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Targeted Therapy for Ovarian Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 53218

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Special Issue Editor

Prof. Katsutoshi Oda

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Guest Editor

Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
Interests: genome medicine; translational research; molecular targeted therapy; endometrial cancer; ovarian cancer

Special Issue Information

Dear Colleagues,

Ovarian cancer is a heterologous disease with various histological types, including high-grade serous, mucinous, endometrioid, clear-cell and low-grade serous carcinomas. Although carcinogenesis and molecular profiling are distinct among histological types, the treatment regimen is not histology-specific (i.e., Platinum–taxane is still a standard first-line regimen). To date, clinical application of targeted therapies for ovarian cancer has been limited. However, in addition to monotherapy of anti-angiogenic inhibitors and PARP inhibitors (such as olaparib, niraparib, and rucaparib), a lot of clinical trials with a combination of molecular targeted therapies have been performed and are designed. Especially, there are a lot of clinical trials of combinations of immune checkpoint blockades with an anti-angiogenic inhibitor or PARP inhibitor (or both) in ovarian cancer.

This Special Issue anticipates preclinical and clinical advances in the field of molecular-targeted therapy in ovarian cancer. Topics include advances in candidate molecular targets, new drug development, new clinical trials, biomarkers for drug sensitivity, translational research, perspectives of immune checkpoint blockades, mechanisms of drug resistance, tumor-agnostic strategies, and promising combination therapies (combined with either chemotherapy or targeted therapy). In particular, this Special issue will highlight (i) histology-specific, (ii) pathway-specific, (iii) genotype/molecular-specific (alterations in BRCA1/2 and other HRD genes, microsatellite instability, tumor mutational burden, and immune-related signatures), and (iv) phenotype-specific (such as ascites, peritoneal dissemination, lymph node metastasis, platinum-resistance, PARP resistance, anti-angiogenic resistance) targeted therapy in ovarian cancer.

Prof. Katsutoshi Oda
Prof. Dr. Koji Matsuo
Guest Editors

Manuscript Submission Information

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Keywords

Ovarian cancer
Targeted therapy
Clinical trials
Biomarkers
New drugs
Combination therapy
Translational research
Anti-angiogenic drug
PARP inhibitor
Immune checkpoint blockade

Published Papers (12 papers)

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Research

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10 pages, 535 KiB

Open AccessArticle

Bevacizumab in First-Line Chemotherapy Improves Progression-Free Survival for Advanced Ovarian Clear Cell Carcinoma

by Shinichi Tate, Kyoko Nishikimi, Ayumu Matsuoka, Satoyo Otsuka, Yuki Shiko, Yoshihito Ozawa, Yohei Kawasaki and Makio Shozu

Cancers 2021, 13(13), 3177; https://doi.org/10.3390/cancers13133177 - 25 Jun 2021

Cited by 16 | Viewed by 2256

Abstract

(1) Background: We investigated survival outcomes following first-line chemotherapy before and after approval of bevacizumab (Bev) for ovarian cancer in Japan to evaluate the efficacy of Bev for advanced clear cell carcinoma (CCC). (2) Methods: We investigated 28 consecutive patients diagnosed with CCC (stages III/IV) at our hospital between 2008 and 2018. Bev was administered for treatment of advanced CCC after approval in Japan in November 2013. Progression-free survival (PFS) was compared between 10 patients treated before Bev approval (2008–2013, Bev- group) and 18 patients treated after Bev approval (2014–2018, Bev+ group) for first-line chemotherapy. (3) Results: No intergroup difference was observed in patient characteristics. The rate of completeness of resection was higher in the Bev − group (9/10, 90%) than in the Bev+ group (15/18, 83%) (p = 0.044). Eleven (61%) patients in the Bev + group received ≥ 21 cycles of Bev. The median PFS increased from 12.0 months before Bev approval to 29.8 months after Bev approval (Wilcoxon test, p = 0.026). Multivariate analysis showed that performance status (p = 0.049), Bev administration (p = 0.023) and completeness of resection (p = 0.023) were independent prognostic factors for PFS. (4) Conclusions: Bev incorporated into first-line chemotherapy might improve PFS in patients with advanced CCC. We hope that our findings will be confirmed in adequate clinical trials. Full article

