Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancerMout, Lisanne; Moll, Jan M.; Chen, Mingqing; de Morrée, Eleonora S.; de Ridder, Corrina M. A.; Gibson, Alice; Stuurman, Debra; Aghai, Ashraf; Erkens-Schulze, Sigrun; Mathijssen, Ron H. J.; Sparreboom, Alex; de Wit, Ronald; Lolkema, Martijn P.; van Weerden, Wytske M.
doi: 10.1038/s41416-020-01105-ypmid: 32989230
Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.
First-in-human Phase 1 open label study of the BET inhibitor ODM-207 in patients with selected solid tumoursAmeratunga, Malaka; Braña, Irene; Bono, Petri; Postel-Vinay, Sophie; Plummer, Ruth; Aspegren, John; Korjamo, Timo; Snapir, Amir; de Bono, Johann S
doi: 10.1038/s41416-020-01077-zpmid: 32989226
BackgroundBromodomain and extra-terminal domain (BET) proteins are reported to be epigenetic anti-cancer drug targets. This first-in-human study evaluated the safety, pharmacokinetics and preliminary anti-tumour activity of the BET inhibitor ODM-207 in patients with selected solid tumours.MethodsThis was an open-label Phase 1 study comprised of a dose escalation part, and evaluation of the effect of food on pharmacokinetics. ODM-207 was administered orally once daily. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design.ResultsThirty-five patients were treated with ODM-207, of whom 12 (34%) had castrate-resistant prostate cancer. One dose-limiting toxicity of intolerable fatigue was observed. The highest studied dose achieved was 2 mg/kg due to cumulative toxicity observed beyond the dose-limiting toxicity (DLT) treatment window. Common AEs included thrombocytopenia, asthenia, nausea, anorexia, diarrhoea, fatigue, and vomiting. Platelet count decreased proportionally to exposure with rapid recovery upon treatment discontinuation. No partial or complete responses were observed.ConclusionsODM-207 shows increasing exposure in dose escalation and was safe at doses up to 2 mg/kg but had a narrow therapeutic window.Clinical trial registrationThe clinical trial registration number is NCT03035591.
CB11, a novel purine-based PPARɣ ligand, overcomes radio-resistance by regulating ATM signalling and EMT in human non-small-cell lung cancer cellsKim, Tae Woo; Hong, Da-Won; Park, Joung Whan; Hong, Sung Hee
doi: 10.1038/s41416-020-01088-wpmid: 32958825
BackgroundPeroxisome proliferator-activated receptor γ (PPARγ) agonists frequently induce cell death in human non-small-cell lung cancer (NSCLC) cells. However, majority of NSCLC patients acquire resistance after cancer therapy, and it is still unclear.MethodsIn this study we investigated the apoptotic mechanism and the anti-cancer effects of a novel purine-based PPARγ agonist, CB11 (8-(2-aminophenyl)-3-butyl-1,6,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), on human NSCLC cells. CB11 mediates PPARγ-dependent cell death, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) collapse, cell cycle arrest, lactate dehydrogenase (LDH) cytotoxicity, and caspase-3 activity in human NSCLC cells.ResultsCB11 causes cell death via ROS-mediated ATM-p53-GADD45α signalling in human NSCLC cells, and diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, decreases cell death by inhibiting CB11-mediated ATM signalling. In a xenograft experiment, CB11 dramatically reduced tumour volume when compared to a control group. Furthermore, CB11 induced cell death by inhibiting epithelial-to-mesenchymal transition (EMT) under radiation exposure in radiation-resistant human NSCLC cells. However, PPARγ deficiency inhibited cell death by blocking the ATM-p53 axis in radiation/CB11-induced radiation-resistant human NSCLC cells.ConclusionsTaken together, our results suggest that CB11, a novel PPARγ agonist, may be a novel anti-cancer agent, and it could be useful in a therapeutic strategy to overcome radio-resistance in radiation-exposed NSCLC.
