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Structural basis for the modulation of MRP2 activity by phosphorylation and drugs.
No full textMultidrug resistance-associated protein 2 (MRP2/ABCC2) is a polyspecific efflux transporter of organic anions expressed in hepatocyte canalicular membranes. MRP2 dysfunction, in Dubin-Johnson syndrome or by off-target inhibition, for example by the uricosuric drug probenecid, elevates circulating bilirubin glucuronide and is a cause of jaundice. Here, we determine the cryo-EM structure of rat Mrp2 (rMrp2) in an autoinhibited state and in complex with probenecid. The autoinhibited state exhibits an unusual conformation for this class of transporter in which the regulatory domain is folded within the transmembrane domain cavity. In vitro phosphorylation, mass spectrometry and transport assays show that phosphorylation of the regulatory domain relieves this autoinhibition and enhances rMrp2 transport activity. The in vitro data is confirmed in human hepatocyte-like cells, in which inhibition of endogenous kinases also reduces human MRP2 transport activity. The drug-bound state reveals two probenecid binding sites that suggest a dynamic interplay with autoinhibition. Mapping of the Dubin-Johnson mutations onto the rodent structure indicates that many may interfere with the transition between conformational states
Oncology-Led Early Identification of Nutritional Risk: A Pragmatic, Evidence-Based Protocol (PRONTO).
Get PDFNutritional issues, including malnutrition, low muscle mass, sarcopenia (i.e., low muscle mass and strength), and cachexia (i.e., weight loss characterized by a continuous decline in skeletal muscle mass, with or without fat loss), are commonly experienced by patients with cancer at all stages of disease. Cancer cachexia may be associated with poor nutritional status and can compromise a patient's ability to tolerate antineoplastic therapy, increase the likelihood of post-surgical complications, and impact long-term outcomes including survival, quality of life, and function. One of the primary nutritional problems these patients experience is malnutrition, of which muscle depletion represents a clinically relevant feature. There have been recent calls for nutritional screening, assessment, treatment, and monitoring as a consistent component of care for all patients diagnosed with cancer. To achieve this, there is a need for a standardized approach to enable oncologists to identify patients commencing and undergoing antineoplastic therapy who are or who may be at risk of malnutrition and/or muscle depletion. This approach should not replace existing tools used in the dietitian's role, but rather give the oncologist a simple nutritional protocol for optimization of the patient care pathway where this is needed. Given the considerable time constraints in day-to-day oncology practice, any such approach must be simple and quick to implement so that oncologists can flag individual patients for further evaluation and follow-up with appropriate members of the multidisciplinary care team. To enable the rapid and routine identification of patients with or at risk of malnutrition and/or muscle depletion, an expert panel of nutrition specialists and practicing oncologists developed the PROtocol for NuTritional risk in Oncology (PRONTO). The protocol enables the rapid identification of patients with or at risk of malnutrition and/or muscle depletion and provides guidance on next steps. The protocol is adaptable to multiple settings and countries, which makes implementation feasible by oncologists and may optimize patient outcomes. We advise the use of this protocol in countries/clinical scenarios where a specialized approach to nutrition assessment and care is not available
Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7.
No full textThe F-box and WD repeat domain containing 7 (FBXW7) tumour suppressor gene encodes a substrate-recognition subunit of Skp, cullin, F-box (SCF)-containing complexes. The tumour-suppressive role of FBXW7 is ascribed to its ability to drive ubiquitination and degradation of oncoproteins. Despite this molecular understanding, therapeutic approaches that target defective FBXW7 have not been identified. Using genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screens, focussed RNA-interference screens and whole and phospho-proteome mass spectrometry profiling in multiple FBXW7 wild-type and defective isogenic cell lines, we identified a number of FBXW7 synthetic lethal targets, including proteins involved in the response to replication fork stress and proteins involved in replication origin firing, such as cell division cycle 7-related protein kinase (CDC7) and its substrate, DNA replication complex GINS protein SLD5 (GINS4). The CDC7 synthetic lethal effect was confirmed using small-molecule inhibitors. Mechanistically, FBXW7/CDC7 synthetic lethality is dependent upon the replication factor telomere-associated protein RIF1 (RIF1), with RIF1 silencing reversing the FBXW7-selective effects of CDC7 inhibition. The delineation of FBXW7 synthetic lethal effects we describe here could serve as the starting point for subsequent drug discovery and/or development in this area
Reappraisal of prognostic factors used in the European Pediatric Soft Tissue Sarcoma Study Group RMS 2005 study for localized rhabdomyosarcoma to optimize risk stratification and generate a prognostic nomogram.
