Identification of Tumor Antigens in Ovarian Cancers Using Local and Circulating Tumor-Specific Antibodies

Ovarian cancers include several disease subtypes and patients often present with advanced metastatic disease and a poor prognosis. New biomarkers for early diagnosis and targeted therapy are, therefore, urgently required. This study uses antibodies produced locally in tumor-draining lymph nodes (ASC probes) of individual ovarian cancer patients to screen two separate protein microarray platforms and identify cognate tumor antigens. The resulting antigen profiles were unique for each individual cancer patient and were used to generate a 50-antigen custom microarray. Serum from a separate cohort of ovarian cancer patients encompassing four disease subtypes was screened on the custom array and we identified 28.8% of all ovarian cancers, with a higher sensitivity for mucinous (50.0%) and serous (40.0%) subtypes. Combining local and circulating antibodies with high-density protein microarrays can identify novel, patient-specific tumor-associated antigens that may have diagnostic, prognostic or therapeutic uses in ovarian cancer.

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Colorectal Cancer Risk in Women with Gynecologic Cancers—A Population Retrospective Cohort Study

Journal of Clinical Medicine ◽

10.3390/jcm10143127 ◽

2021 ◽

Vol 10 (14) ◽

pp. 3127

Author(s):

Szu-Chia Liao ◽

Hong-Zen Yeh ◽

Chi-Sen Chang ◽

Wei-Chih Chen ◽

Chih-Hsin Muo ◽

...

Keyword(s):

Colorectal Cancer ◽

Ovarian Cancer ◽

Cervical Cancer ◽

Cohort Study ◽

Cancer Patients ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Gynecologic Cancer ◽

Ovarian Cancers ◽

Increased Risk

We conducted a retrospective cohort study to evaluate the subsequent colorectal cancer (CRC) risk for women with gynecologic malignancy using insurance claims data of Taiwan. We identified patients who survived cervical cancer (N = 25,370), endometrial cancer (N = 8149) and ovarian cancer (N = 7933) newly diagnosed from 1998 to 2010, and randomly selected comparisons (N = 165,808) without cancer, matched by age and diagnosis date. By the end of 2011, the incidence and hazard ratio (HR) of CRC were estimated. We found that CRC incidence rates were 1.26-, 2.20-, and 1.61-fold higher in women with cervical, endometrial and ovarian cancers, respectively, than in comparisons (1.09/1000 person–years). The CRC incidence increased with age. Higher adjusted HRs of CRC appeared within 3 years for women with endometrial and ovarian cancers, but not until the 4th to 7th years of follow up for cervical cancer survivals. Cancer treatments could reduce CRC risks, but not significantly. However, ovarian cancer patients receiving surgery alone had an incidence of 3.33/1000 person–years for CRC with an adjusted HR of 3.79 (95% CI 1.11–12.9) compared to patients without any treatment. In conclusion, gynecologic cancer patients are at an increased risk of developing CRC, sooner for those with endometrial or ovarian cancer than those with cervical cancer.

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Antibody Immunity to the p53 Oncogenic Protein Is a Prognostic Indicator in Ovarian Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.2813 ◽

2006 ◽

Vol 24 (5) ◽

pp. 762-768 ◽

Cited By ~ 92

Author(s):

Vivian Goodell ◽

Lupe G. Salazar ◽

Nicole Urban ◽

Charles W. Drescher ◽

Heidi Gray ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Cancer Patients ◽

Tumor Antigens ◽

Enzyme Linked Immunosorbent Assay ◽

Advanced Stage ◽

Topoisomerase Iiα ◽

P53 Antibodies ◽

Stage Disease ◽

Her 2

Purpose Presence of intratumoral T-cell infiltration has been linked to improved survival in ovarian cancer patients. We questioned whether antibody immunity specific for ovarian cancer tumor antigens would predict disease outcome. We evaluated humoral immune responses against ovarian cancer antigens p53, HER-2/neu, and topoisomerase IIα. Patients and Methods Serum was collected from 104 women (median age, 59 years; range, 34 to 89 years) at the time of their initial definitive surgery for ovarian cancer. Serum was analyzed by enzyme-linked immunosorbent assay for antibodies to p53, HER-2/neu, and topoisomerase IIα proteins. Antibody immunity to tetanus toxoid was assessed as a control. The incidence of humoral immunity at the time of diagnosis to any of these three antigens was tabulated. For patients with advanced-stage disease (III/IV), correlation was made between the presence of tumor-specific immunity at the time of diagnosis and overall survival. Patients were followed for a median of 1.8 years. Results Multivariate analysis showed the presence of p53 antibodies to be an independent variable for prediction of overall survival in advanced-stage patients. Overall survival was significantly higher for patients with antibodies to p53 when compared with patients without p53 antibodies (P = .01). The median survival for p53 antibody-positive patients was 51 months (95% CI, 23.5 to 60.5 months) compared with 24 months (95% CI, 19.4 to 28.6 months) for patients without antibodies to p53. Conclusion Data presented here demonstrate that advanced stage ovarian cancer patients can have detectable tumor-specific antibody immunity and that immunity to p53 may predict improved overall survival in patients with advanced-stage disease.

