Sir Peter MacCallum Department of Oncology - Research Publications

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    Arginine-rich C9ORF72 ALS proteins stall ribosomes in a manner distinct from a canonical ribosome-associated quality control substrate.
    Kriachkov, V ; Ormsby, AR ; Kusnadi, EP ; McWilliam, HEG ; Mintern, JD ; Amarasinghe, SL ; Ritchie, ME ; Furic, L ; Hatters, DM (Elsevier BV, 2023-01)
    Hexanucleotide expansion mutations in C9ORF72 are a frequent cause of amyotrophic lateral sclerosis. We previously reported that long arginine-rich dipeptide repeats (DPRs), mimicking abnormal proteins expressed from the hexanucleotide expansion, caused translation stalling when expressed in cell culture models. Whether this stalling provides a mechanism of pathogenicity remains to be determined. Here, we explored the molecular features of DPR-induced stalling and examined whether known mechanisms such as ribosome quality control (RQC) regulate translation elongation on sequences that encode arginine-rich DPRs. We demonstrate that arginine-rich DPRs lead to stalling in a length-dependent manner, with lengths longer than 40 repeats invoking severe translation arrest. Mutational screening of 40×Gly-Xxx DPRs shows that stalling is most pronounced when Xxx is a charged amino acid (Arg, Lys, Glu, or Asp). Through a genome-wide knockout screen, we find that genes regulating stalling on polyadenosine mRNA coding for poly-Lys, a canonical RQC substrate, act differently in the case of arginine-rich DPRs. Indeed, these findings point to a limited scope for natural regulatory responses to resolve the arginine-rich DPR stalls, even though the stalls may be sensed, as evidenced by an upregulation of RQC gene expression. These findings therefore implicate arginine-rich DPR-mediated stalled ribosomes as a source of stress and toxicity and may be a crucial component in pathomechanisms.
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    Microbeam Radiation Therapy Controls Local Growth of Radioresistant Melanoma and Treats Out-of-Field Locoregional Metastasis.
    Trappetti, V ; Potez, M ; Fernandez-Palomo, C ; Volarevic, V ; Shintani, N ; Pellicioli, P ; Ernst, A ; Haberthür, D ; Fazzari, JM ; Krisch, M ; Laissue, JA ; Anderson, RL ; Martin, OA ; Djonov, VG (Elsevier BV, 2022-11-01)
    PURPOSE: Synchrotron-generated microbeam radiation therapy (MRT) represents an innovative preclinical type of cancer radiation therapy with an excellent therapeutic ratio. Beyond local control, metastatic spread is another important endpoint to assess the effectiveness of radiation therapy treatment. Currently, no data exist on an association between MRT and metastasis. Here, we evaluated the ability of MRT to delay B16F10 murine melanoma progression and locoregional metastatic spread. METHODS AND MATERIALS: We assessed the primary tumor response and the extent of metastasis in sentinel lymph nodes in 2 cohorts of C57BL/6J mice, one receiving a single MRT and another receiving 2 MRT treatments delivered with a 10-day interval. We compared these 2 cohorts with synchrotron broad beam-irradiated and nonirradiated mice. In addition, using multiplex quantitative platforms, we measured plasma concentrations of 34 pro- and anti-inflammatory cytokines and frequencies of immune cell subsets infiltrating primary tumors that received either 1 or 2 MRT treatments. RESULTS: Two MRT treatments were significantly more effective for local control than a single MRT. Remarkably, the second MRT also triggered a pronounced regression of out-of-radiation field locoregional metastasis. Augmentation of CXCL5, CXCL12, and CCL22 levels after the second MRT indicated that inhibition of melanoma progression could be associated with increased activity of antitumor neutrophils and T-cells. Indeed, we demonstrated elevated infiltration of neutrophils and activated T-cells in the tumors after the second MRT. CONCLUSIONS: Our study highlights the importance of monitoring metastasis after MRT and provides the first MRT fractionation schedule that promotes local and locoregional control with the potential to manage distant metastasis.