No full textBACKGROUND: The objective of this study was to investigate the role of clinical factors together with FOXO1 fusion status in patients with nonmetastatic rhabdomyosarcoma (RMS) to develop a predictive model for event-free survival and provide a rationale for risk stratification in future trials. METHODS: The authors used data from patients enrolled in the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS 2005 study (EpSSG RMS 2005; EudraCT number 2005-000217-35). The following baseline variables were considered for the multivariable model: age at diagnosis, sex, histology, primary tumor site, Intergroup Rhabdomyosarcoma Studies group, tumor size, nodal status, and FOXO1 fusion status. Main effects and significant second-order interactions of candidate predictors were included in a multiple Cox proportional hazards regression model. A nomogram was generated for predicting 5-year event-free survival (EFS) probabilities. RESULTS: The EFS and overall survival rates at 5 years were 70.9% (95% confidence interval, 68.6%-73.1%) and 81.0% (95% confidence interval, 78.9%-82.8%), respectively. The multivariable model retained five prognostic factors, including age at diagnosis interacting with tumor size, tumor primary site, Intergroup Rhabdomyosarcoma Studies clinical group, and FOXO1 fusion status. Based on each patient's total score in the nomogram, patients were stratified into four groups. The 5-year EFS rates were 94.1%, 78.4%, 65.2%, and 52.1% in the low-risk, intermediate-risk, high-risk, and very-high-risk groups, respectively, and the corresponding 5-year overall survival rates were 97.2%, 91.5%, 74.3%, and 60.8%, respectively. CONCLUSIONS: The results presented here provide the rationale to modify the EpSSG stratification, with the most significant change represented by the replacement of histology with fusion status. This classification was adopted in the new international trial launched by the EpSSG
Secretome of Cancer-Associated Fibroblasts (CAFs) Influences Drug Sensitivity in Cancer Cells.
No full textResistance is a major problem with effective cancer treatment and the stroma forms a significant portion of the tumor mass but traditional drug screens involve cancer cells alone. Cancer-associated fibroblasts (CAFs) are a major tumor stroma component and its secreted proteins may influence the function of cancer cells. The majority of secretome studies compare different cancer or CAF cell lines exclusively. Here, we present the direct characterization of the secreted protein profiles between CAFs and KRAS mutant-cancer cell lines from colorectal, lung, and pancreatic tissues using multiplexed mass spectrometry. 2573 secreted proteins were annotated, and differential analysis highlighted understudied CAF-enriched secreted proteins, including Wnt family member 5B (WNT5B), in addition to established CAF markers, such as collagens. The functional role of CAF secreted proteins was explored by assessing its effect on the response to 97 anticancer drugs since stromal cells may cause a differing cancer drug response, which may be missed on routine drug screening using cancer cells alone. CAF secreted proteins caused specific effects on each of the cancer cell lines, which highlights the complexity and challenges in cancer treatment and so the importance to consider stromal elements
Comparison of Circulating Tumor DNA Assays for Molecular Residual Disease Detection in Early-Stage Triple-Negative Breast Cancer.
