Harnessing IMGN853-mediated cell cytoxicity response by modulating FRα expression in ovarian cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17061-e17061
Author(s):  
Rajesh Kumar ◽  
Wei Wei ◽  
Sam Lauffer ◽  
Giulia Fulci ◽  
Michael J. Birrer
Keyword(s):  
Ovarian Cancer ◽  
The United States ◽  
Therapeutic Window ◽  
Low Grade ◽  
Cancer Drugs ◽  
Phase I Clinical Trials ◽  
Expression Levels ◽  
Resistant Disease ◽  
Therapeutic Benefits ◽  
Anti Cancer

e17061 Background: Ovarian cancer (OC) is the fifth leading cause of cancer-related death among women in the United States. Standard treatment includes debulking surgery followed by platinum based chemotherapy. While most tumors respond to this treatment, 70% of the tumors recur and develop into a chemo-resistant disease. There is a need for new therapies targeting recurrent chemoresistant OC. To address this need, Mirvetuximab Soravtansine (ImmunoGen, Waltham, MA) has developed an antigen-drug conjugate (ADC) containing DM4, a highly potent maytansinoid derivative that induces the cell cycle arrest, conjugated to an antibody targeting folate receptor alpha (FRα). Mirvetuximab Soravtansine (IMGN853), was tested in Phase I clinical trials on women with recurrent OC and showed low grade toxicity profile and activity in platinum-resistant disease. The goal of this study is to characterize the mechanism(s) leading to IMGN853 resistance in OC and test whether anticancer drugs targeting these mechanisms could be used in combination with IMGN853 for an additive/synergistic therapeutic effect. Methods: In vitro experiments were performed to detect and modulate FRα expression. Results: We show that sensitivity of OC cell lines to IMGN853 correlates with the expression levels of FRα (R = 0.82). Long-term exposure of sensitive cells to sublethal doses of IMGN853 induces drug resistance which correlates with decreased FRα expression. Anti-cancer drugs such as dexamethasone (Dex), which induces glucocorticoid receptors, or epigenetic modulators (Trichostatin A and 5-Azacytidine) induce FRα expression in SKOV3 and OVCAR8 OC cells, suggesting the possibility to use these drugs to maintain sensitivity of OC cells to IMGN853 and increase its therapeutic window. The therapeutic benefits of combining each of these drugs with IMGN853 will be further tested in mice using ovarian cancer patients’ derived xenografts with different FRα expression levels. Conclusions: These findings have clinical implications as they indicate that OC sensitivity to IMGN853 is modulated in part by changes in FRα levels. Resistance to this drug may be overcome by simultaneous treatment with Dex or other anti-cancer drugs such as TSA or AZA.

scholarly journals TRPV4 is a Prognostic Biomarker that Correlates with the Immunosuppressive Microenvironment and Chemoresistance of Anti-Cancer Drugs

2021 ◽  
Vol 8 ◽  
Author(s):  
Kai Wang ◽  
Xingjun Feng ◽  
Lingzhi Zheng ◽  
Zeying Chai ◽  
Junhui Yu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Transient Receptor Potential ◽  
Immune Cell ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
High Expression ◽  
Cancer Drugs ◽  
Free Interval ◽  
Anti Cancer ◽  
Pan Cancer

Background: Transient receptor potential cation channel subfamily V member 4 (TRPV4) has been reported to regulate tumor progression in many tumor types. However, its association with the tumor immune microenvironment remains unclear.Methods: TRPV4 expression was assessed using data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database. The clinical features and prognostic roles of TRPV4 were assessed using TCGA cohort. Gene set enrichment analysis (GSEA) of TRPV4 was conducted using the R package clusterProfiler. We analyzed the association between TRPV4 and immune cell infiltration scores of TCGA samples downloaded from published articles and the TIMER2 database. The IC50 values of 192 anti-cancer drugs were downloaded from the Genomics of Drug Sensitivity in Cancer (GDSC) database and the correlation analysis was performed.Results: TRPV4 was highly expressed and associated with worse overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI) in colon adenocarcinoma (COAD) and ovarian cancer. Furthermore, TRPV4 expression was closely associated with immune regulation-related pathways. Moreover, tumor-associated macrophage (TAM) infiltration levels were positively correlated with TRPV4 expression in TCGA pan-cancer samples. Immunosuppressive genes such as PD-L1, PD-1, CTLA4, LAG3, TIGIT, TGFB1, and TGFBR1 were positively correlated with TRPV4 expression in most tumors. In addition, patients with high expression of TRPV4 might be resistant to the treatment of Cisplatin and Oxaliplatin.Conclusion: Our results suggest that TRPV4 is an oncogene and a prognostic marker in COAD and ovarian cancer. High TRPV4 expression is associated with tumor immunosuppressive status and may contribute to TAM infiltration based on TCGA data from pan-cancer samples. Patients with high expression of TRPV4 might be resistant to the treatment of Cisplatin and Oxaliplatin.

