77 results found
Varghese V, Magnani L, Harada N, et al., 2019, FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression, Scientific Reports, Vol: 9, ISSN: 2045-2322
Resistance to 5-Fluoruracil (5-FU) has been linked to elevated expression of the main target, thymidylate synthase (TYMS), which catalyses the de novo pathway for production of deoxythymidine monophosphate. The potent oncogenic forkhead box transcription factor, FOXM1 is is regulated by E2F1 which also controls TYMS. This study reveals a significant role of FOXM1 in 5-FU resistance. Overexpression and knock-down studies of FOXM1 in colon cancer cells suggest the importance of FOXM1 in TYMS regulation. ChIP and global ChIP-seq data also confirms that FOXM1 can also potentially regulate other 5-FU targets, such as TYMS, thymidine kinase 1 (TK-1) and thymidine phosphorylase (TYMP). In human colorectal cancer tissue specimens, a strong correlation of FOXM1 and TYMS staining was observed. Elevated FOXM1 and TYMS expression was also observed in acquired 5-FU resistant colon cancer cells (HCT116 5-FU Res). A synergistic effect was observed following treatment of CRC cells with an inhibitor of FOXM1, thiostrepton, in combination with 5-FU. The combination treatment decreased colony formation and migration, and induced cell cycle arrest, DNA damage, and apoptosis in CRC cell lines. In summary, this research demonstrated that FOXM1 plays a pivotal role in 5-FU resistance at least partially through the regulation of TYMS.
Dubash SR, Merchant S, Heinzmann K, et al., 2018, Clinical translation of [F-18]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer, EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, Vol: 45, Pages: 2285-2299, ISSN: 1619-7070
Kramer GM, Liu Y, de Langen AJ, et al., 2018, Repeatability of quantitative18F-FLT uptake measurements in solid tumors: an individual patient data multi-center meta-analysis, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 45, Pages: 951-961, ISSN: 1619-7070
INTRODUCTION: 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) positron emission tomography (PET) provides a non-invasive method to assess cellular proliferation and response to antitumor therapy. Quantitative18F-FLT uptake metrics are being used for evaluation of proliferative response in investigational setting, however multi-center repeatability needs to be established. The aim of this study was to determine the repeatability of18F-FLT tumor uptake metrics by re-analyzing individual patient data from previously published reports using the same tumor segmentation method and repeatability metrics across cohorts. METHODS: A systematic search in PubMed, EMBASE.com and the Cochrane Library from inception-October 2016 yielded five18F-FLT repeatability cohorts in solid tumors.18F-FLT avid lesions were delineated using a 50% isocontour adapted for local background on test and retest scans. SUVmax, SUVmean, SUVpeak, proliferative volume and total lesion uptake (TLU) were calculated. Repeatability was assessed using the repeatability coefficient (RC = 1.96 × SD of test-retest differences), linear regression analysis, and the intra-class correlation coefficient (ICC). The impact of different lesion selection criteria was also evaluated. RESULTS: Images from four cohorts containing 30 patients with 52 lesions were obtained and analyzed (ten in breast cancer, nine in head and neck squamous cell carcinoma, and 33 in non-small cell lung cancer patients). A good correlation was found between test-retest data for all18F-FLT uptake metrics (R2 ≥ 0.93; ICC ≥ 0.96). Best repeatability was found for SUVpeak(RC: 23.1%), without significant differences in RC between different SUV metrics. Repeatability of proliferative volume (RC: 36.0%) and TLU (RC: 36.4%) was worse than SUV. Lesion selection methods based on SUVmax ≥ 4.0 improved the repeatability of volumetric metrics (RC: 26-28%), but did not affect the repe
Palmieri C, Stein RC, Liu X, et al., 2018, Correction to: IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients (vol 165, pg 343, 2017), Breast Cancer Research and Treatment, Vol: 167, Pages: 407-407, ISSN: 0167-6806
Palmieri C, Szydlo R, Miller M, et al., 2017, IPET study: an FLT-PET window study to assess the activity of the steroid sulfatase inhibitor irosustat in early breast cancer, Breast Cancer Research and Treatment, Vol: 166, Pages: 527-539, ISSN: 0167-6806