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    Whole Genome Sequencing Shows Genetic Diversity, as Well as Clonal Complex and Gene Polymorphisms Associated with Fluconazole Non-Susceptible Isolates of Candida tropicalis
    Keighley, C ; Gall, M ; van Hal, SJ ; Halliday, CL ; Chai, LYA ; Chew, KL ; Biswas, C ; Slavin, MA ; Meyer, W ; Sintchenko, V ; Chen, SCA (MDPI, 2022-09-01)
    Resistance to azoles in Candida tropicalis is increasing and may be mediated by genetic characteristics. Using whole genome sequencing (WGS), we examined the genetic diversity of 82 bloodstream C. tropicalis isolates from two countries and one ATCC strain in a global context. Multilocus sequence typing (MLST) and single nucleotide polymorphism (SNP)-based phylogenies were generated. Minimum inhibitory concentrations (MIC) for antifungal agents were determined using Sensititre YeastOne YO10. Eleven (13.2%) isolates were fluconazole-resistant and 17 (20.5%) were classified as fluconazole-non susceptible (FNS). Together with four Canadian isolates, the genomes of 12 fluconazole-resistant (18 FNS) and 69 fluconazole-susceptible strains were examined for gene mutations associated with drug resistance. Fluconazole-resistant isolates contained a mean of 56 non-synonymous SNPs per isolate in contrast to 36 SNPs in fluconazole-susceptible isolates (interquartile range [IQR] 46-59 vs. 31-48 respectively; p < 0.001). Ten of 18 FNS isolates contained missense ERG11 mutations (amino acid substitutions S154F, Y132F, Y257H). Two echinocandin-non susceptible isolates had homozygous FKS1 mutations (S30P). MLST identified high genetic diversity with 61 diploid sequence types (DSTs), including 53 new DSTs. All four isolates in DST 773 were fluconazole-resistant within clonal complex 2. WGS showed high genetic variation in invasive C. tropicalis; azole resistance was distributed across different lineages but with DST 773 associated with in vitro fluconazole resistance.
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    Together Alone: Going Online during COVID-19 Is Changing Scientific Conferences
    Bray, HJ ; Stone, J ; Litchfield, L ; Britt, KL ; Hopper, JL ; Ingman, WV (MDPI AG, )
    The COVID-19 pandemic caused many scientific conferences to move online, posing a great challenge for scientific communication. This change offers potential advantages and disadvantages for inclusion, diversity, and scientific advancement. Here, we analyse participants’ experiences of the Why Study Mammographic Density? Conference to explore some of these issues and identify key points of contention between different stakeholders. We found that while increasing participant diversity is facilitated by online conferencing, if the participants cannot interact informally with each other, there is value which is lost. In returning to in-person conferences, it will be important not to “shut the door” on those whose participation was enabled by the online format.
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    Leveraging Comprehensive Cancer Registry Data to Enable a Broad Range of Research, Audit and Patient Support Activities
    Lee, B ; Gately, L ; Lok, SW ; Tran, B ; Lee, M ; Wong, R ; Markman, B ; Dunn, K ; Wong, V ; Loft, M ; Jalili, A ; Anton, A ; To, R ; Andrews, M ; Gibbs, P (MDPI, 2022-09-01)
    Traditional cancer registries have often been siloed efforts, established by single groups with limited objectives. There is the potential for registry data to support a broad range of research, audit and education initiatives. Here, we describe the establishment of a series of comprehensive cancer registries across the spectrum of common solid cancers. The experience and learnings of each registry team as they develop, implement and then use collected data for a range of purposes, that informs the conduct and output of other registries in a virtuous cycle. Each registry is multi-site, multi-disciplinary and aims to collect data of maximal interest and value to a broad range of enquiry, which would be accessible to any researcher with a high-quality proposal. Lessons learnt include the need for careful and continuous curation of data fields, with regular database updates, and the need for a continued focus on data quality. The registry data as a standalone resource has supported numerous projects, but linkage with external datasets with patients in common has enhanced the audit and research potential. Multiple projects have linked registry data with matched tissue specimens to support prognostic and predictive biomarker studies, both validation and discovery. Registry-based biomarker trials have been successfully supported, generating novel and practice-changing data. Registry-based clinical trials, particularly randomised studies exploring the optimal use of available therapy options are now complementing the research conducted in traditional clinical trials. More recent projects supported by the registries include health economic studies, personalised patient education material, and increased consumer engagement, including consumer entered data.
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    Changes in Apparent Diffusion Coefficient (ADC) in Serial Weekly MRI during Radiotherapy in Patients with Head and Neck Cancer: Results from the PREDICT-HN Study
    Ng, SP ; Cardenas, CE ; Bahig, H ; Elgohari, B ; Wang, J ; Johnson, JM ; Moreno, AC ; Shah, SJ ; Garden, AS ; Phan, J ; Gunn, GB ; Frank, SJ ; Ding, Y ; Na, L ; Yuan, Y ; Urbauer, D ; Mohamed, ASR ; Rosenthal, D ; Morrison, WH ; MacManus, MP ; Fuller, CD (MDPI, 2022-09-01)
    Background: The PREDICT-HN study aimed to systematically assess the kinetics of imaging MR biomarkers during head and neck radiotherapy. Methods: Patients with intact squamous cell carcinoma of the head and neck were enrolled. Pre-, during, and post-treatment MRI were obtained. Serial GTV and ADC measurements were recorded. The correlation between each feature and the GTV was calculated using Spearman's correlation coefficient. The linear mixed model was used to evaluate the change in GTV over time. Results: A total of 41 patients completed the study. The majority (76%) had oropharyngeal cancer. A total of 36 patients had intact primary tumours that can be assessed on MRI, and 31 patients had nodal disease with 46 nodes assessed. Median primary GTV (GTVp) size was 14.1cc. The rate of GTVp shrinkage was highest between pre-treatment and week 4. Patients with T3-T4 tumours had a 3.8-fold decrease in GTVp compared to T1-T2 tumours. The ADC values correlated with residual GTVp. The median nodal volume (GTVn) was 12.4cc. No clinical features were found to correlate with GTVn reduction. The overall change in ADC for GTVn from pre-treatment was significant for 35th-95th percentiles in weeks 1-4 (p < 0.001). Conclusion: A discrepancy in the trajectory of ADC between primary and nodal sites suggested that they exhibit different treatment responses and should be analysed separately in future studies.