Characterization of CXCR4 Expression in Chondrosarcoma of Bone

2011 ◽  
Vol 135 (6) ◽  
pp. 753-758 ◽  
Author(s):  
Shuting Bai ◽  
Dezhi Wang ◽  
Michael J. Klein ◽  
Gene P. Siegal
Keyword(s):  
Ductal Carcinoma ◽  
Staining Intensity ◽  
The United States ◽  
Cxcr4 Expression ◽  
Low Grade ◽  
High Grade ◽  
Neoplastic Progression ◽  
Regional Lymph Nodes ◽  
Expression Levels ◽  
Potential Marker

Abstract Context.—Alterations in molecular elements derived from the CXC chemokine receptor 4 (CXCR4)/stromal-derived factor 1 (SDF-1) cytokine system have been found to strongly correlate with neoplastic progression leading to metastasis in a number of tumors, including osteosarcoma. Excluding hematologic malignancies, chondrosarcoma of bone is the most common primary malignant tumor of bone in adults in the United States. Like osteosarcoma, chondrosarcoma preferentially metastasizes to lung, bone, and very rarely to regional lymph nodes. However, the role of the signal pathway(s) driving neoplastic progression in chondrosarcoma has not yet been clearly elucidated. Objective.—To test whether CXCR4 was detectable in chondrosarcoma and whether CXCR4 expression levels correlated with chondrosarcoma grade. Design.—Twenty-two chondrosarcoma samples banked at our institution between 2001 and 2006 were retrieved for study. By using invasive ductal carcinoma of the breast and osteosarcoma as the positive controls, immunohistochemistry was performed on paraffin-embedded tissue sections and the intensity of the tumor cells was analyzed by morphometric techniques. Results.—All chondrosarcoma cases (22 of 22) were immunoreactive for CXCR4. However, the staining intensity of the CXCR4 between the low- and high-grade groups was significantly different. There was a higher staining intensity in high-grade chondrosarcoma cells (P < .001). Conclusion.—CXCR4 is expressed in chondrosarcomas. CXCR4 expression levels were higher in high-grade chondrosarcoma cells than in low-grade specimens. A larger number of cases will be required to confirm these results and expand the observation, but preliminary data would argue for CXCR4 immunohistochemistry as a potential marker for biologic aggressiveness in chondrosarcoma of bone.

Prognostic significance of obesity in high-grade serous carcinoma of the ovary

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16528-e16528 ◽  
Author(s):  
M. Schlumbrecht ◽  
D. Urbauer ◽  
D. Gershenson ◽  
R. Broaddus
Keyword(s):  
Ovarian Cancer ◽  
Body Mass Index ◽  
Overall Survival ◽  
Body Mass ◽  
Neoadjuvant Treatment ◽  
The United States ◽  
Wilcoxon Test ◽  
Serous Carcinoma ◽  
Low Grade ◽  
High Grade

e16528 Background: Obesity is an epidemic public health problem in the United States. In gynecologic oncology, obesity is an established risk factor for endometrial cancer. However, its role in the pathogenesis and survival in ovarian cancer is debated. Recent studies have attempted to elucidate a possible relationship, but variations in design and heterogeneity in patient characteristics make it difficult to draw definitive conclusions. The purpose of our study was to determine if body mass index at the time of treatment initiation for high grade serous ovarian carcinoma has an effect on patient outcome. Methods: Nine-hundred four patients treated for ovarian cancer at M.D. Anderson Cancer Center were identified between 2002 and 2007. Patients were excluded for low grade or non-serous histology, neoadjuvant treatment, or if presenting with recurrent disease. Clinicopathologic data were extracted by retrospective chart review. Patients were stratified by body mass index (BMI) as normal (BMI<25), overweight (BMI 25-<30), or obese (BMI>30). All were treated with primary cytoreduction and standard platinum/taxane chemotherapy. Chemotherapy was dosed using adjusted body weights. Outcomes included time to recurrence, overall survival, success of surgical debulking, and chemotherapeutic toxicities. Statistical analysis was performed using Fisher's exact test, Wilcoxon test, and Kaplan-Meier estimates. Results: A total of 127 patients were included for analysis. Patients were followed for a mean of 37 months (range 3–86 months). Twenty-one patients were obese (16.5%), and 35 were overweight (27.5%). Diabetes was more prevalent in the obese cohort (p = 0.0038). There was a trend towards greater likelihood of suboptimal debulking in obese patients, but this did not reach statistical significance (p = 0.06). BMI had no effect on recurrence-free survival (HR 0.69 [CI 0.39–1.23], p = 0.21) or overall survival (HR 0.95 [CI 0.68–2.43], p = 0.91). There was no difference in chemotherapy side effects or chemoresistance across BMI strata. Conclusions: Body mass index has no effect on survival in women with high grade serous ovarian cancer. Effectively managing comorbidities and ensuring adequate chemotherapy dosing in the obese patient is crucial for optimizing outcome. No significant financial relationships to disclose.

