Tumorgrafts as in vivo surrogates for women with ovarian cancer.
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ABSTRACT:
SUBMITTER: Weroha SJ
PROVIDER: S-EPMC3947430 | biostudies-literature | 2014 Mar
REPOSITORIES: biostudies-literature
Publications
Tumorgrafts as in vivo surrogates for women with ovarian cancer.
Weroha S John SJ Becker Marc A MA Enderica-Gonzalez Sergio S Harrington Sean C SC Oberg Ann L AL Maurer Matthew J MJ Perkins Sarah E SE AlHilli Mariam M Butler Kristina A KA McKinstry Sarah S Fink Stephanie S Jenkins Robert B RB Hou Xiaonan X Kalli Kimberly R KR Goodman Karin M KM Sarkaria Jann N JN Karlan Beth Y BY Kumar Amanika A Kaufmann Scott H SH Hartmann Lynn C LC Haluska Paul P
Clinical cancer research : an official journal of the American Association for Cancer Research 20140107 5
<h4>Purpose</h4>Ovarian cancer has a high recurrence and mortality rate. A barrier to improved outcomes includes a lack of accurate models for preclinical testing of novel therapeutics.<h4>Experimental design</h4>Clinically relevant, patient-derived tumorgraft models were generated from sequential patients and the first 168 engrafted models are described. Fresh ovarian, primary peritoneal, and fallopian tube carcinomas were collected at the time of debulking surgery and injected intraperitoneall ...[more]
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Project description:Purpose:Ovarian cancer has a high recurrence and mortality rate. A barrier to improved outcomes includes a lack of accurate models for preclinical testing of novel therapeutics. Experimental Design:Clinically-relevant, patient-derived tumorgraft models were generated from sequential patients and the first 168 engrafted models are described. Fresh ovarian, primary peritoneal, and fallopian tube carcinomas were collected at the time of debulking surgery and injected intraperitoneally into severe combined immunodeficient mice. Results:Tumorgrafts demonstrated a 74% engraftment rate with microscopic fidelity of primary tumor characteristics. Low-passage tumorgrafts also showed comparable genomic aberrations with the corresponding primary tumor and exhibit gene set enrichment of multiple ovarian cancer molecular subtypes, similar to patient tumors. Importantly, each of these tumorgraft models are annotated with clinical data and for those that have been tested, response to platinum chemotherapy correlates with the source patient. Conclusions:Presented herein is the largest known living tumor bank of patient-derived, ovarian tumorgraft models that can be applied to the development of personalized cancer treatment.
2015-03-09 | GSE66667 | GEO
Project description:The majority of ovarian cancer patients acquire resistance to standard platinum chemotherapy and novel therapies to reduce tumor burden and ascites accumulation are needed. Pregnancy-associated plasma protein-A (PAPP-A) plays a key role in promoting insulin-like growth factor (IGF) pathway activity, which directly correlates to ovarian cancer cell transformation, growth, and invasiveness. Herein, we evaluate PAPP-A expression in tumors and ascites of women with ovarian cancer, and determine the antitumor efficacy of a neutralizing monoclonal PAPP-A antibody (mAb-PA) in ovarian cancer using primary patient ovarian tumorgrafts ("Ovatars"). PAPP-A mRNA expression in patient ovarian tumors correlated with poor outcome and was validated as a prognostic surrogate in Ovatar tumors. Following confirmation of mAb-PA bioavailability and target efficacy in vivo, the antitumor efficacy of mAb-PA in multiple Ovatar tumor models was examined and the response was found to depend on PAPP-A expression. Strikingly, the addition of mAb-PA to standard platinum chemotherapy effectively sensitized platinum-resistant Ovatar tumors. PAPP-A protein in ascites was also assessed in a large cohort of patients and very high levels were evident across the entire sample set. Therefore, we evaluated targeted PAPP-A inhibition as a novel approach to managing ovarian ascites, and found that mAb-PA inhibited the development, attenuated the progression, and induced the regression of Ovatar ascites. Together, these data indicate PAPP-A as a potential palliative and adjunct therapeutic target for women with ovarian cancer.