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Label-free microfluidic enrichment of cancer cells from non-cancer cells in ascites

Scientific Reports ◽

10.1038/s41598-021-96862-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nicholas E. Stone ◽

Abhishek Raj ◽

Katherine M. Young ◽

Adam P. DeLuca ◽

Fatima Ezahra Chrit ◽

...

Keyword(s):

Ovarian Cancer ◽

Personalized Medicine ◽

Cancer Cells ◽

Cancer Patients ◽

Cell Sorting ◽

Metastatic Cancer ◽

Patient Specific ◽

Surface Markers ◽

Label Free ◽

Metastatic Cancer Cells

AbstractThe isolation of a patient's metastatic cancer cells is the first, enabling step toward treatment of that patient using modern personalized medicine techniques. Whereas traditional standard-of-care approaches select treatments for cancer patients based on the histological classification of cancerous tissue at the time of diagnosis, personalized medicine techniques leverage molecular and functional analysis of a patient's own cancer cells to select treatments with the highest likelihood of being effective. Unfortunately, the pure populations of cancer cells required for these analyses can be difficult to acquire, given that metastatic cancer cells typically reside in fluid containing many different cell populations. Detection and analyses of cancer cells therefore require separation from these contaminating cells. Conventional cell sorting approaches such as Fluorescence Activated Cell Sorting or Magnetic Activated Cell Sorting rely on the presence of distinct surface markers on cells of interest which may not be known nor exist for cancer applications. In this work, we present a microfluidic platform capable of label-free enrichment of tumor cells from the ascites fluid of ovarian cancer patients. This approach sorts cells based on differences in biomechanical properties, and therefore does not require any labeling or other pre-sort interference with the cells. The method is also useful in the cases when specific surface markers do not exist for cells of interest. In model ovarian cancer cell lines, the method was used to separate invasive subtypes from less invasive subtypes with an enrichment of ~ sixfold. In ascites specimens from ovarian cancer patients, we found the enrichment protocol resulted in an improved purity of P53 mutant cells indicative of the presence of ovarian cancer cells. We believe that this technology could enable the application of personalized medicine based on analysis of liquid biopsy patient specimens, such as ascites from ovarian cancer patients, for quick evaluation of metastatic disease progression and determination of patient-specific treatment.

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Randomized phase II trial of patient-specific dendritic cell vaccines loaded with autologous tumor antigens versus autologous monocytes in patients with primary advanced ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.8_suppl.tps10 ◽

2019 ◽

Vol 37 (8_suppl) ◽

pp. TPS10-TPS10

Author(s):

Robert O. Dillman ◽

Lisa Abaid ◽

Candace Hsieh ◽

Christopher Langford ◽

Gabriel I. Nistor

Keyword(s):

Ovarian Cancer ◽

Tumor Cell ◽

Cell Line ◽

Tumor Antigens ◽

Tumor Cell Line ◽

Patient Specific ◽

Autologous Tumor Cell ◽

Autologous Tumor ◽

Primary Therapy ◽

Newly Diagnosed

TPS10 Background: With standard debulking surgery and combination chemotherapy (adjuvant ± neoadjuvant) the 5-year survival for women with newly diagnosed advanced epithelial ovarian cancer (stage III or IV) is less than 40%. After completion of primary therapy there is an opportunity to introduce an immunotherapy modality in an effort to improve long-term survival. In patients with metastatic melanoma, patient-specific vaccines consisting of autologous dendritic cells (DC) loaded with autologous tumor antigens (ATA) derived from a short-term autologous tumor cell line were associated with minimal toxicity and a 5-year survival of 50% in a single arm trial, and more than doubled median survival (43 vs. 20 months) in a randomized trial. Newly diagnosed patients with ovarian cancer might benefit from addition of such patient-specific therapeutic vaccines (DC-ATA) to standard therapy. Methods: This is a double-blind, 2:1 randomized trial comparing adjunctive treatment with DC-ATA to autologous monocytes (MC) in patients with newly diagnosed stage III or IV epithelial cancer of the ovary, fallopian tube, or peritoneum. Patients eligible for randomization are those who have completed or discontinued standard primary therapy, have a Karnofsky performance status ≥70, have an autologous tumor cell line, and have a monocyte product from which DC can be derived. The tumor cell line is derived from fresh tumor; MC are derived from leukapheresis, and MC are converted to DC by incubation with GM-CSF and IL-4. Patients are stratified by whether there is no evidence of disease at completion of primary therapy, and then are randomized, typically 6 to 7 months after tumor collection. Treatment can begin about 4 weeks from randomization. The trial has been open at a single site since mid-November 2017; the first tumor was collected in December. Appropriate tumor samples have been submitted from 11 patients and all 11 have resulted in cell lines. The first patient was randomized in May 2018. As of October 2018 four patients had been randomized and all four had started treatment. Additional clinical sites are being initiated. Clinical trial information: NCT02033616.