BACKGROUND: Steroid sulfatase (STS) is involved in oestrogen biosynthesis and irosustat is a first generation, irreversible steroid sulfatase inhibitor. A pre-surgical window-of-opportunity study with irosustat was undertaken in estrogen receptor-positive (ER+) breast cancer to assess the effect of irosustat on tumour cell proliferation as measured by 3'-deoxy-3'-[18F] fluorothymidine uptake measured by PET scanning (FLT-PET) and Ki67. METHODS: Postmenopausal women with untreated ER+ early breast cancer were recruited, and imaged with FLT-PET at baseline and after at least 2 weeks treatment with irosustat, 40 mg once daily orally. The primary endpoint was changed in FLT uptake; secondary endpoints included safety and tolerability of irosustat, changes in tumoral Ki67 and steroidogenic enzymes expression and circulating steroid hormone levels. RESULTS: Thirteen women were recruited, and ten started irosustat for 2 weeks, followed by repeat FLT-PET scans in eight. Defining response as decreases of ≥20% in standardized uptake value (SUV) or ≥30% in Ki, 1 (12.5% (95% CI 2-47%, p = 0.001)) and 3 (43% (95% CI 16-75%, p = <0.001) patients, respectively, responded. 6 out of 7 patients had a Ki67 reduction (range = -19.3 to 76.4%), and median percentage difference in Ki67 was 52.3% (p = 0.028). In one patient with a low baseline STS expression, a 19.7% increase in Ki67 was recorded. STS decreases were seen in tumours with high basal STS expression, significant decreases were also noted in aromatase, and 17β-hydroxysteroid dehydrogenase type 1 and 2. Irosustat was generally well tolerated with all adverse event CTCAE Grade ≤2. CONCLUSIONS: Irosustat resulted in a significant reduction in FLT uptake and Ki67, and is well tolerated. These data are the first demonstrating clinical activity of irosustat in early breast cancer. Baseline expression of STS may be a biomarker of sensitivity to irosustat.
Dubash SR, Merchant S, Mauri F, et al., 2017, Clinical translation of the caspase 3/7 specific PET radiotracer [F-18]ICMT-11 for measuring chemotherapy induced apoptosis in breast and lung cancer, Publisher: SPRINGER, Pages: S378-S379, ISSN: 1619-7070
Saleem A, Searle GE, Kenny LM, et al., 2017, Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer (vol 5, 30, 2015), EJNMMI RESEARCH, Vol: 7, ISSN: 2191-219X
Saleem A, Searle GE, Kenny LM, et al., 2017, Erratum to: Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer., EJNMMI Research, Vol: 7, Pages: 74-74, ISSN: 2191-219X
Palmieri C, Stein RC, Liu X, et al., 2017, IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients, Breast Cancer Research and Treatment, Vol: 165, Pages: 343-353, ISSN: 0167-6806
Purpose Irosustat is a first-generation, orally active, irreversiblesteroid sulfatase inhibitor. We performed a multicentre,open label phase II trial of the addition of Irosustatto a first-line aromatase inhibitor (AI) in patients withadvanced BC to evaluate the safety of the combination andto test the hypothesis that the addition of Irosustat to AImay further suppress estradiol levels and result in clinicalbenefit.Experimental design Postmenopausal women with ERpositivelocally advanced or metastatic breast cancer whohad derived clinical benefit from a first-line AI and whosubsequently progressed were enrolled. The first-line AIwas continued and Irosustat (40 mg orally daily) added.The primary endpoint was clinical benefit rate (CBR).Secondary endpoints included safety, tolerability, andpharmacodynamic end points.Results Twenty-seven women were recruited, four discontinuedtreatment without response assessment. Basedon local reporting, the CBR was 18.5% (95% CI6.3–38.1%) on an intent to treat basis, increasing to 21.7%(95% CI 7.4–43.7%) by per-protocol analysis. In thosepatients that achieved clinical benefit (n = 5), the median(interquartile range) duration was 9.4 months (8.1–11.3)months. The median progression-free survival time was2.7 months (95% CI 2.5–4.6) in both the ITT and perprotocolanalyses. The most frequently reported grade 3/4toxicities were dry skin (28%), nausea (13%), fatigue(13%), diarrhoea (8%), headache (7%), anorexia (7%) andlethargy (7%).Conclusions The addition of Irosustat to aromatase inhibitortherapy resulted in clinical benefit with an acceptablesafety profile. The study met its pre-defined successcriterion by both local and central radiological assessments.