No full textPURPOSE: Detection of circulating tumor DNA (ctDNA) in patients who have completed treatment for early-stage breast cancer is associated with a high risk of relapse, yet the optimal assay for ctDNA detection is unknown. EXPERIMENTAL DESIGN: The cTRAK-TN clinical trial prospectively used tumor-informed digital PCR (dPCR) assays for ctDNA molecular residual disease (MRD) detection in early-stage triple-negative breast cancer. We compared tumor-informed dPCR assays with tumor-informed personalized multimutation sequencing assays in 141 patients from cTRAK-TN. RESULTS: MRD was first detected by personalized sequencing in 47.9% of patients, 0% first detected by dPCR, and 52.1% with both assays simultaneously (P < 0.001; Fisher exact test). The median lead time from ctDNA detection to relapse was 6.1 months with personalized sequencing and 3.9 months with dPCR (P = 0.004, mixed-effects Cox model). Detection of MRD at the first time point was associated with a shorter time to relapse compared with detection at subsequent time points (median lead time 4.2 vs. 7.1 months; P = 0.02). CONCLUSIONS: Personalized multimutation sequencing assays have potential clinically important improvements in clinical outcome in the early detection of MRD
The Lancet Commission on prostate cancer: planning for the surge in cases.
No full textProstate cancer is the most common cancer in men in 112 countries, and accounts for 15% of cancers. In this Commission, we report projections of prostate cancer cases in 2040 on the basis of data for demographic changes worldwide and rising life expectancy. Our findings suggest that the number of new cases annually will rise from 1·4 million in 2020 to 2·9 million by 2040. This surge in cases cannot be prevented by lifestyle changes or public health interventions alone, and governments need to prepare strategies to deal with it. We have projected trends in the incidence of prostate cancer and related mortality (assuming no changes in treatment) in the next 10–15 years, and make recommendations on how to deal with these issues. For the Commission, we established four working groups, each of which examined a different aspect of prostate cancer: epidemiology and future projected trends in cases, the diagnostic pathway, treatment, and management of advanced disease, the main problem for most men diagnosed with prostate cancer worldwide. Throughout we have separated problems in high-income countries (HICs) from those in low-income and middle-income countries (LMICs), although we acknowledge that this distinction can be an oversimplification (some rich patients in LMICs can access high-quality care, whereas many patients in HICs, especially the USA, cannot because of inadequate insurance coverage). The burden of disease globally is already substantial, but options to improve care are already available at moderate cost. We found that late diagnosis is widespread worldwide, but especially in LMICs, where it is the norm. Early diagnosis improves prognosis and outcomes, and reduces societal and individual costs, and we recommend changes to the diagnostic pathway that can be immediately implemented. For men diagnosed with advanced disease, optimal use of available technologies, adjusted to the resource levels available, could produce improved outcomes. We also found that demographic changes (ie, changing age structures and increasing life expectancy) in LMICs will drive big increases in prostate cancer, and cases are also projected to rise in high-income countries. This projected rise in cases has driven the main thrust of our recommendations throughout. Dealing with this rise in cases will require urgent and radical interventions, particularly in LMICs, including an emphasis on education (both of health professionals and the general population) linked to outreach programmes to increase awareness. If implemented, these interventions would shift the case mix from advanced to earlier-stage disease, which in turn would necessitate different treatment approaches: earlier diagnosis would prompt a shift from palliative to curative therapies based around surgery and radiotherapy. Although age-adjusted mortality from prostate cancer is falling in HICs, it is rising in LMICs. And, despite large, well known differences in disease incidence and mortality by ethnicity (eg, incidence in men of African heritage is roughly double that in men of European heritage), most prostate cancer research has disproportionally focused on men of European heritage. Without urgent action, these trends will cause global deaths from prostate cancer to rise rapidly
Outcomes of relapsed clinical stage I versus de novo metastatic testicular cancer patients: an analysis of the IGCCCG Update database.
