scholarly journals Circulating CD14highCD16lowintermediate blood monocytes as a biomarker of ascites immune status and ovarian cancer progression

2020 ◽  
Vol 8 (1) ◽  
pp. e000472
Author(s):  
Mélissa Prat ◽  
Augustin Le Naour ◽  
Kimberley Coulson ◽  
Fanny Lemée ◽  
Hélène Leray ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
Treatment Response ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Immune Status ◽  
Tumor Development ◽  
Tumor Burden ◽  
Blood Monocytes ◽  
Monocyte Subsets

BackgroundBesides the interest of an early detection of ovarian cancer, there is an urgent need for new predictive and prognostic biomarkers of tumor development and cancer treatment. In healthy patients, circulating blood monocytes are typically subdivided into classical (85%), intermediate (5%) and non-classical (10%) populations. Although these circulating monocyte subsets have been suggested as biomarkers in several diseases, few studies have investigate their potential as a predictive signature for tumor immune status,tumor growth and treatment adaptation.MethodsIn this study, we used a homogeneous cohort of 28 chemotherapy-naïve patients with ovarian cancer to evaluate monocyte subsets as biomarkers of the ascites immunological status. We evaluated the correlations between circulating monocyte subsets and immune cells and tumor burden in peritoneal ascites. Moreover, to validate the use of circulating monocyte subsets tofollow tumor progression and treatment response, we characterized blood monocytes from ovarian cancer patients included in a phase 1 clinical trial at baseline and following murlentamab treatment.ResultsWe demonstrate here a robust expansion of the intermediate blood monocytes (IBMs) in ovarian cancer patients. We establish a significant positive correlation between IBM percentage and tumor–associate macrophages with a CCR2high/CD163high/CD206high/CD86lowprofile. Moreover, IBM expansion is associated with a decreased effector/regulatory T-cell ratio in ascites and with the presence of soluble immunosuppressive mediators. We also establish that IBM proportion positively correlates with the peritoneum tumor burden. Finally, the study of IBMs in patients with ovarian cancer under immunotherapy during the phase clinical trial supports IBMs to follow the evolution of tumor development and the treatment adaptation.ConclusionsThis study, which links IBM level with immunosuppression and tumor burden in peritoneum, identifies IBMs as apotential predictive signature of ascites immune status and as a biomarker ofovarian cancer development and treatment response.Trial registration numberEudraCT: 2015-004252-22NCT02978755.

Phase 1A clinical trial of the first-in-class fascin inhibitor NP-G2-044 evaluating safety and anti-tumor activity in patients with advanced and metastatic solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2548-2548
Author(s):  
Vincent Chung ◽  
Komal L. Jhaveri ◽  
Daniel D. Von Hoff ◽  
Xin-Yun Huang ◽  
Edward Graeme Garmey ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
Dendritic Cells ◽  
Cancer Patients ◽  
Checkpoint Inhibitors ◽  
Drug Synergism ◽  
Duration Of Treatment ◽  
Antigen Uptake ◽  
Increased Risk ◽  
Metastatic Activity