(This article belongs to the Special Issue Targeted Therapy for Ovarian Cancer)

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13 pages, 1249 KiB

Open AccessArticle

Intersection of DNA Repair Pathways and the Immune Landscape Identifies PD-L2 as a Prognostic Marker in Epithelial Ovarian Cancer

by Samantha Batman, Koji Matsuo, Paulette Mhawech-Fauceglia, Elizabeth Munro, Mercedes Weisenberger, Allison Allen, Sonali Joshi, Hiroko Machida, Shinya Matsuzaki, Tatjana Bozanovic and Tanja Pejovic

Cancers 2021, 13(8), 1972; https://doi.org/10.3390/cancers13081972 - 20 Apr 2021

Cited by 1 | Viewed by 2115

Abstract

Background: Targeting DNA repair and immune checkpoint pathways has been the focus of multiple clinical trials. In this study, we explore the association between DNA repair proteins, immune response markers, and clinical outcome in women with EOC. Methods: Immunohistochemical analysis of TMA with 181 EOC samples was used to determine expression levels for DNA repair proteins (PARP, PTEN, p53, H2Ax, FANCD2, and ATM) and immune-markers (CD4, CD8, CD68, PD-L2, PD-L1, and FOXP3). Biomarker expression was correlated to clinical data. Prognostic discriminatory ability was assessed per the combination of biomarkers. Results: Tumor immunity biomarkers correlated with HRD biomarkers. High PD-L2 was significantly associated with high expression of CD8 (r = 0.18), CD68 (r = 0.17), and FOXp3 (r = 0.16) (all, p < 0.05). In a multivariate analysis, PD-L2 (hazard ratio (HR) 1.89), PARP (HR 1.75), and PTEN (HR 1.96) expressions were independently associated with decreased progression-free survival (PFS), whereas PD-L1 (HR 0.49) and CD4 (HR 0.67) were associated with improved PFS (all, p < 0.05). In 15 biomarker combinations, six combinations exhibited a discriminatory ability of >20% for the 4.5-year PFS rate, with four based on PD-L2 (PARP, PTEN, CD4, and PD-L1, 20.5–30.0%). Conclusions: Increased PD-L2 expression is a prognostic marker of decreased survival in EOC. Interaction between tumor DNA repair and microenvironment determines tumor progression and survival. Full article

(This article belongs to the Special Issue Targeted Therapy for Ovarian Cancer)

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17 pages, 3217 KiB

Open AccessArticle

Synergistic Anti-Tumor Activity by Targeting Multiple Signaling Pathways in Ovarian Cancer

by Wei Wen, Ernest S. Han, Thanh H. Dellinger, Leander X. Lu, Jun Wu, Richard Jove and John H. Yim

Cancers 2020, 12(9), 2586; https://doi.org/10.3390/cancers12092586 - 10 Sep 2020

Cited by 8 | Viewed by 2307

Abstract

More effective therapy is needed to improve the survival of patients with advanced and recurrent ovarian cancer. Preclinical and early clinical studies with single molecular targeted agents have shown limited antitumor activity in ovarian cancer, likely due to compensation by alternative growth/survival pathways. An emerging strategy in overcoming resistance is to combine inhibitors targeting multiple pathways. In this study, we used a novel strategy of combining several FDA-approved targeted drugs, including sunitinib, dasatinib, and everolimus, in human ovarian cancers. Combination of the tyrosine kinase inhibitor sunitinib with the SRC inhibitor dasatinib showed synergistic anti-tumor activity in human ovarian cancer cells. The increased activity was associated with inhibition of the STAT3, SRC, and MAPK signaling pathways, but not AKT signaling. To inhibit the PI3K/AKT/mTOR pathway, we added the mTOR inhibitor everolimus, which further increased anti-tumor activity in cells. Combined treatment with sunitinib, dasatinib, and everolimus also resulted in greater inhibition of human ovarian tumor growth in mice. Furthermore, the triple combination also synergistically increased the anti-tumor activity of paclitaxel, both in vitro and in vivo. Taken together, our results demonstrate that simultaneous inhibition of several signaling pathways results in better anti-tumor activity compared to inhibiting any of these signaling pathways alone. Full article

