16F10 tumor growth relative to control mice. Analyses of this interplay in human tumor samples reveal that high expression of a MAIT cell gene signature negatively impacts the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or activating MAIT cells in vivo, enhances anti-tumor immunity in B16F10 and E0771 mouse tumor models, including in the context of established metastasis. These effects are associated with enhanced NK cell responses and increased expression of both IFN-γ-dependent and inflammatory genes in NK cells. Importantly, activated human MAIT cells also promote the function of NK cells isolated from patient tumor samples. Our results thus describe an activation-dependent, MAIT cell-mediated regulation of NK cells, and suggest a potential therapeutic avenue for cancer treatment.
Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind ...acetylated chromatin marks. Early clinical trials have shown promise, especially in acute myeloid leukaemia, and therefore the evaluation of resistance mechanisms is crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increased Wnt/β-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Anal squamous cell carcinoma is a human papillomavirus-related disease, in which no substantial advances in treatment have been made in over 40 years, especially for those patients who ...develop disease relapse and for whom no surgical options exist. HPV can evade the immune system and its role in disease progression can be exploited in novel immunotherapy platforms. Although several studies have investigated the expression and inactivation (through loss of heterozygosity) of tumour suppressor genes in the pathways to cancer, no clinically valuable biomarkers have emerged. Regulators of apoptosis, including survivin, and agents targeting the PI3K/AKT pathway, offer opportunities for targeted therapy, although robust data are scarce. Additionally, antibody therapy targeting EGFR may prove effective, although its safety profile in combination with standard chemoradiotherapy has proven to be suboptimal. Finally, progress in the treatment of anal cancer has remained stagnant due to a lack of preclinical models, including cell lines and mouse models. In this Review, we discuss the molecular biology of anal squamous cell carcinoma, clinical trials in progress, and implications for novel therapeutic targets. Future work should focus on preclinical models to provide a resource for investigation of new molecular pathways and for testing novel targets.
PDF