2548 Background: Fascin inhibitors block tumor metastasis and increase antigen uptake in intra-tumoral dendritic cells. Filopodia, finger-like protrusions on cell surfaces, are necessary for migration of metastatic tumor cells and intra-tumoral dendritic cells. Fascin is the primary actin cross-linker in filopodia and elevated levels correlate with increased risk of metastasis, disease progression and mortality. NP-G2-044 is a novel small molecule that inhibits function of fascin. Pre-clinical data demonstrate drug-associated reductions in tumor growth and metastasis, enhanced immune response and survival in treated animals, and drug-drug synergism when combined with anti-PD-1 antibodies. Methods: This multicenter phase 1A clinical trial was designed to evaluate safety and tolerability of NP-G2-044 and to identify the drug’s recommended phase 2 dose (RP2D) using a 3+3 dose escalation design. NP-G2-044 was administered to patients (pts.) with treatment-refractory solid tumor malignancies as a single oral daily dose for 6-week cycles that included 4 weeks on (daily dosing) and 2 weeks off (rest). Results: A total of 23 pts. were enrolled in 7 dose cohorts ranging from 200-2100 mg. QD. Overall, NP-G2-044 appeared well-absorbed and distributed with Tmax of ̃4 hrs and T1/2 of 20-24 hrs. Across all cohorts, no DLTs, drug-related SAEs or patient deaths were observed. Based on PK and safety findings, 1600 mg. daily was selected as the provisional RP2D. While no formal RECIST-based objective responses were observed, consistent with the drug’s non-cytotoxic mechanism of action, preliminary signals of anti-tumor and anti-metastatic activity were observed. These include dose proportional increases in duration of treatment, progression-free-survival, and metastasis-free interval, in particular for 4/4 late-stage ovarian cancer patients (table). Comparison of time on treatment (TOT) for ovarian cancer patients. Conclusions: In this first-in-human clinical trial, the novel fascin inhibitor, NP-G2-044, appeared safe and well tolerated. Signals of single-drug anti-tumor and anti-metastatic activity were observed. A phase 2A clinical trial with a particular focus on Ovarian Cancer will seek to elucidate signals of RP2D activity in both monotherapy and the combination of NP-G2-044 with anti-PD-(L)1 immune checkpoint inhibitors. Clinical trial information: NCT03199586. [Table: see text]

scholarly journals The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation

2020 ◽  
Vol 48 (7) ◽  
pp. 3816-3831 ◽  
Author(s):  
Tao Liu ◽  
Qinglv Wei ◽  
Jing Jin ◽  
Qingya Luo ◽  
Yi Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Rna Modification ◽  
Dependent Manner ◽  
The Novel ◽  
A Subunit

Abstract N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests the key roles of m6A in human tumorigenesis. However, whether m6A, especially its ‘reader’ YTHDF1, targets a gene involving in protein translation and thus affects overall protein production in cancer cells is largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified a novel mechanism involving EIF3C, a subunit of the protein translation initiation factor EIF3, as the direct target of the YTHDF1. YTHDF1 augments the translation of EIF3C in an m6A-dependent manner by binding to m6A-modified EIF3C mRNA and concomitantly promotes the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. YTHDF1 is frequently amplified in ovarian cancer and up-regulation of YTHDF1 is associated with the adverse prognosis of ovarian cancer patients. Furthermore, the protein but not the RNA abundance of EIF3C is increased in ovarian cancer and positively correlates with the protein expression of YTHDF1 in ovarian cancer patients, suggesting modification of EIF3C mRNA is more relevant to its role in cancer. Collectively, we identify the novel YTHDF1-EIF3C axis critical for ovarian cancer progression which can serve as a target to develop therapeutics for cancer treatment.

scholarly journals Functional genetic variants of CTNNBIP1 predict platinum treatment response of Chinese epithelial ovarian cancer patients

2020 ◽  
Vol 11 (23) ◽  
pp. 6850-6860
Author(s):  
Haoran Li ◽  
Lihua Chen ◽  
Xiaoxia Tong ◽  
Hongji Dai ◽  
Tingyan Shi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Treatment Response ◽  
Cancer Patients ◽  
Genetic Variants

scholarly journals Lipid Regulatory Proteins as Potential Therapeutic Targets for Ovarian Cancer in Obese Women

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3469
Author(s):  
Jing Yang ◽  
M. Sharon Stack
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
De Novo ◽  
Regulatory Element ◽  
Tumor Burden ◽  
Regulatory Proteins ◽  
De Novo Lipogenesis ◽  
Obese Women ◽  
Gynecological Malignancy ◽  
Global Epidemic