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    Efficacy and safety of lorlatinib in Asian and non-Asian patients with ALK-positive advanced non-small cell lung cancer: Subgroup analysis of a global phase 2 trial
    Soo, RA ; Tan, EH ; Hayashi, H ; Seto, T ; Lin, C-C ; Ou, S-HI ; Kim, D-W ; Liu, G ; Abbattista, A ; Martini, J-F ; Martini, F ; Wong, CH ; Toffalorio, F ; Solomon, BJ (ELSEVIER IRELAND LTD, 2022-06-01)
    OBJECTIVES: To analyze the efficacy and safety of lorlatinib in Asian and non-Asian patients with pretreated anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer (NSCLC) from a phase 1/2 study. MATERIALS AND METHODS: In this ongoing phase 2 part of the trial, patients with ALK- or ROS1-positive, advanced NSCLC enrolled into six expansion cohorts (EXP1-6), based on ALK and ROS1 status and previous therapy, and received lorlatinib 100 mg once daily. The primary endpoint was objective tumor response and intracranial response. Post hoc analyses of activity were conducted in Asian and non-Asian (based on race) ALK-positive patients who received either previous crizotinib with or without chemotherapy (EXP2-3A) or at least one second-generation ALK tyrosine kinase inhibitor with any number of chemotherapy regimens (EXP3B-5). Analysis of safety (adverse events [AEs]) was in the phase 1 and 2 study population who started lorlatinib 100 mg once daily. RESULTS: 17 Asian patients were enrolled in EXP2-3A and 53 in EXP3B-5; 33 non-Asian patients were enrolled in EXP2-3A and 73 in EXP3B-5. Objective response rates in the Asian and non-Asian subgroups were 82.4% (95% confidence interval [CI]: 56.6-96.2) and 63.6% (95% CI: 45.1-79.6) in EXP2-3A, and 47.2% (95% CI: 33.3-61.4) and 30.1% (95% CI: 19.9-42.0) in EXP3B-5, and median progression-free survival was 13.6 and 12.5 months (EXP2-3A) and 6.9 and 5.5 months (EXP3B-5). Lorlatinib exhibited antitumor activity across ALK resistance mutations, while no differences according to the EML4-ALK variant could be detected. The most common treatment-related AEs were hypercholesterolemia, hypertriglyceridemia, edema, and peripheral neuropathy in both Asian and non-Asian subgroups. CONCLUSION: Lorlatinib showed substantial overall and intracranial activity in pretreated patients with ALK-positive NSCLC in both Asian and non-Asian patients. AE profiles were similar between Asian and non-Asian patients. CLINICALTRIALS: gov NCT01970865.
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    Identification and characterization of a novel SNAT2 (SLC38A2) inhibitor reveals synergy with glucose transport inhibition in cancer cells.
    Gauthier-Coles, G ; Bröer, A ; McLeod, MD ; George, AJ ; Hannan, RD ; Bröer, S (Frontiers Media SA, 2022)
    SNAT2 (SLC38A2) is a sodium-dependent neutral amino acid transporter, which is important for the accumulation of amino acids as nutrients, the maintenance of cellular osmolarity, and the activation of mTORC1. It also provides net glutamine for glutaminolysis and consequently presents as a potential target to treat cancer. A high-throughput screening assay was developed to identify new inhibitors of SNAT2 making use of the inducible nature of SNAT2 and its electrogenic mechanism. Using an optimized FLIPR membrane potential (FMP) assay, a curated scaffold library of 33934 compounds was screened to identify 3-(N-methyl (4-methylphenyl)sulfonamido)-N-(2-trifluoromethylbenzyl)thiophene-2-carboxamide as a potent inhibitor of SNAT2. In two different assays an IC50 of 0.8-3 µM was determined. The compound discriminated against the close transporter homologue SNAT1. MDA-MB-231 breast cancer and HPAFII pancreatic cancer cell lines tolerated the SNAT2 inhibitor up to a concentration of 100 µM but in combination with tolerable doses of the glucose transport inhibitor Bay-876, proliferative growth of both cell lines was halted. This points to synergy between inhibition of glycolysis and glutaminolysis in cancer cells.