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Searching for new biomarkers in ovarian cancer patients: Rationale and design of a retrospective study under the Mermaid III project

Contemporary Clinical Trials Communications ◽

10.1016/j.conctc.2017.10.003 ◽

2017 ◽

Vol 8 ◽

pp. 167-174 ◽

Cited By ~ 5

Author(s):

Julie L. Hentze ◽

Claus Høgdall ◽

Susanne K. Kjær ◽

Jan Blaakær ◽

Estrid Høgdall

Keyword(s):

Ovarian Cancer ◽

Retrospective Study ◽

Cancer Patients ◽

New Biomarkers

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The ABCs of ovarian cancer immunology: IgA, B cells, and CTLs

Science Immunology ◽

10.1126/sciimmunol.abh3184 ◽

2021 ◽

Vol 6 (57) ◽

pp. eabh3184

Author(s):

Andrew Lichtman

Keyword(s):

Ovarian Cancer ◽

B Cells ◽

Tumor Growth ◽

Cancer Cells ◽

Tumor Antigens ◽

Myeloid Cell ◽

Nonspecific Binding ◽

Inhibit Tumor Growth ◽

Ovarian Cancers ◽

Secreted Factors

Intratumoral B cells in ovarian cancers produce IgA, which binds tumor antigens and inhibit tumor growth through myeloid cell–dependent mechanisms or by neutralization of secreted factors, and by antigen-nonspecific binding to poly-Ig receptor on cancer cells leading to transcytosis, which sensitizes the cells for CTL killing.

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BRCA1/2 Molecular Assay for Ovarian Cancer Patients: A Survey through Italian Departments of Oncology and Molecular and Genomic Diagnostic Laboratories

Diagnostics ◽

10.3390/diagnostics9040146 ◽

2019 ◽

Vol 9 (4) ◽

pp. 146 ◽

Cited By ~ 1

Author(s):

Capoluongo ◽

Verde ◽

Barberis ◽

Bella ◽

Buttitta ◽

...

Keyword(s):

Ovarian Cancer ◽

Molecular Biology ◽

Cancer Patients ◽

Multidisciplinary Team ◽

Medical Oncology ◽

Molecular Assay ◽

Scientific Societies ◽

Survey Form ◽

Ovarian Cancers ◽

Post Test

In Italy, 5200 new ovarian cancers were diagnosed in 2018, highlighting an increasing need to test women for BRCA1/2. The number of labs offering this test is continuously increasing. The aim of this study was to show the results coming from the intersociety survey coordinated by four different Clinical and Laboratory Italian Scientific Societies (AIOM, SIAPEC-IAP, SIBIOC, and SIGU). A multidisciplinary team belonging to the four scientific societies drew up two different questionnaires: One was targeted toward all Italian Departments of Medical Oncology, and the second toward laboratories of clinical molecular biology. This survey was implemented from September 2017 to March 2018. Seventy-seven out of 305 (25%) Departments of Medical Oncology filled our survey form. Indeed, 59 molecular laboratories were invited. A total of 41 laboratories (70%) filled in the questionnaire. From 2014 to 2017, 16 new molecular laboratories were activated. A total of 12,559 tests were performed in the year 2016, with a mean of 339 tests and a median of 254 tests per laboratory, showing a glimpse of an extreme low number of tests performed per year by some laboratories. In terms of the type and number of professionals involved in the pre- and post-test counseling, results among the onco-genetic team were heterogeneous. Our data show that the number of laboratories providing BRCA1/2 germline assays is significantly increased with further implementation of the somatic test coming soon. The harmonization of the complete laboratory diagnostic path should be encouraged, particularly in order to reduce the gap between laboratories with high and low throughput.