(This article belongs to the Special Issue Targeted Therapy for Ovarian Cancer)

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Review

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39 pages, 1591 KiB

Open AccessReview

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

by Cassie Liu, Carter J. Barger and Adam R. Karpf

Cancers 2021, 13(12), 3065; https://doi.org/10.3390/cancers13123065 - 19 Jun 2021

Cited by 33 | Viewed by 7989

Abstract

Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. In this review article, we address the current knowledge regarding the mechanisms of regulation and oncogenic functions of FOXM1, particularly in the context of ovarian cancer. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell (CSC) properties, (5) genomic instability, and (6) altered cellular metabolism. We additionally discuss the evidence for FOXM1 as a cancer biomarker, describe the rationale for FOXM1 as a cancer therapeutic target, and provide an overview of therapeutic strategies used to target FOXM1 for cancer treatment. Full article

(This article belongs to the Special Issue Targeted Therapy for Ovarian Cancer)

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12 pages, 1403 KiB

Open AccessReview

Acquired Evolution of Mitochondrial Metabolism Regulated by HNF1B in Ovarian Clear Cell Carcinoma

by Ken Yamaguchi, Sachiko Kitamura, Yoko Furutake, Ryusuke Murakami, Koji Yamanoi, Mana Taki, Masayo Ukita, Junzo Hamanishi and Masaki Mandai

Cancers 2021, 13(10), 2413; https://doi.org/10.3390/cancers13102413 - 17 May 2021

Cited by 9 | Viewed by 2712

Abstract

Clear cell carcinoma (CCC) of the ovary exhibits a unique morphology and clinically malignant behavior. The eosinophilic cytoplasm includes abundant glycogen. Although the growth is slow, the prognosis is poor owing to resistance to conventional chemotherapies. CCC often arises in endometriotic cysts and is accompanied by endometriosis. Based on these characteristics, three clinical questions are considered: why does ovarian cancer, especially CCC and endometrioid carcinoma, frequently occur in endometriotic cysts, why do distinct histological subtypes (CCC and endometrioid carcinoma) arise in the endometriotic cyst, and why does ovarian CCC possess unique characteristics? Mutations in AT-rich interacting domain-containing protein 1A and phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit alpha genes may contribute to the carcinogenesis of ovarian CCC, whereas hepatocyte nuclear factor-1-beta (HNF1B) plays crucial roles in sculpting the unique characteristics of ovarian CCC through metabolic alterations. HNF1B increases glutathione synthesis, activates anaerobic glycolysis called the Warburg effect, and suppresses mitochondria. These metabolic changes may be induced in stressful environments. Life has evolved to utilize and control energy; eukaryotes require mitochondria to transform oxygen reduction into useful energy. Because mitochondrial function is suppressed in ovarian CCC, these cancer cells probably acquired further metabolic evolution during the carcinogenic process in order to survive stressful environments. Full article

(This article belongs to the Special Issue Targeted Therapy for Ovarian Cancer)

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13 pages, 991 KiB

Open AccessReview

Treatment Strategies for ARID1A-Deficient Ovarian Clear Cell Carcinoma

by Kazuaki Takahashi, Masataka Takenaka, Aikou Okamoto, David D. L. Bowtell and Takashi Kohno