Cysouw MCF, Kramer GM, Frings V, et al., 2017, Baseline and longitudinal variability of normal tissue uptake values of [F-18]-fluorothymidine-PET images, Nuclear Medicine and Biology, Vol: 51, Pages: 18-24, ISSN: 0969-8051
Purpose[18F]-fluorothymidine ([18F]-FLT) is a PET-tracer enabling in-vivo visualization and quantification of tumor cell proliferation. For qualitative and quantitative analysis, adequate knowledge of normal tissue uptake is indispensable. This study aimed to quantitatively investigate baseline tracer uptake of blood pool, lung, liver and bone marrow and their precision, and to assess the longitudinal effect of systemic treatment on biodistribution.Methods18F–FLT-PET(/CT) scans (dynamic or static) of 90 treatment-naïve oncological patients were retrospectively evaluated. Twenty-three patients received double baseline scans, and another 39 patients were also scanned early and late during systemic treatment with a tyrosine kinase inhibitor. Reproducible volume of interest were placed in blood pool, lung, liver, and bone marrow. For semi-quantitative analysis, SUVmean, SUVmax, and SUVpeak with several normalizations were derived.ResultsSUVs of basal lung, liver, and bone marrow were not significantly different between averaged dynamic and static images, in contrast with blood pool and apical lung. Highest repeatability was seen for liver and bone marrow, with repeatability coefficients of 18.6% and 20.4% when using SUVpeak. Systemic treatment with TKIs both increased and decreased normal tissue tracer uptake at early and late time points during treatment.ConclusionSimultaneous evaluation of liver and bone marrow uptake in longitudinal response studies may be used to assess image quality, where changes in uptake outside repeatability limits should trigger investigators to perform additional quality control on individual PET images.Advances in knowledgeFor [18F]-FLT PET images, liver and bone marrow have low intra-patient variability when quantified with SUVpeak, but may be affected by systemic treatment.Implications for patient careIn [18F]-FLT-PET response monitoring trials, liver and bone marrow uptake may be used for quality control of [18F]-FLT PET images
Kramer GM, Liu Y, de langen AJ, et al., 2016, Repeatability of Quantitative F-18-FLT Uptake Measurements in Solid Tumors: A multi-centre Meta-Analysis, Annual Congress of the European-Association-of-Nuclear-Medicine, Publisher: SPRINGER, Pages: S357-S358, ISSN: 1619-7070
Palmieri C, Szydlo R, Miller M, et al., 2016, The effects of the first in class steroid sulfatase inhibitor Irosustat on FLT uptake and Ki67 in estrogen receptor positive early breast cancer: Results of the perioperative IPET study., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Kenny L, 2016, The Use of Novel PET Tracers to Image Breast Cancer Biologic Processes Such as Proliferation, DNA Damage and Repair, and Angiogenesis, JOURNAL OF NUCLEAR MEDICINE, Vol: 57, Pages: 89S-95S, ISSN: 0161-5505
Harada N, Varghese V, Xie L, et al., 2015, Targeting lactate metabolism as a novel therapeutic target in platinum-resistant triple negative breast cancer (TNBC), 37th Annual CTRC-AACR San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Merchant S, Aboagye EO, Lim A, et al., 2015, Evaluation of apoptosis in breast cancer using the novel PET probe [F-18]ICMT-11 in patients treated with neoadjuvant FEC chemotherapy: Initial assessment of optimum imaging time and relation to caspase-3 immunostaining, 37th Annual CTRC-AACR San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Saleem A, Searle GE, Kenny LM, et al., 2015, Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer, EJNMMI Research, Vol: 5, ISSN: 2191-219X