No full textBACKGROUND: Active surveillance after orchiectomy is the preferred management in clinical stage I (CSI) germ-cell tumours (GCT) associated with a 15 to 30% relapse rate. PATIENTS AND METHODS: In the IGCCCG Update database, we compared the outcomes of gonadal disseminated GCT relapsing from initial CSI to outcomes of patients with de novo metastatic GCT. RESULTS: A total of 1014 seminoma (Sem) [298 (29.4%) relapsed from CSI, 716 (70.6%) de novo] and 3103 non-seminoma (NSem) [626 (20.2%) relapsed from CSI, 2477 (79.8%) de novo] were identified. Among Sem, no statistically significant differences in PFS and OS were found between patients relapsing from CSI and de novo metastatic disease [5-year progression-free survival (5y-PFS) 87.6% versus 88.5%; 5-year overall survival (5y-OS) 93.2% versus 96.1%). Among NSem, PFS and OS were higher overall in relapsing CSI patients (5y-PFS 84.6% versus 80.0%; 5y-OS 93.3% versus 88.7%), but there were no differences within the same IGCCCG prognostic groups (HR = 0.89; 95% CI: 0.70-1.12). Relapses in the intermediate or poor prognostic groups occurred in 11/298 (4%) Sem and 112/626 (18%) NSem. CONCLUSION: Relapsing CSI GCT patients expect similar survival compared to de novo metastatic patients of the same ICCCCG prognostic group. Intermediate and poor prognosis relapses from initial CSI expose patients to unnecessary toxicity from more intensive treatments
NTRK gene fusion testing and management in lung cancer.
No full textNeurotrophic tyrosine receptor kinase (NTRK) gene fusions are recurrent oncogenic drivers found in a variety of solid tumours, including lung cancer. Several tropomyosin receptor kinase (TRK) inhibitors have been developed to treat tumours with NTRK gene fusions. Larotrectinib and entrectinib are first-generation TRK inhibitors that have demonstrated efficacy in patients with TRK fusion lung cancers. Genomic testing is recommended for all patients with metastatic non-small cell lung cancer for optimal drug therapy selection. Multiple testing methods can be employed to identify NTRK gene fusions in the clinic and each has its own advantages and limitations. Among these assays, RNA-based next-generation sequencing (NGS) can be considered a gold standard for detecting NTRK gene fusions; however, several alternatives with minimally acceptable sensitivity and specificity are also available in areas where widespread access to NGS is unfeasible. This review highlights the importance of testing for NTRK gene fusions in lung cancer, ideally using the gold-standard method of RNA-based NGS, the various assays that are available, and treatment algorithms for patients
Epigenetically defined therapeutic targeting in H3.3G34R/V high-grade gliomas.
No full textHigh-grade gliomas with arginine or valine substitutions of the histone H3.3 glycine-34 residue (H3.3G34R/V) carry a dismal prognosis, and current treatments, including radiotherapy and chemotherapy, are not curative. Because H3.3G34R/V mutations reprogram epigenetic modifications, we undertook a comprehensive epigenetic approach using ChIP sequencing and ChromHMM computational analysis to define therapeutic dependencies in H3.3G34R/V gliomas. Our analyses revealed a convergence of epigenetic alterations, including (i) activating epigenetic modifications on histone H3 lysine (K) residues such as H3K36 trimethylation (H3K36me3), H3K27 acetylation (H3K27ac), and H3K4 trimethylation (H3K4me3); (ii) DNA promoter hypomethylation; and (iii) redistribution of repressive histone H3K27 trimethylation (H3K27me3) to intergenic regions at the leukemia inhibitory factor (LIF) locus to drive increased LIF abundance and secretion by H3.3G34R/V cells. LIF activated signal transducer and activator of transcription 3 (STAT3) signaling in an autocrine/paracrine manner to promote survival of H3.3G34R/V glioma cells. Moreover, immunohistochemistry and single-cell RNA sequencing from H3.3G34R/V patient tumors revealed high STAT3 protein and RNA expression, respectively, in tumor cells with both inter- and intratumor heterogeneity. We targeted STAT3 using a blood-brain barrier–penetrable small-molecule inhibitor, WP1066, currently in clinical trials for adult gliomas. WP1066 treatment resulted in H3.3G34R/V tumor cell toxicity in vitro and tumor suppression in preclinical mouse models established with KNS42 cells, SJ-HGGx42-c cells, or in utero electroporation techniques. Our studies identify the LIF/STAT3 pathway as a key epigenetically driven and druggable vulnerability in H3.3G34R/V gliomas. This finding could inform development of targeted, combination therapies for these lethal brain tumors