Evaluation of the impact of treatment delays and dose reductions in human ovarian cancer orthotopic mouse models

The roles of protection of telomeres 1 (POT1) in human ovarian cancer have not been fully elucidated. Here, we investigated the impact of POT1 knockdown (POT1-KD) on in vitro cell proliferation, tumorigenesis, and histone deacetylase inhibitor (HDACi) response in human ovarian cancer-derived SK-OV3 cells. The POT1 gene was knocked down by infection with POT1 lenti-shRNA. POT1, c-Myc, and hTERT mRNA levels and relative telomere length were determined by qRT-PCR; POT1 protein levels were determined by western blot. The relative telomerase activity levels were detected using qTRAP; cell proliferation was assessed using cumulative population doubling (cPD) experiments. Cell tumorigenicity was evaluated by anchorage-independent cell growth assays, and cell response to HDACi was determined by luminescence cell viability assays. Results indicate that lenti-shRNA-mediated POT1-KD significantly reduced POT1 mRNA and protein expression. POT1-KD immediately downregulated c-Myc expression, which led to the inhibition of cell proliferation, tumorigenesis, and HDACi response. However, after brief suppression, c-Myc expression increased in the medium term, which resulted in enhanced cell proliferation, tumorigenesis, and HDACi response in the POT1-KD cells. Furthermore, we discovered that c-Myc regulated cell proliferation and tumorigenesis via hTERT/telomerase/telomere pathway.

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404 LY2228820 Dimesylate, a P38 MAPK Inhibitor, Demonstrates Anti-Neoplastic Activity in Mouse Models of Human Ovarian Cancer

European Journal of Cancer ◽

10.1016/s0959-8049(12)72202-5 ◽

2012 ◽

Vol 48 ◽

pp. 123

Author(s):

S. Pratt ◽

R. Gilmour ◽

N. Brooks ◽

E. Chan ◽

L. Stancato

Keyword(s):

Ovarian Cancer ◽

P38 Mapk ◽

Mouse Models ◽

Human Ovarian Cancer ◽

P38 Mapk Inhibitor ◽

Mapk Inhibitor

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Abstract 4900: Cysteamine suppresses tumor metastasis by inhibiting activity of matrix metalloproteases without inducing toxicity in mouse models of human ovarian cancer

10.1158/1538-7445.am2017-4900 ◽

2017 ◽

Author(s):

Akiko Suzuki ◽

Rukmini Bhardwaj ◽

Pamela Leland ◽

Bharat H. Joshi ◽

Raj K. Puri

Keyword(s):

Ovarian Cancer ◽

Mouse Models ◽

Tumor Metastasis ◽

Matrix Metalloproteases ◽

Human Ovarian Cancer ◽

Inhibiting Activity

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Modeling the impact of genetic heterogeneity on immunotherapy

Science Translational Medicine ◽

10.1126/scitranslmed.abf7104 ◽

2020 ◽

Vol 12 (571) ◽

pp. eabf7104

Author(s):

Ioannis Zervantonakis

Keyword(s):

Ovarian Cancer ◽

Mouse Models ◽

Genetic Heterogeneity ◽

Genetically Engineered ◽

Genetically Engineered Mouse Models ◽

The Impact

A panel of genetically engineered mouse models recapitulates genotype-driven responses to immunotherapy and uncovers a driver of immunotherapy resistance in ovarian cancer.