scholarly journals Ovarian Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology

2021 ◽  
Vol 19 (2) ◽  
pp. 191-226
Author(s):  
Deborah K. Armstrong ◽  
Ronald D. Alvarez ◽  
Jamie N. Bakkum-Gamez ◽  
Lisa Barroilhet ◽  
Kian Behbakht ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Gynecologic Cancer ◽  
Germ Cell Tumors ◽  
Mucinous Carcinoma ◽  
The United States ◽  
Parp Inhibitors ◽  
Primary Treatment ◽  
Low Grade ◽  
Nccn Guidelines ◽  
Primary Surgery

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country’s fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.

Obesity and Gynecologic Cancer Etiology and Survival

2013 ◽  
pp. e222-e228 ◽  
Author(s):  
Penelope M. Webb
Keyword(s):  
Ovarian Cancer ◽  
Endometrial Cancer ◽  
Strong Association ◽  
Gynecologic Cancer ◽  
The United States ◽  
Overweight And Obesity ◽  
Low Grade ◽  
Cancer Specific Survival ◽  
Increased Risk ◽  
Wide Range

The prevalence of overweight and obesity in the United States and elsewhere has increased dramatically in recent decades. It has long been known that obese women have an increased risk of developing endometrial cancer, but recent studies suggest this association is strongest for the most common low-grade endometrioid endometrial cancers and weaker for the other histologic subtypes. There are insufficient data to assess whether obesity affects endometrial cancer-specific survival or whether the relation with all-cause mortality is similar to that seen in the general population. Recent data suggest obesity also increases risk of ovarian cancer, although it may not influence risk of the high-grade serous cancers that account for the majority of ovarian cancer deaths, and that it is also associated with poorer outcomes. There is currently insufficient evidence to draw any clear conclusions regarding the relation between obesity and risk of/survival from other gynecologic cancers although there are suggestions that obesity may increase risk of cervical cancer, particularly adenocarcinoma, and perhaps vulvar cancer. Possible mechanisms whereby obesity might influence gynecologic cancer risk and survival include: its strong association with endogenous estrogen levels among postmenopausal women, its effects on glucose metabolism, its effects on the wide range of adipocytokines and inflammatory mediators that are produced by adipose tissue and altered in concentration among obese individuals, and its potential effects on patient management, particularly with regard to chemotherapy dosing.

Bevacizumab (Bev) for treatment of recurrent serous borderline (SB) or low-grade serous (LGS) ovarian cancer: A retrospective review of the Memorial Sloan-Kettering Cancer Center (MSKCC) experience.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5545-5545
Author(s):  
Rachel N. Grisham ◽  
Evis Sala ◽  
Qin Zhou ◽  
Alexia Iasonos ◽  
Deborah DeLair ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Response Rates ◽  
Cancer Center ◽  
Low Grade ◽  
Primary Peritoneal Cancer ◽  
Peritoneal Cancer ◽  
Resistant Disease ◽  
Recist 1.1 ◽  
The Mean ◽  
A Prospective Study

5545 Background: LGS ovarian cancer is a rare subtype of ovarian cancer, accounting for 10% of ovarian cancer cases. Patients typically present at an early age, exhibit a protracted clinical course, and have response rates to chemotherapy of < 4%. Limited clinical data suggests that bev may have activity in this disease. The objective of this study was to determine the response rate to treatment with bev in patients with SB or LGS ovarian cancer treated at MSKCC. Methods: Following IRB approval, all patients with a diagnosis of SB or LGS ovarian or primary peritoneal cancer treated with ≥ 1 dose of bev for persistent or recurrent disease were identified. 17 patients were treated at MSKCC between July 2005 and June 2012. Diagnosis was confirmed by a gynecologic pathologist. All imaging was independently reviewed by the study radiologist and response was determined by RECIST 1.1 criteria. Results: 17 patients, 10 with LGS ovarian cancer, 3 with LGS primary peritoneal cancer, and 4 with SB disease were included in the analysis. The mean number of prior therapies was 3.4 (range: 1-9, median: 2). Two patients were treated with bev alone, the remainder (15) received bev in combination with paclitaxel (Pac, 6), topotecan (1), pemetrexed (1), oral cyclophosphamide (3), gemcitabine (Gem, 2), Gem and carboplatin (Carbo) (1), or Pac and Carbo (1) .Two patients were not evaluable for response due to termination of treatment prior to first radiographic assessment. The median duration of bev treatment was 23 weeks (mean: 32.2; range 6-79.4). Conclusions: This data suggests that the addition of bev to cytotoxic chemotherapy may produce dramatically higher response rates than chemotherapy alone in patients with SB and LGS ovarian cancer. A prospective study of bev for treatment of this chemotherapy resistant disease is warranted. [Table: see text]