Cancers 2021, 13(8), 1769; https://doi.org/10.3390/cancers13081769 - 07 Apr 2021

Cited by 22 | Viewed by 5069

Abstract

Ovarian clear cell carcinoma (OCCC) is a histological subtype of ovarian cancer that is more frequent in Asian countries (~25% of ovarian cancers) than in US/European countries (less than 10%). OCCC is refractory to conventional platinum-based chemotherapy, which is effective against high-grade serous carcinoma (HGSC), a major histological subtype of ovarian cancer. Notably, deleterious mutations in SWI/SNF chromatin remodeling genes, such as ARID1A, are common in OCCC but rare in HGSC. Because this complex regulates multiple cellular processes, including transcription and DNA repair, molecularly targeted therapies that exploit the consequences of SWI/SNF deficiency may have clinical efficacy against OCCC. Three such strategies have been proposed to date: prioritizing a gemcitabine-based chemotherapeutic regimen, synthetic lethal therapy targeting vulnerabilities conferred by SWI/SNF deficiency, and immune checkpoint blockade therapy that exploits the high mutational burden of ARID1A-deficient tumor. Thus, ARID1A deficiency has potential as a biomarker for precision medicine of ovarian cancer. Full article

(This article belongs to the Special Issue Targeted Therapy for Ovarian Cancer)

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14 pages, 11233 KiB

Open AccessReview

How Does Endometriosis Lead to Ovarian Cancer? The Molecular Mechanism of Endometriosis-Associated Ovarian Cancer Development

by Nozomi Yachida, Kosuke Yoshihara, Manako Yamaguchi, Kazuaki Suda, Ryo Tamura and Takayuki Enomoto

Cancers 2021, 13(6), 1439; https://doi.org/10.3390/cancers13061439 - 22 Mar 2021

Cited by 21 | Viewed by 5292

Abstract

Numerous epidemiological and histopathological studies support the notion that clear cell and endometrioid carcinomas derive from ovarian endometriosis. Accordingly, these histologic types are referred to as “endometriosis-associated ovarian cancer” (EAOC). Although the uterine endometrium is also considered an origin of endometriosis, the molecular mechanism involved in transformation of the uterine endometrium to EAOC via ovarian endometriosis has not yet been clarified. Recent studies based on high-throughput sequencing technology have revealed that cancer-associated gene mutations frequently identified in EAOC may exist in the normal uterine endometrial epithelium and ovarian endometriotic epithelium. The continuum of genomic alterations from the uterine endometrium to endometriosis and EAOC has been described, though the significance of cancer-associated gene mutations in the uterine endometrium or endometriosis remains unclear. In this review, we summarize current knowledge regarding the molecular characteristics of the uterine endometrium, endometriosis, and EAOC and discuss the molecular mechanism of cancer development from the normal endometrium through endometriosis in an effort to prevent EAOC. Full article

(This article belongs to the Special Issue Targeted Therapy for Ovarian Cancer)

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13 pages, 963 KiB

Open AccessReview

Ovarian Cancer-Associated Mesothelial Cells: Transdifferentiation to Minions of Cancer and Orchestrate Developing Peritoneal Dissemination

by Kazumasa Mogi, Masato Yoshihara, Shohei Iyoshi, Kazuhisa Kitami, Kaname Uno, Sho Tano, Yoshihiro Koya, Mai Sugiyama, Yoshihiko Yamakita, Akihiro Nawa, Hiroyuki Tomita and Hiroaki Kajiyama

Cancers 2021, 13(6), 1352; https://doi.org/10.3390/cancers13061352 - 17 Mar 2021

Cited by 21 | Viewed by 5955

Abstract

Ovarian cancer has one of the poorest prognoses among carcinomas. Advanced ovarian cancer often develops ascites and peritoneal dissemination, which is one of the poor prognostic factors. From the perspective of the “seed and soil” hypothesis, the intra-abdominal environment is like the soil for the growth of ovarian cancer (OvCa) and mesothelial cells (MCs) line the top layer of this soil. In recent years, various functions of MCs have been reported, including supporting cancer in the OvCa microenvironment. We refer to OvCa-associated MCs (OCAMs) as MCs that are stimulated by OvCa and contribute to its progression. OCAMs promote OvCa cell adhesion to the peritoneum, invasion, and metastasis. Elucidation of these functions may lead to the identification of novel therapeutic targets that can delay OvCa progression, which is difficult to cure. Full article

