High-grade epithelial ovarian carcinomas containing mutated
or
(
) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of ...HR function due to secondary mutations in
has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pretreatment and postprogression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase II study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed ovarian carcinoma. In 6 of 12 pretreatment biopsies, a truncation mutation in
, or
was identified. In five of six paired postprogression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for
complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations.
Analyses of primary and secondary mutations in
and
provide evidence for these primary mutations in conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance. PARPi resistance due to secondary mutations underpins the need for early delivery of PARPi therapy and for combination strategies.
.
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Background: Rare gynecologic cancers, such as ovarian carcinosarcoma (OCS), uterine serous carcinoma (USC) and ovarian clear cell adenocarcinoma (OCCA), have limited treatment options and ...molecular alterations that drive cell proliferation and drug resistance, resulting in poor overall survival. The anti-microtubule agent (AMA) paclitaxel is used in first-line treatment of most gynecologic cancers; however, the AMA eribulin is known to have additional anticancer properties (Goto et al. Anticancer Res 38:2929, 2018; Ho et al. Cancer Res 82:4457, 2022). Eribulin ADCs have been developed for targeted delivery to limit toxicity and maximize response. FZEC is an anti-folate receptor α (FRA)-eribulin ADC (Shimizu et al. Clin Cancer Res 27:3905, 2021) and MORAb-109 targets eribulin to mesothelin (MSLN; Albone et al. Annals Oncol 31:S491, 2020). Here we provide preclinical data to support clinical trials of FZEC and MORAb-109 in rare gynecologic cancers. Methods: Fresh tumor tissue from patients consented to the WEHI Stafford Fox Rare Cancer Program was used to establish a cohort of patient-derived xenograft (PDX) models of high-grade serous ovarian carcinoma (HGSOC), OCS, USC and OCCA. PDX models were screened for FRA and MSLN expression by IHC and quantified by HALO software, and 15 models were selected for in vivo testing. Tumor-bearing mice were treated with eribulin (1 mg/kg TIW 3 wks), FZEC (12.5 mg/kg Q14Dx3) or MORAb-109 (25 mg/kg Q14Dx3) and compared to standard of care treatments. Results: About 80% of HGSOC PDX models were FRA positive with no difference between models from chemonaïve samples vs multiple lines of prior treatment. FRA expression was frequent in USC and OCCA models, with MSLN seen in a smaller subset. Despite most (80%) models being cisplatin refractory, 11/15 responded to eribulin with the 4 non-responders having high MDR1 expression and being from previously treated patients. Overall, responses to FZEC and MORAb-109 appeared to correlate with FRA and MSLN expression; importantly, some models with moderate to high target antigen expression showed deeper and more durable responses to FZEC and MORAb-109 compared to eribulin. Conclusions: Responses to FZEC and MORAb-109 correlated with FRA and MSLN expression, with equivalent or better activity compared to eribulin in target-positive PDX models of HGSOC, USC and OCCA. Table: see text
Abstract
The high mortality (>80%) seen in high-grade serous ovarian cancer (HGSOC) highlights the unmet clinical need for treatments capable of producing long-term sustained responses. The related ...cancer, ovarian carcinosarcoma (OCS), has even poorer survival rates, which is due in part to being a rare cancer but also because of its unique phenotype. OCS are composed of both epithelial (carcinoma) and mesenchymal (sarcoma) components and molecular analysis has shown that most OCS are monoclonal and are derived from a common progenitor with sarcomatous transformation occurring by a stable epithelial-to-mesenchymal transition (EMT) process involving reprogramming of gene expression. Paclitaxel is an effective microtubule-stabilizing drug that is used in the treatment of HGSOC and OCS, however, resistance to platinum-taxane treatment usually occurs within 2-3 years and earlier in many OCS. We have been investigating the microtubule inhibitors, vinorelbine and eribulin, which each bind to distinct regions of microtubules and have a different mechanism of inhibition compared to paclitaxel. Eribulin has also been shown to reverse EMT, inducing vasculature remodeling and changes to the tumor-immune microenvironment. This dual activity of eribulin provides greater potential for improved efficacy in the clinic. Focusing on platinum resistant/refractory patient-derived xenografts (PDX) of HGSOC and OCS we assessed response to paclitaxel, vinorelbine and eribulin treatment and observed that around 50% of PDX were sensitive (HGSOC 8/13, 8/13 and 4/8 respectively; OCS 3/6 for all treatments). To deliver higher doses of drug to tumors but also limit toxicity, antibody-drug conjugates (ADCs) are being developed. MORAb-202 is an eribulin-anti-folate receptor alpha (FRα) ADC. It has been reported that 80-90% of HGSOC express FRα and in our HGSOC PDX cohort 14/15 (93%) were positive. However, only 1/5 (20%) OCS model showed any FRα and this was restricted to epithelial glandular structures, <5% of total area. We treated HGSOC and OCS PDX models with a single dose of MORAb-202, equivalent to a single ¼ dose of eribulin. Impressive sensitivity to MORAb-202 was observed in 2/3 HGSOC PDX, with the third model showing a response initially, then relapsing around 60 days post treatment. Two OCS PDX assessed were refractory to MORAb-202 due to insufficient FRα expression. These data provide validation that MORAb-202 is targeted to FRα-expressing tumors exclusively and in this preclinical setting is highly efficacious. This work was funded by Eisai Inc.