BackgroundBrain metastases are common in human epidermal growth factor receptor (Her)-2-positive breast cancer. Drug access to brain metastases and normal brain is key to management of cranial disease. In this study, positron emission tomography (PET) scanning after administration of radiolabelled lapatinib was used to obtain direct evidence of cranial drug access.MethodsPatients with Her-2+ metastatic breast cancer either with at least one 1-cm diameter brain metastasis or without brain metastases underwent dynamic carbon-11 radiolabelled lapatinib ([11C]lapatinib)-PET. Less than 20 μg of [11C]lapatinib was administered before and after 8 days of oral lapatinib (1,500 mg once daily). Radial arterial blood sampling was performed throughout the 90-min scan. The contribution of blood volume activity to the tissue signal was excluded to calculate lapatinib uptake in normal brain and metastases. Partitioning of radioactivity between plasma and tissue (V T) was calculated and the tissue concentration of lapatinib derived. Plasma lapatinib levels were measured and adverse events noted.ResultsSix patients (three with brain metastases) were recruited. About 80% plasma radioactivity corresponded to intact [11C]lapatinib after 60 min. PET signal in the brain corresponded to circulating radioactivity levels, with no [11C]lapatinib uptake observed in normal brain tissue. In contrast, radioactivity uptake in cranial metastases was significantly higher (p = 0.002) than that could be accounted by circulating radioactivity levels, consistent with [11C]lapatinib uptake in brain metastases. There was no difference in lapatinib uptake between the baseline and day 8 scans, suggesting no effect of increased drug access by inhibition of the drug efflux proteins by therapeutic doses of lapatinib.ConclusionsIncreased lapatinib uptake was observed in brain metastases but not in normal brain.
Hoyng LL, Frings V, Hoekstra OS, et al., 2015, Metabolically active tumour volume segmentation from dynamic [F-18] FLT PET studies in non-small cell lung cancer, EJNMMI RESEARCH, Vol: 5, ISSN: 2191-219X
Varghese V, Magnani L, Harada N, et al., 2015, Inhibition of FOXM1 by thiostrepton increases sensitivity to 5-fluorouracil (5-FU) by downregulating thymidylate synthase (TS) in colorectal cancer, AACR Precision Medicine Conference on Drug Sensitivity and Resistance - Improving Cancer Therapy, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 1078-0432
Blighe K, Kenny L, Patel N, et al., 2014, Whole Genome Sequence Analysis Suggests Intratumoral Heterogeneity in Dissemination of Breast Cancer to Lymph Nodes, PLOS One, Vol: 9, ISSN: 1932-6203
Background: Intratumoral heterogeneity may help drive resistance to targetedtherapies in cancer. In breast cancer, the presence of nodal metastases is a keyindicator of poorer overall survival. The aim of this study was to identify somaticgenetic alterations in early dissemination of breast cancer by whole genome nextgeneration sequencing (NGS) of a primary breast tumor, a matched locally-involvedaxillary lymph node and healthy normal DNA from blood.Methods: Whole genome NGS was performed on 12 mg (range 11.1–13.3 mg) ofDNA isolated from fresh-frozen primary breast tumor, axillary lymph node andperipheral blood following the DNA nanoball sequencing protocol. Single nucleotidevariants, insertions, deletions, and substitutions were identified through abioinformatic pipeline and compared to CIN25, a key set of genes associated withtumor metastasis.Results: Whole genome sequencing revealed overlapping variants between thetumor and node, but also variants that were unique to each. Novel mutations uniqueto the node included those found in two CIN25 targets, TGIF2 and CCNB2, whichare related to transcription cyclin activity and chromosomal stability, respectively,and a unique frameshift in PDS5B, which is required for accurate sister chromatidsegregation during cell division. We also identified dominant clonal variants thatprogressed from tumor to node, including SNVs in TP53 and ARAP3, whichmediates rearrangements to the cytoskeleton and cell shape, and an insertion in TOP2A, the expression of which is significantly associated with tumor proliferationand can segregate breast cancers by outcome.Conclusion: This case study provides preliminary evidence that primary tumor andearly nodal metastasis have largely overlapping somatic genetic alterations. Therewere very few mutations unique to the involved node. However, significantconclusions regarding early dissemination needs analysis of a larger number ofpatient samples.