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Comparison of standard versus reduced-dose pegfilgrastim on clinical outcomes and chemotherapy dose intensity in patients with advanced pancreatic cancer receiving cytotoxic combination chemotherapy (NAPPCG) in an outpatient oncology infusion clinic.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15710 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15710-e15710

Author(s):

Krystal Hicks ◽

Adam Odeh

Keyword(s):

Pancreatic Cancer ◽

Dose Intensity ◽

Treatment Delays ◽

Myelosuppressive Chemotherapy ◽

Full Dose ◽

Reduced Dose ◽

Chemotherapy Dose ◽

The Impact ◽

Dose Reductions ◽

Chemotherapy Dose Intensity

e15710 Background: Pegfilgrastim use has been shown to reduce the incidence of febrile neutropenia when given at recommended dosage (6 mg) following myelosuppressive chemotherapy. Despite lack of supportive data, many prescribers have adopted the practice of utilizing reduced dosages (3-4 mg) of pegfilgrastim, often citing bone pain as reason for dose reduction. We sought to explore the impact of reduced-dose pegfilgrastim on chemotherapy dose intensity in patients with pancreatic cancer treated with the triplet combination of nab-paclitaxel, cisplatin and gemcitabine (NabPlagem) at our facility. Methods: A retrospective analysis was conducted on all patients who received NabPlagem chemotherapy in combination with pegfilgrastim during the period of 1/1/16 - 9/30/16. Patients who received at least 2 cycles were considered evaluable. Chemotherapy was administered on Days 1 and 8 of a 21-day cycle with pegfilgrastim administered Days 2 and 9. Chemotherapy doses were considered full-intensity if no reduction made from original treatment schema (i.e. 125 mg/m2 nab-paclitaxel, 25 mg/m2 cisplatin and gemcitabine 1000 mg/m2) with no doses delayed or omitted from treatment plan. Results: A total of 54 chemotherapy cycles were administered, with patients receiving between 5-13 cycles. Of these 54 cycles, 14 were given with reduced-dose pegfilgrastim (26%) and 40 at full dosage (74%). In the patients receiving full dose pegfilgrastim, treatment delays and omissions were observed in 5% cycles (n = 2), with no dose reductions required. Full dose-intensity was obtained in 90% cycles (36/40). In comparison, treatment delays and omissions were observed in 14% cycles given with reduced-dose pegfilgrastim. Dose reductions were required in 10/14 cycles (71%). Full dose-intensity was observed in 28.5% cycles (4/14). Conclusions: Based on this data, dosage of pegfilgrastim dose is an important factor in maintaining dose-intensity of chemotherapy, and full dosing (6 mg) should be preferred dosing schedule when used with myelosuppressive chemotherapy.

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Metastasis suppressor 1 expression in human ovarian cancer: The impact on cellular migration and metastasis

International Journal of Oncology ◽

10.3892/ijo.2015.3121 ◽

2015 ◽

Vol 47 (4) ◽

pp. 1429-1439 ◽

Cited By ~ 5

Author(s):

RONG LIU ◽

TRACEY A. MARTIN ◽

NICOLA J. JORDAN ◽

FIONA RUGE ◽

LIN YE ◽

...

Keyword(s):

Ovarian Cancer ◽

Cellular Migration ◽

Metastasis Suppressor ◽

Human Ovarian Cancer ◽

Metastasis Suppressor 1 ◽

The Impact

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Tumour-suppressor microRNAs regulate ovarian cancer cell physical properties and invasive behaviour

Open Biology ◽

10.1098/rsob.160275 ◽

2016 ◽

Vol 6 (11) ◽

pp. 160275 ◽

Cited By ~ 13

Author(s):

Clara K. Chan ◽

Yinghong Pan ◽

Kendra Nyberg ◽

Marco A. Marra ◽

Emilia L. Lim ◽

...