Citation Format: Cassandra J. Vandenberg, Gwo-Yaw Ho, Ksenija Nesic, Elizabeth M. Swisher, Sean M. Grimmond, Matthew J. Wakefield, Holly E. Barker, David D. Bowtell, Clare L. Scott. Improving efficacy of microtubule inhibitors in the treatment of high-grade serous ovarian cancer and ovarian carcinosarcoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1074.
Discourses of government and the nuclear industry erase previous fear and knowledge about the damages and injuries from nuclear weapons that impact indigenous communities. This cover-up enables ...nuclear states and nuclear industries to promote nuclear energy as a viable response to climate change. Many people, including environmentalists, consider nuclear energy to be the only viable energy source for the future global economy in that it does not contribute to climate change. It is difficult for us to consider the full scope of the risks that accompany decisions to embrace nuclear energy as a means to reduce greenhouse gas emissions, however, because lessons learned about radiation remain secret or silenced.
Trait anxiety can affect cognitive control resulting in ineffective and/or inefficient task performance. Moreover, previous functional Magnetic Resonance Imaging (fMRI) studies have reported altered ...dorsolateral prefrontal cortex (DLPFC) activity in anxious cohorts, particularly when executive control is required. Recently, it has been demonstrated that cortical glutamate levels can predict both functional activation during cognitive control, and anxiety levels. In the present study we sought to investigate the relationship between trait anxiety, prefrontal glutamate levels and functional activation in DLPFC during a cognitive control task. Thirty-nine participants assigned to either low trait anxiety (LTA) or high trait anxiety (HTA) groups underwent 1H-Magnetic Resonance Spectroscopy (1H-MRS) to measure levels of resting glutamate in the prefrontal cortex (PFC). Participants also completed fMRI during a Stroop task comprising congruent and incongruent colour word trials. The HTA group showed reduced task performance relative to the LTA group. In the LTA group, there was a positive association between PFC Glu levels and DLPFC activation during incongruent trials. This association was absent in the HTA group. Individual differences in trait anxiety affect the relationship between PFC glutamate levels and DLPFC activation, possibly contributing to ineffective task performance when cognitive control is required.
Background:
Depression and low mood are leading contributors to disability worldwide. Research indicates that clinical depression may be associated with low creatine concentrations in the brain and ...low prefrontal grey matter volume. Because subclinical depression also contributes to difficulties in day-to-day life, understanding the neural mechanisms of depressive symptoms in all individuals, even at a subclinical level, may aid public health.
Methods:
Eighty-four young adult participants completed the Depression, Anxiety and Stress Scale (DASS) to quantify severity of depression, anxiety and stress, and underwent 1H-Magnetic Resonance Spectroscopy of the medial prefrontal cortex and structural magnetic resonance imaging (MRI) to determine whole-brain grey matter volume.
Results/outcomes:
DASS depression scores were negatively associated (a) with concentrations of creatine (but not other metabolites) in the prefrontal cortex and (b) with grey matter volume in the right superior medial frontal gyrus. Medial prefrontal creatine concentrations and right superior medial frontal grey matter volume were positively correlated. DASS anxiety and DASS stress scores were not related to prefrontal metabolite concentrations or whole-brain grey matter volume.
Conclusions/interpretations:
This study provides preliminary evidence from a representative group of individuals who exhibit a range of depression levels that prefrontal creatine and grey matter volume are negatively associated with depression. While future research is needed to fully understand this relationship, these results provide support for previous findings, which indicate that increasing creatine concentrations in the prefrontal cortex may improve mood and well-being.
Abstract Purpose Radiotherapy (RT) is used frequently in patients with melanoma, but results are suboptimal because the disease is often radioresistant. This may be due to constitutive activation of ...MAPK pathway signalling through mutations involving RAS/RAF. Thus, we studied whether trametinib, a potent and selective allosteric inhibitor of MEK1/2 could improve the efficacy of RT. Methods and materials Clonogenic survival assays were performed in human BRAF-mutant (A375), NRAS-mutant (D04, WM1631), KRAS-mutant (WM1791c) and wild-type (PMWK) melanoma cell lines. The effects of trametinib with and without radiation on protein levels of MEK effectors were measured by immunoblot analyses. Cell cycle effects, DNA damage repair, mitotic catastrophe and senescence were measured using flow cytometry, γH2Ax staining, nuclear fragmentation and β-galactosidase staining, respectively. Additionally, athymic mice with D04 flank tumours were treated with fractionated RT after gavage with trametinib and monitored for tumour growth. Results All cell lines, except PMWK, exhibited enhanced cytotoxicity when RT was combined with trametinib compared to either agent alone. Sensitiser enhancement ratios were 1.70, 1.32, 1.10, and 1.70 for A375, D04, WM1361 and WM1791c, respectively. Trametinib efficiently blocked RT-induced phosphorylation of ERK at nanomolar concentrations. Increased radiosensitivity correlated with prolonged G1 arrest and reduction in the radioresistant S phase up to 48 h following RT. A larger population of senescence-activated β-galactosidase-positive cells was seen in the trametinib pretreated group, and this correlated with activation of two of the major mediators of induced senescence, p53 and pRb. Mice receiving the combination treatment (trametinib 1 mg/kg and RT over 3 days) showed a reduced mean tumour volume compared with mice receiving trametinib alone ( p = 0.016), or RT alone ( p = 0.047). No overt signs of drug toxicity were observed. Conclusion Trametinib radiosensitised RAS-/RAF-mutated melanoma cells by inducing prolonged G1 arrest and premature senescence. In this pre-clinical study we demonstrate that combining trametinib and RT is well tolerated, and reduces tumour growth in vivo.
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