Kenny LM, Aboagye EO, 2014, Clinical Translation of Molecular Imaging Agents Used in PET Studies of Cancer, EMERGING APPLICATIONS OF MOLECULAR IMAGING TO ONCOLOGY, Vol: 124, Pages: 329-374, ISSN: 0065-230X
Varghese V, Magnani L, Harada N, et al., 2014, Forkhead box transciption factor M1 (FOXM1) plays a critical role in colorectal cancer resistance by regulating thymidylate synthase (TS), 105th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Kenny LM, Tomasi G, Turkheimer F, et al., 2014, Preliminary clinical assessment of the relationship between tumor alphavbeta3 integrin and perfusion in patients studied with [F-18]fluciclatide kinetics and [O-15]H2O PET, EJNMMI RESEARCH, Vol: 4, ISSN: 2191-219X
Harada N, Varghese V, Tharayil IA, et al., 2013, Metformin has an additive effect to cisplatin in triple negative breast cancer cells with high lactate dehydrogenase B (LDHB) expression, CANCER RESEARCH, Vol: 73, ISSN: 0008-5472
Tharayil IA, Harada N, Patel N, et al., 2013, Measurement of tumour lesion glycolysis by FDG-PET in triple negative breast cancer, CANCER RESEARCH, Vol: 73, ISSN: 0008-5472
Kenny LM, 2013, 18F-FDG PET/CT for early prediction of response to neoadjuvant lapatinib, trastuzumab, and their combination in HER2-positive breast cancer: results from Neo-ALTTO., J Nucl Med, Vol: 54, Pages: 1855-1856
Challapalli A, Kenny LM, Hallett WA, et al., 2013, F-18-ICMT-11, a Caspase-3-Specific PET Tracer for Apoptosis: Biodistribution and Radiation Dosimetry, JOURNAL OF NUCLEAR MEDICINE, Vol: 54, Pages: 1551-1556, ISSN: 0161-5505
Saleem A, Searle G, Kenny LM, et al., 2013, Brain and tumor penetration of carbon-11-labeled lapatinib ([C-11]Lap) in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC), 49th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Willaime JMY, Turkheimer FE, Kenny LM, et al., 2013, Quantification of intra-tumour cell proliferation heterogeneity using imaging descriptors of 18F fluorothymidine-positron emission tomography, Physics in medicine and biology, Vol: 58, Pages: 187-203
Intra-tumour heterogeneity is a characteristic shared by all cancers. We explored the use of texture variables derived from images of [(18)F]fluorothymidine-positron emission tomography (FLT-PET), thus notionally assessing the heterogeneity of proliferation in individual tumours. Our aims were to study the range of textural feature values across tissue types, verify the repeatability of these image descriptors and further, to explore associations with clinical response to chemotherapy in breast cancer patients. The repeatability of 28 textural descriptors was assessed in patients who had two FLT-PET scans prior to therapy using relative differences and the intra-class correlation coefficient (ICC). We tested associations between features at baseline and clinical response measured in 11 patients after three cycles of chemotherapy, and explored changes in FLT-PET at one week after the start of therapy. A subset of eight features was characterized by low variations at baseline (<30%) and high repeatability (0.7 ≤ ICC ≤ 1). The intensity distribution profile suggested fewer highly proliferating cells in lesions of non-responders compared to responders at baseline. A true increase in CV and homogeneity was measured in four out of six responders one week after the start of therapy. A number of textural features derived from FLT-PET are altered following chemotherapy in breast cancer, and should be evaluated in larger clinical trials for clinical relevance.
Cseh Z, Kenny L, Swingland J, et al., 2013, Neural Networks Combined with Region Growing Techniques for Tumor Detection in [F-18]-Fluorothymidine Dynamic Positron Emission Tomography Breast Cancer Studies, Conference on Medical Imaging - Computer-Aided Diagnosis, Publisher: SPIE-INT SOC OPTICAL ENGINEERING, ISSN: 0277-786X
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