Keyword(s):

Ovarian Cancer ◽

Physical Properties ◽

Cancer Cells ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Single Cells ◽

Tumour Suppressor ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

The Impact

The activities of pathways that regulate malignant transformation can be influenced by microRNAs (miRs). Recently, we showed that increased expression of five tumour-suppressor miRs, miR-508-3p, miR-508-5p, miR-509-3p, miR-509-5p and miR-130b-3p, correlate with improved clinical outcomes in human ovarian cancer patients, and that miR-509-3p attenuates invasion of ovarian cancer cell lines. Here, we investigate the mechanism underlying this reduced invasive potential by assessing the impact of these five miRs on the physical properties of cells. Human ovarian cancer cells (HEYA8, OVCAR8) that are transfected with miR mimics representing these five miRs exhibit decreased invasion through collagen matrices, increased cell size and reduced deformability as measured by microfiltration and microfluidic assays. To understand the molecular basis of altered invasion and deformability induced by these miRs, we use predicted and validated mRNA targets that encode structural and signalling proteins that regulate cell mechanical properties. Combined with analysis of gene transcripts by real-time PCR and image analysis of F-actin in single cells, our results suggest that these tumour-suppressor miRs may alter cell physical properties by regulating the actin cytoskeleton. Our findings provide biophysical insights into how tumour-suppressor miRs can regulate the invasive behaviour of ovarian cancer cells, and identify potential therapeutic targets that may be implicated in ovarian cancer progression.

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Are XELOX and FOLFOX equivalent in colorectal cancer? Dose intensity, toxicity, and treatment duration in clinical practice.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e14556 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e14556-e14556

Author(s):

Ya Ning Gao ◽

Aline Mamo ◽

Michael Ostaric Palumbo ◽

Gerald Batist ◽

Prosanto Chaudhury ◽

...

Keyword(s):

Clinical Practice ◽

Treatment Duration ◽

Dose Intensity ◽

Sensory Neuropathy ◽

Treatment Delays ◽

Metastatic Setting ◽

Impact On Survival ◽

Peripheral Sensory ◽

The Impact ◽

Dose Reductions

e14556 Background: Xelox and Folfox regimens have been shown to be equivalent in clinical trials for colorectal cancers. However, concerns about toxicity induced by Xelox in clinical practice have been reported, resulting in reduced dose intensity. In this retrospective analysis, we compared the dose intensity of Xelox to Folfox in relation to toxicity. Methods: 208 patients were treated in adjuvant (Xelox: n=56, median age 65 years; Folfox: n=40, median age 66 years) or metastatic (Xelox: n=65, median age 66 years; Folfox: n=47 median age 62 years) settings. 90% of patients had ECOG 0-1. Results: In the adjuvant setting, 86% of patients treated with Xelox received a lower dose of the drug up front, compared to only 10% of Folfox-treated patients. Additional dose reductions occurred in subsequent cycles in 23% of Xelox-treated patients (mean relative dose intensity (RDI) Oxaliplatin: 72%; Capecitabine: 74%) but not Folfox-treated patients (mean RDI Oxaliplatin: 85%, 5-FU: 86%). A higher percentage of Folfox-treated patients had toxicities compared to Xelox-treated patients: nausea (30% vs 18%), diarrhea (47% vs 24%), and peripheral sensory neuropathy (32% vs 3%). Treatment delays were more frequent in Folfox (40%); mean cumulative delay, 9.4 (range 2.1-52.4) weeks, compared to Xelox (20%); mean cumulative delay, 10.2 (3.1-48.1) weeks. Mean treatment duration was equal (Xelox: 22.8 (3.0-78.1); Folfox: 22.6 (2.3-64.4) weeks). In the metastatic setting, results followed a similar pattern. 75% of Xelox-treated patients received a lower dose up front compared to 33% of Folfox-treated patients. Further dose reductions occurred in 31% of Xelox-treated patients (mean RDI Oxaliplatin: 70%; Capecitabine: 67%) compared to 20% of Folfox-treated patients (mean RDI oxaliplatin: 75%; 5-FU: 69%). Treatment delays occurred in 60% of Folfox-treated patients and 43% of Xelox-treated patients becauseof toxicities. Mean treatment duration was 24.9 (3.0-65.0) and 26.1 (4.0-60.1) weeks respectively. Conclusions: The higher dose reduction of Xelox compared to Folfox appeared to enable treatment completion with less toxicities. The impact on survival and cost of treatments will be presented.

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