Price trajectories assessment for Medicare Part B generic anti-cancer drugs.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6624-6624
Author(s):  
Noa Gordon ◽  
Omer Ben-Aharon ◽  
Salomon M. Stemmer ◽  
Dan Greenberg ◽  
Daniel A. Goldstein
Keyword(s):  
Generic Drug ◽  
Generic Drugs ◽  
The United States ◽  
Medicare Part ◽  
Cancer Drugs ◽  
Patent Expiration ◽  
Price Increases ◽  
Anti Cancer ◽  
Medicare Part B

6624 Background: Patented anti-cancer drugs launch prices have increased in recent years with subsequent increases after launch. Recently, large price increases of generic drugs were at the center of public attention in the United States. Our aim was to assess price changes with time for Medicare part B anti-cancer generic drugs and to understand how drug characteristics and market structure influence price trajectories. Methods: We included all Medicare part B anti-cancer drugs with price reported in both 2006 and 2016. Patent expiration dates were attached using the Medicare Drug Patent Expiration engine and drugs with a patent expiration date later than 2006 were excluded. Generic manufacturers' FDA approvals for each drug were extracted from the FDA Orange Book. For each drug we extracted the Average Sales Price (ASP) history from October 2006 to October 2016, published by the Center for Medicare and Medicaid services (CMS). Prices were adjusted for inflation, using information obtained from the United States Department of Labor. For each drug we calculated the cumulative ASP change during the follow-up period. Data were analyzed using IBM SPSS Statistics software. Results: We identified 31 anti-cancer generic drugs that met the inclusion and exclusion criteria. During the follow-up period, 15 (48%) drugs had increases in price (median 139%, range 18-2632%). Seven (23%) drugs increased by more than 200% (Table 1). Both gradual price and acute price increases were observed. Some of the drugs which had substantial price increases had no market competition market. Conclusions: Generic drug prices may change substantially with time. Gradual or rapid price increases may be due to lack of generic drug competition, substitution shortages or marketing reasons. New regulations may be needed to prevent further increases in generic drug costs, while balancing the need to maintain financial incentives for drug production and competition. [Table: see text]

Abstract 2570: Combination studies of EC145 with approved anti-cancer drugs for ovarian cancer

2011 ◽  
Author(s):  
Joseph A. Reddy ◽  
Alicia Bloomfield ◽  
Melissa Nelson ◽  
Ryan Dorton ◽  
Christopher P. Leamon
Keyword(s):  
Ovarian Cancer ◽  
Cancer Drugs ◽  
Anti Cancer ◽  
Combination Studies

Beta-glucans is a potential inhibitor of ovarian cancer: based on molecular and biological aspects

2021 ◽  
Vol 22 ◽  
Author(s):  
Fatemeh Sadoughi ◽  
Zatollah Asemi ◽  
Jamal Hallajzadeh ◽  
Mohammad Ali Mansournia ◽  
Bahman Yousefi
Keyword(s):  
Ovarian Cancer ◽  
Cancer Treatment ◽  
Linear Polymers ◽  
Cancer Drugs ◽  
Potential Inhibitor ◽  
Anti Cancer ◽  
Beta Glucans ◽  
Biological Aspects

: Ovarian cancer is a lethal type of cancer which is initiated in the ovaries and affects 1 out of every 75 women. Due to the high number of deaths (almost 152,000) related to this cancer, it seems that novel effiecient therapeutic methods are required in this field. Beta-glucans are a type of glucose linear polymers which have proven to have a lot of advantageous activities. Recently, investigations have declared that these polysaccharides have the potential to be used as anti-cancer drugs. These agents are able to affect several mechanisms such as inflammation and apoptosis and that is how cancers are prone to be affected by them. In this review, we attempt to investigate the role of beta-glucans on ovarian cancer. We hope that this paper might give novel insights in the field of ovarian cancer treatment.

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