| S-EPMC4394033 | biostudies-literature
Project description:Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer.We used original data from 21 studies, which included 12?390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype.Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ?35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5?kg?m(-2)) and endometrioid subtypes (pHR: 1.08 per 5?kg?m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5?kg?m(-2)) subtype, but only the association with high-grade serous cancers was significant.Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.
| S-EPMC4559823 | biostudies-other
Project description:BackgroundAs a special reproductive hormone and ovarian reserve indicator, the role of anti-Müllerian hormone (AMH) in premenopausal women with breast cancer deserves further study.MethodsWe conducted an in-depth analysis of the data from the EGOFACT study (NCT02518191), a phase Ⅲ, randomized, controlled trial involving premenopausal female breast cancer patients in two parallel groups: chemotherapy with or without gonadotropin-releasing hormone analogs (GnRHa). Three hundred thirty premenopausal women aged 25-49 years with operable stage I to III breast cancer were included in this study. The characteristics of ovarian reserve changes marked by AMH in the EGOFACT study and the factors affecting ovarian function in premenopausal women with breast cancer were analyzed.ResultsThe AMH level of the chemotherapy alone group decreased gradually within one year, while the AMH level of the GnRHa group was significantly higher as early as 6 months after chemotherapy and recovered to close to the baseline level 12 months after chemotherapy (F = 34.991, P < 0.001). Correlation analysis showed that the factors affecting AMH levels mainly included age, menarche age, body mass index (BMI), reproductive history, baseline follicle stimulating hormone (FSH) level, pathological stage and GnRHa application, but they had different effects on the incidence of premature ovarian insufficiency (POI) at different periods. Multivariate logistic regression analysis showed that menarche age younger than 14 years (OR 0.470 [0.259, 0.852], P = 0.013), baseline AMH level higher than 0.5 ng/mL (OR 9.590 [3.366, 27.320], P < 0.001), pathological stage Ⅰ(OR 0.315 [0.124, 0.798], P = 0.015) and GnRHa application (OR 0.090 [0.045, 0.183], P < 0.001) were independent factors conducive to protection of ovarian reserve, as well as to recovery of ovarian reserve.ConclusionsAge, menarche age, baseline AMH level, and GnRHa application are the most important influencing factors for ovarian reserve in premenopausal women with breast cancer.Trial registrationClinicalTrials.gov, NCT02518191, registered on Aug 5, 2015.
| S-EPMC9194452 | biostudies-literature
Project description:BackgroundWomen with ovarian cancer have been shown to be at significant risk of malnutrition with incidence rates described as being between 28% to 67%. Nutrition interventions may improve clinical outcomes positively, nutritional status or quality of life measures in this patient group.ObjectivesThis review was conducted to assess the effects of nutrition interventions during the perioperative period for women with ovarian cancer.Search methodsElectronic searches were conducted of the Cochrane Gynaecological Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL 2012, Issue 7), Medline (1946 to July week 4 2012), Embase (1980 to 2012 week 31), DARE (to 7th August 2012) AMED (1985 to April 2012), BNI (1992 to April 2012), CINAHL (to April 2012). We also searched trials databases, conference proceedings and related citation lists. Reference listings were handsearched. No restrictions were applied on language or date.Selection criteriaRandomised controlled trials (RCTs) in which women 18 years and over with any stage of ovarian cancer, including recurrent cancer, were in the perioperative phase of treatment and received any type of nutrition intervention.Data collection and analysisTitles and abstracts were screened by two review authors with study selection discussed by a team. Pairs of review authors worked independently on data collection and compared findings.Main resultsA total of 4092 titles were screened and 14 full text reports reviewed; a single small study met the inclusion criteria. In the included RCT, 40 women (35 with ovarian cancer) had extensive elective surgery including bowel resection for treatment of gynaecological malignancy. Randomisation was made to either early oral feeding (oral fluids in the first 24 hours, solid foods on the following day) or to a 'traditional' feeding regimen where oral fluids and foods were delayed until there was evidence of bowel function. Most women in the early feeding group (14/18) were able to resume eating solid food one day after surgery. This resulted in a significantly shorter hospital stay with no increase in postoperative complications or change in quality of life measures in comparison with the women on the 'traditional' feeding regimen. The incidence of nausea and vomiting during the postoperative stay was similar in both groups and was noted in slightly more than half of the women. Overall survival was evaluated until 30 days following discharge from hospital; in this period, there was one death of a woman who had been in the 'traditional oral feeding' group, cause of death was not noted. We assessed risk of bias and found no high risk of bias was identified in the methodology and reporting of the included study, although there was an increased risk of bias due to the small size of the study in which not all of the women had ovarian cancer.Authors' conclusionsAlthough women with ovarian cancer have been shown to be at risk of malnutrition, there is a lack of evidence derived from RCTs evaluating the identification, assessment and treatment of malnutrition during the perioperative phase of treatment. There is evidence from one small study that some women with ovarian cancer undergoing surgery with associated bowel resection may safely commence oral fluids within 24 hours of surgery and solid foods on the following day. Further research is required, including a RCT, to generate guidance concerning the treatment of malnutrition in this patient group.