Obesity has become a recognized global epidemic that is associated with numerous comorbidities including type II diabetes, cardiovascular disease, hypertension, and cancer incidence and progression. Ovarian cancer (OvCa) has a unique mechanism of intra-peritoneal metastasis, already present in 80% of women at the time of diagnosis, making it the fifth leading cause of death from gynecological malignancy. Meta-analyses showed that obesity increases the risk of OvCa progression, leads to enhanced overall and organ-specific tumor burden, and adversely effects survival of women with OvCa. Recent data discovered that tumors grown in mice fed on a western diet (40% fat) have elevated lipid levels and a highly increased expression level of sterol regulatory element binding protein 1 (SREBP1). SREBP1 is a master transcription factor that regulates de novo lipogenesis and lipid homeostasis, and induces lipogenic reprogramming of tumor cells. Elevated SREBP1 levels are linked to cancer cell proliferation and metastasis. This review will summarize recent findings to provide a current understanding of lipid regulatory proteins in the ovarian tumor microenvironment with emphasis on SREBP1 expression in the obese host, the role of SREBP1 in cancer progression and metastasis, and potential therapeutic targeting of SREBPs and SREBP-pathway genes in treating cancers, particularly in the context of host obesity.

A B-spline image registration based CAD scheme to evaluate drug treatment response of ovarian cancer patients

2016 ◽  
Author(s):  
Maxine Tan ◽  
Zheng Li ◽  
Kathleen Moore ◽  
Theresa Thai ◽  
Kai Ding ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Image Registration ◽  
Drug Treatment ◽  
Treatment Response ◽  
Cancer Patients ◽  
B Spline

Immunonutrition limits pro-inflammatory and pro-oxidant effects of radiochemotherapy in cancer patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e17022-e17022
Author(s):  
Marie-Paule Vasson ◽  
Jeremie Talvas ◽  
Nicolas Goncalves-Mendes ◽  
Fabrice Kwiatkowski ◽  
Jacques Bienvenu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Enteral Nutrition ◽  
Cancer Patients ◽  
Oesophageal Cancer ◽  
Immune Status ◽  
Ex Vivo ◽  
Ros Production ◽  
Double Blind ◽  
Plasma Antioxidant Capacity ◽  
Functional Capacities

e17022 Background: Peri-operative immunonutrition improves digestive surgical outcomes of cancer patients reducing complications and length of stay. Radiochemotherapy (RCT) generates deleterious effects on nutritional and immune status limiting functional capacities of patients. This study aimed to evaluate if immunonutrition enriched in arginine, EPA & DHA and nucleotides could limit these side effects in Head&Neck (HN), and oesophageal cancer patients. Methods: A double-blind randomized clinical trial was driven with two groups receiving either an Immune Enteral Nutrition (IEN, n=13, Impact, Nestlé) or a Standardized Enteral Nutrition (SEN, n=15) during all RCT (5-7 weeks). Nutritional status, plasma antioxidant capacity (TEAC, FRAP) and functional capacities (WHO score, Karnofsky index) were assessed at the beginning (Db) and at the end (De) of RCT. Immune functions were assessed by leukocytes phenotyping, ex vivo PMN ROS production, and PBMC cytokines & eicosanoids (PGE2) secretion and gene expression. Results: At De vs Db, a significant improvement in total body weight (+2.1kg) was observed in IEN patients as well as albuminemia and NRI in IEN malnourished patients. TEAC and FRAP were increased (+100µM EqTrolox) in IEN patients and higher at De than for SEN patients. Functional capacities were maintained upper the autonomy threshold only in IEN patients. The PMN density of chemo-attractant receptors (CD62L, CD15) and ROS production (+30%) were significantly increased in IEN patients at De vs Db. PBMC PGE2 secretion was unchanged at De in IEN patients and lesser than for SEN patients (65.9±56.8 vs 106.8±59.3 ng/ml, p<0,05). Folding ratios (De/Db) of PBMC mRNA expression were strongly increased for antioxidant response genes (catalase, gpx1&4, sod1&2) and for bactericidal NOX system (cybA, rac1&2). Conclusions: Immunonutrition in adjunction to RCT contributes to maintain functional capacities of patients through improvement of nutritional, anti-oxidant and immune status. Immunonutrition could provide a higher bactericidal capacity and limit inflammatory and oxidative responses induced by RCT in immune cells of HN and oesophageal cancer patients. Clinical trial information: NCT00333099.

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