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Eukaryotic Initiation Factor 5A2 (EIF5A2) Contributes to Ovarian Tumor Growth and Metastasis

10.21007/etd.cghs.2020.0521 ◽

2020 ◽

Author(s):

◽

Guannan Zhao ◽

Keyword(s):

Ovarian Cancer ◽

Mortality Rate ◽

Early Diagnosis ◽

Cancer Patients ◽

Ovarian Tumor ◽

Initiation Factor ◽

Advanced Stage ◽

Eukaryotic Initiation Factor ◽

Ovarian Cancers ◽

Tumor Growth And Metastasis

Ovarian cancer has the highest mortality rate among all gynecological malignancies due to lack of effective biomarkers for early diagnosis. The majority of ovarian cancer patients are already at an advanced stage when diagnosed. In addition, ovarian cancers often become chemoresistant and metastatic, and recur following initial chemotherapy.

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Immunoprofiling of Breast Cancer Antigens Using Antibodies Derived from Local Lymph Nodes

Cancers ◽

10.3390/cancers11050682 ◽

2019 ◽

Vol 11 (5) ◽

pp. 682 ◽

Cited By ~ 4

Author(s):

Anna Rachel Young ◽

Jessica Da Gama Duarte ◽

Rhiannon Coulson ◽

Megan O’Brien ◽

Siddhartha Deb ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Nodes ◽

Cancer Patients ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Tumor Antigens ◽

Cancer Cell Line ◽

Protein Microarrays ◽

Breast Cancer Cell Lines ◽

Breast Cancer Patients

Tumor antigens are responsible for initiating an immune response in cancer patients, and their identification may provide new biomarkers for cancer diagnosis and targets for immunotherapy. The general use of serum antibodies to identify tumor antigens has several drawbacks, including dilution, complex formation, and background reactivity. In this study, antibodies were generated from antibody-secreting cells (ASC) present in tumor-draining lymph nodes of 20 breast cancer patients (ASC-probes) and were used to screen breast cancer cell lines and protein microarrays. Half of the ASC-probes reacted strongly against extracts of the MCF-7 breast cancer cell line, but each with a distinct antigen recognition profile. Three of the positive ASC-probes reacted differentially with recombinant antigens on a microarray containing cancer-related proteins. The results of this study show that lymph node-derived ASC-probes provide a highly specific source of tumor-specific antibodies. Each breast cancer patient reacts with a different antibody profile which indicates that targeted immunotherapies may need to be personalized for individual patients. Focused microarrays in combination with ASC-probes may be useful in providing immune profiles and identifying tumor antigens of individual cancer patients.

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MicroRNAs and Long Noncoding RNAs as Novel Therapeutic Targets in Estrogen Receptor-Positive Breast and Ovarian Cancers

International Journal of Molecular Sciences ◽

10.3390/ijms22084072 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4072

Author(s):

Tushar Singh Barwal ◽

Uttam Sharma ◽

Sonali Bazala ◽

Ipsa Singh ◽

Manju Jain ◽

...

Keyword(s):

Ovarian Cancer ◽

Estrogen Receptor ◽

Side Effects ◽

Cancer Patients ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Breast And Ovarian Cancer ◽

Ovarian Cancers ◽

Er Positive ◽

Novel Therapeutic

Aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane have shown to prevent metastasis and angiogenesis in estrogen receptor (ER)-positive breast and ovarian tumors. They function primarily by reducing estrogen production in ER-positive post-menopausal breast and ovarian cancer patients. Unfortunately, current AI-based therapies often have detrimental side-effects, along with acquired resistance, with increased cancer recurrence. Thus, there is an urgent need to identify novel AIs with fewer side effects and improved therapeutic efficacies. In this regard, we and others have recently suggested noncoding RNAs (ncRNAs), specifically microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), as potential molecular targets for utilization in modulating cancer hallmarks and overcoming drug resistance in several cancers, including ER-positive breast and ovarian cancer. Herein, we describe the disruptive functions of several miRNAs and lncRNAs seen in dysregulated cancer metabolism, with a focus on the gene encoding for aromatase (CYP19A1 gene) and estrogen synthesis as a novel therapeutic approach for treating ER-positive breast and ovarian cancers. Furthermore, we discuss the oncogenic and tumor-suppressive roles of several miRNAs (oncogenic miRNAs: MIR125b, MIR155, MIR221/222, MIR128, MIR2052HG, and MIR224; tumor-suppressive miRNAs: Lethal-7f, MIR27B, MIR378, and MIR98) and an oncogenic lncRNA (MIR2052HG) in aromatase-dependent cancers via transcriptional regulation of the CYP19A1 gene. Additionally, we discuss the potential effects of dysregulated miRNAs and lncRNAs on the regulation of critical oncogenic molecules, such as signal transducer, and activator of transcription 3, β-catenin, and integrins. The overall goal of this review is to stimulate further research in this area and to facilitate the development of ncRNA-based approaches for more efficacious treatments of ER-positive breast and ovarian cancer patients, with a slight emphasis on associated treatment–delivery mechanisms.

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