CRISPR/Cas9 genome-wide loss-of-function screening identifies druggable cellular factors involved in sunitinib resistance in renal cell carcinomaMakhov, Peter; Sohn, Ji A.; Serebriiskii, Ilya G.; Fazliyeva, Rushaniya; Khazak, Vladimir; Boumber, Yanis; Uzzo, Robert G.; Kolenko, Vladimir M.
doi: 10.1038/s41416-020-01087-xpmid: 32968206
BackgroundMulti-targeted tyrosine kinase inhibitors (TKIs) are the standard of care for patients with advanced clear cell renal cell carcinoma (ccRCC). However, a significant number of ccRCC patients are primarily refractory to targeted therapeutics, showing neither disease stabilisation nor clinical benefits.MethodsWe used CRISPR/Cas9-based high-throughput loss of function (LOF) screening to identify cellular factors involved in the resistance to sunitinib. Next, we validated druggable molecular factors that are synthetically lethal with sunitinib treatment using cell and animal models of ccRCC.ResultsOur screening identified farnesyltransferase among the top hits contributing to sunitinib resistance in ccRCC. Combined treatment with farnesyltransferase inhibitor lonafarnib potently augmented the anti-tumour efficacy of sunitinib both in vitro and in vivo.ConclusionCRISPR/Cas9 LOF screening presents a promising approach to identify and target cellular factors involved in the resistance to anti-cancer therapeutics.
Development of a non-invasive exhaled breath test for the diagnosis of head and neck cancerDharmawardana, Nuwan; Goddard, Thomas; Woods, Charmaine; Watson, David I.; Ooi, Eng H.; Yazbeck, Roger
doi: 10.1038/s41416-020-01051-9pmid: 32901136
BackgroundImproving the ability to identify early-stage head and neck squamous cell carcinoma (HNSCC) can improve treatment outcomes and patient morbidity. We sought to determine the diagnostic accuracy of breath analysis as a non-invasive test for detecting HNSCC.MethodsStandardised breath samples were collected from 181 patients suspected of HNSCC prior to any treatment. A selected ion flow-tube mass spectrometer was used to analyse breath for volatile organic compounds. Diagnosis was confirmed by histopathology. A binomial logistic regression model was used to differentiate breath profiles between cancer and control (benign disease) patients based on mass spectrometry derived variables.ResultsIn all, 66% of participants had early-stage primary tumours (T1 and T2) and 58% had regional node metastasis. The optimised logistic regression model using three variables had a sensitivity and specificity of 80% and 86%, respectively, with an AUC for ROC curve of 0.821 (95%CI 0.625–1.0) in the testing cohort.ConclusionsBreath analysis for non-invasive diagnosis of HNSCC appears to be practical and accurate. Future studies should be conducted in a primary care setting to determine the applicability of breath analysis for early identification of HNSCC.
Population-scale predictions of DPD and TPMT phenotypes using a quantitative pharmacogene-specific ensemble classifierZhou, Yitian; Dagli Hernandez, Carolina; Lauschke, Volker M.
doi: 10.1038/s41416-020-01084-0pmid: 32973300
BackgroundInter-individual differences in dihydropyrimidine dehydrogenase (DPYD encoding DPD) and thiopurine S-methyltransferase (TPMT) activity are important predictors for fluoropyrimidine and thiopurine toxicity. While several variants in these genes are known to decrease enzyme activities, many additional genetic variations with unclear functional consequences have been identified, complicating informed clinical decision-making in the respective carriers.MethodsWe used a novel pharmacogenetically trained ensemble classifier to analyse DPYD and TPMT genetic variability based on sequencing data from 138,842 individuals across eight populations.ResultsThe algorithm accurately predicted in vivo consequences of DPYD and TPMT variants (accuracy 91.4% compared to 95.3% in vitro). Further analysis showed high genetic complexity of DPD deficiency, advocating for sequencing-based DPYD profiling, whereas genotyping of four variants in TPMT was sufficient to explain >95% of phenotypic TPMT variability. Lastly, we provided population-scale profiles of ethnogeographic variability in DPD and TPMT phenotypes, and revealed striking interethnic differences in frequency and genetic constitution of DPD and TPMT deficiency.ConclusionThese results provide the most comprehensive data set of DPYD and TPMT variability published to date with important implications for population-adjusted genetic profiling strategies of fluoropyrimidine and thiopurine risk factors and precision public health.