| S-EPMC8730356 | biostudies-literature
Project description:BackgroundWhile there is an increasing trend of ovarian conservation at the time of surgical treatment for young women with stage I cervical cancer, the risk for subsequent ovarian cancer after ovarian conservation has not been well studied.ObjectiveWe sought to examine the incidence of and risk factors for metachronous ovarian cancer among young women with stage I cervical cancer who had ovarian conservation at the time of hysterectomy.Study designThe Surveillance, Epidemiology, and End Results Program was used to identify women aged <50 years who underwent hysterectomy with ovarian conservation for stage I cervical cancer from 1983 through 2013 (n = 4365). Time-dependent analysis was performed for ovarian cancer risk after cervical cancer diagnosis.ResultsMean age at cervical cancer diagnosis was 37 years, and the majority of patients had stage IA disease (68.2%) and squamous histology (72.9%). Median follow-up time was 10.8 years, and there were 13 women who developed metachronous ovarian cancer. The 10- and 20-year cumulative incidences of metachronous ovarian cancer were 0.2% (95% confidence interval, 0.1-0.4) and 0.5% (95% confidence interval, 0.2-0.8), respectively. Mean age at the time of diagnosis of metachronous ovarian cancer was 47.5 years, and stage III-IV disease was seen in 55.6%. Age (≥45 vs <45 years, hazard ratio, 4.22; 95% confidence interval, 1.16-15.4; P = .018), ethnicity (non-white vs white, hazard ratio, 4.29; 95% confidence interval, 1.31-14.0; P = .009), cervical cancer histology (adenocarcinoma or adenosquamous vs squamous, hazard ratio, 3.50; 95% confidence interval, 1.17-10.5; P = .028), and adjuvant radiotherapy use (yes vs no, hazard ratio, 3.69; 95% confidence interval, 1.01-13.4; P = .034) were significantly associated with metachronous ovarian cancer risk. The presence of multiple risk factors was associated with a significantly increased risk of metachronous ovarian cancer compared to the no risk factor group: 1 risk factor (hazard ratio range, 2.96-8.43), 2 risk factors (hazard ratio range, 16.6-31.0), and 3-4 risk factors (hazard ratio range, 62.3-109), respectively.ConclusionMetachronous ovarian cancer risk after ovarian conservation for women with stage I cervical cancer is <1%. Older age, non-white ethnicity, adenocarcinoma or adenosquamous histology, and adjuvant radiotherapy may be associated with an increased metachronous ovarian cancer risk.
| S-EPMC7523226 | biostudies-literature
Project description:Patients with many advanced solid cancers have very poor prognosis, and improvements in life expectancy are measured only in months. We have recently reported the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was later treated with DNA-damaging agents, on the basis of the observation of significant activity of this class of drugs against a personalized tumorgraft generated from the patient's surgically resected tumor. Here, we extend the approach to patients with other advanced cancers. Tumors resected from 14 patients with refractory advanced cancers were propagated in immunodeficient mice and treated with 63 drugs in 232 treatment regimens. An effective treatment regimen in the xenograft model was identified for 12 patients. One patient died before receiving treatment, and the remaining 11 patients received 17 prospectively guided treatments. Fifteen of these treatments resulted in durable partial remissions. In 2 subjects, no effective treatments were found. Overall, there was a remarkable correlation between drug activity in the model and clinical outcome, both in terms of resistance and sensitivity. The data support the use of the personalized tumorgraft model as a powerful investigational platform for therapeutic decision making and to efficiently guide cancer treatment in the clinic.