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    A meta-analysis of clinicopathologic features that predict necrosis or fibrosis at post-chemotherapy retroperitoneal lymph node dissection in individuals receiving treatment for non-seminoma germ cell tumours
    Conduit, C ; Hong, W ; Martin, F ; Thomas, B ; Lawrentschuk, N ; Goad, J ; Grimison, P ; Ahmadi, N ; Tran, B ; Lewin, J (FRONTIERS MEDIA SA, 2022-08-17)
    PURPOSE: Post-chemotherapy retroperitoneal lymph node dissection (pcRPLND) for residual nodal masses is a critical component of care in metastatic testicular germ cell tumour (GCT). However, the procedure is not of therapeutic value in up to 50% of individuals in whom histopathology demonstrates post-treatment necrosis or fibrosis alone. Improved diagnostic tools and clinicopathologic features are needed to separate individuals who benefit from pcRPLND and avoid surgery in those who do not. METHODS: A prospectively registered meta-analysis of studies reporting clinicopathologic features associated with teratoma, GCT and/or necrosis/fibrosis at pcRPLND for metastatic non-seminoma GCT (NSGCT) was undertaken. We examined the effect of various clinicopathologic factors on the finding of necrosis/fibrosis at pcRPLND. The log odds ratios (ORs) of each association were pooled using random-effects models. RESULTS: Using the initial search strategy, 4,178 potentially eligible abstracts were identified. We included studies providing OR relating to clinicopathologic factors predicting pcRPLND histopathology, or where individual patient-level data were available to permit the calculation of OR. A total of 31 studies evaluating pcRPLND histopathology in 3,390 patients were eligible for inclusion, including two identified through hand-searching the reference lists of eligible studies. The following were associated with the presence of necrosis/fibrosis at pcRPLND: absence of teratomatous elements in orchidectomy (OR 3.45, 95% confidence interval [CI] 2.94-4.17); presence of seminomatous elements at orchidectomy (OR 2.71, 95% CI 1.37-5.37); normal pre-chemotherapy serum bHCG (OR 1.96, 95% CI 1.62-2.36); normal AFP (OR 3.22, 95% CI 2.49-4.15); elevated LDH (OR 1.72, 95% CI 1.37-2.17); >50% change in mass during chemotherapy (OR 4.84, 95% CI 3.94-5.94); and smaller residual mass size (<2 cm versus >2 cm: OR 3.93, 95% CI 3.23-4.77; <5 cm versus >5 cm: OR 4.13, 95% CI 3.26-5.23). CONCLUSIONS: In this meta-analysis, clinicopathologic features helped predict the presence of pcRPLND necrosis/fibrosis. Collaboration between centres that provide individual patient-level data is required to develop and validate clinical models and inform routine care to direct pcRPLND to individuals most likely to derive benefits. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42021279699.
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    Role of PSMA PET-guided metastases-directed therapy in oligometastatic recurrent prostate cancer
    Alberto, M ; Yim, A ; Papa, N ; Siva, S ; Ischia, J ; Touijer, K ; Eastham, JA ; Bolton, D ; Perera, M (FRONTIERS MEDIA SA, 2022-08-18)
    Oligometastatic prostate cancer (OMPC) has been proposed as an intermediary state between localised disease and widespread metastases, with varying definitions including 1, 3, or ≤5 visceral or bone metastasis. Traditional definitions of OMPC are based on staging with conventional imaging, such as computerised tomography (CT) and whole-body bone scan (WBBS). Novel imaging modalities such as prostate-specific membrane antigen positron emission tomography (PSMA PET) have improved diagnostic utility in detecting early metastatic prostate cancer (PC) metastases compared with conventional imaging. Specifically, meta-analytical data suggest that PSMA PET is sensitive in detecting oligometastatic disease in patients with biochemical recurrence (BCR) post-radical treatment of PC. Recent trials have evaluated PSMA PET-guided metastases-directed therapy (MDT) in oligometastatic recurrent disease, typically with salvage surgery or radiotherapy (RT). To date, these preliminary studies demonstrate promising results, potentially delaying the need for systemic therapy. We aim to report a comprehensive, multidisciplinary review of PSMA-guided MDT in OMPC. In this review, we highlight the utility of PMSA PET in biochemically recurrent disease and impact of PSMA PET on the definition of oligometastatic disease and outline data pertaining to PSMA-guided MDT.