| S-EPMC4629061 | biostudies-literature
Project description:Few models exist for studying neuroendocrine tumors (NETs), and there are mounting concerns that the currently available array of cell lines is not representative of NET biology. The lack of stable patient-derived NET xenograft models further limits the scientific community's ability to make conclusions about NETs and their response to therapy in patients. To address these limitations, we propose the use of an ex vivo 3D flow-perfusion bioreactor system for culturing and studying patient-derived NET surrogates. Herein, we demonstrate the utility of the bioreactor system for culturing NET surrogates and provide methods for evaluating the efficacy of therapeutic agents on human NET cell line xenograft constructs and patient-derived NET surrogates. We also demonstrate that patient-derived NET tissues can be propagated using the bioreactor system and investigate the near-infrared (NIR) dye IR-783 for its use in monitoring their status within the bioreactor. The results indicate that the bioreactor system and similar 3D culture models may be valuable tools for culturing patient-derived NETs and monitoring their response to therapy ex vivo.
| S-EPMC8734644 | biostudies-literature
Project description:BACKGROUND:Treatment options for patients with platinum-resistant ovarian cancer are generally palliative in nature and rarely have realistic potential to be curative. Because many patients with recurrent ovarian cancer receive aggressive chemotherapy for prolonged periods, sometimes continuously, therapy-related toxicities are a major factor in treatment decisions. The use of ex vivo drug sensitivity screens has the potential to improve the treatment of patients with platinum-resistant ovarian cancer by providing personalized treatment plans and thus reducing toxicity from unproductive therapy attempts. MATERIALS AND METHODS:We evaluated the treatment responses of a set of six early-passage patient-derived ovarian cancer cell lines towards a set of 30 Food and Drug Administration-approved chemotherapy drugs using drug-sensitivity testing. RESULTS:We observed a wide range of treatment responses of the cell lines. While most compounds displayed vastly different treatment responses between cell lines, we found that some compounds such as docetaxel and cephalomannine reduced cell survival of all cell lines. CONCLUSION:We propose that ex vivo drug-sensitivity screening holds the potential to greatly improve patient outcomes, especially in a population where multiple continuous treatments are not an option due to advanced disease, rapid disease progression, age or poor overall health. This approach may also be useful to identify potential novel therapeutics for patients with ovarian cancer.
| S-EPMC7323502 | biostudies-literature
Project description:This study evaluated 3 index-based dietary patterns-Healthy Eating Index (HEI)-2005, HEI-2010, and Alternate Healthy Eating Index (AHEI)-2010-in relation to ovarian cancer risk in African-American women. The study was conducted among 415 ovarian cancer cases and 629 age- and site-matched controls of African-American descent recruited from the population-based African American Cancer Epidemiology Study. Multivariable unconditional logistic regression models were used to estimate odds ratios and 95% confidence intervals between quartiles of dietary quality indices and ovarian cancer risk, adjusting for potential confounders. We found that higher AHEI-2010 scores, but not HEI-2005 or HEI-2010 scores, were associated with lower risk of ovarian cancer (comparing the highest quartile (4th) vs. lowest (1st), odds ratio (OR) = 0.66, 95% confidence interval (CI): 0.45, 0.98; P for trend = 0.05). When stratified by menopausal status, no noteworthy associations were observed among premenopausal women. However, among postmenopausal women, greater adherence to HEI-2010 (quartile 4 vs. quartile 1, OR = 0.57, 95% CI: 0.36, 0.92; P for trend = 0.03) and AHEI-2010 (quartile 4 vs. quartile 1, OR = 0.49, 95% CI: 0.31, 0.78; P for trend = 0.01) were inversely associated with ovarian cancer. Our findings indicate that adherence to an overall healthy dietary pattern may reduce ovarian cancer risk in African-American women, and particularly among postmenopausal African-American women.
| S-EPMC5860470 | biostudies-literature