(This article belongs to the Special Issue Targeted Therapy for Ovarian Cancer)

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19 pages, 924 KiB

Open AccessReview

Emerging Trends in Neoadjuvant Chemotherapy for Ovarian Cancer

by Ami Patel, Puja Iyer, Shinya Matsuzaki, Koji Matsuo, Anil K. Sood and Nicole D. Fleming

Cancers 2021, 13(4), 626; https://doi.org/10.3390/cancers13040626 - 05 Feb 2021

Cited by 26 | Viewed by 3638

Abstract

Epithelial ovarian cancer remains a leading cause of death amongst all gynecologic cancers despite advances in surgical and medical therapy. Historically, patients with ovarian cancer underwent primary tumor reductive surgery followed by postoperative chemotherapy; however, neoadjuvant chemotherapy followed by interval tumor reductive surgery has gradually become an alternative approach for patients with advanced-stage ovarian cancer for whom primary tumor reductive surgery is not feasible. Decision-making about the use of these approaches has not been uniform. Hence, it is essential to identify patients who can benefit most from neoadjuvant chemotherapy followed by interval tumor reductive surgery. Several prospective and retrospective studies have proposed potential models to guide upfront decision-making for patients with advanced ovarian cancer. In this review, we summarize important decision-making models that can improve patient selection for personalized treatment. Models based on clinical factors (clinical parameters, radiology studies and laparoscopy scoring) and molecular markers (circulating and tumor-based) are useful, but laparoscopic staging is among the most informative diagnostic methods for upfront decision-making in patients medically fit for surgery. Further research is needed to explore more reliable models to determine personalized treatment for advanced epithelial ovarian cancer. Full article

(This article belongs to the Special Issue Targeted Therapy for Ovarian Cancer)

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24 pages, 2153 KiB

Open AccessReview

Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord–Stromal Tumors: A Contemporary Review

by Asaf Maoz, Koji Matsuo, Marcia A. Ciccone, Shinya Matsuzaki, Maximilian Klar, Lynda D. Roman, Anil K. Sood and David M. Gershenson

Cancers 2020, 12(6), 1398; https://doi.org/10.3390/cancers12061398 - 29 May 2020

Cited by 19 | Viewed by 9503

Abstract

Non-epithelial ovarian tumors are heterogeneous and account for approximately 10% of ovarian malignancies. The most common subtypes of non-epithelial ovarian tumors arise from germ cells or sex cord and stromal cells of the gonads. These tumors are usually detected at an early stage, and management includes surgical staging and debulking. When indicated for advanced disease, most respond to chemotherapy; however, options for patients with refractory disease are limited, and regimens can be associated with significant toxicities, including permanent organ dysfunction, secondary malignancies, and death. Targeted therapies that potentially decrease chemotherapy-related adverse effects and improve outcomes for patients with chemotherapy-refractory disease are needed. Here, we review the molecular landscape of non-epithelial ovarian tumors for the purpose of informing rational clinical trial design. Recent genomic discoveries have uncovered recurring somatic alterations and germline mutations in subtypes of non-epithelial ovarian tumors. Though there is a paucity of efficacy data on targeted therapies, such as kinase inhibitors, antibody–drug conjugates, immunotherapy, and hormonal therapy, exceptional responses to some compounds have been reported. The rarity and complexity of non-epithelial ovarian tumors warrant collaboration and efficient clinical trial design, including high-quality molecular characterization, to guide future efforts. Full article

(This article belongs to the Special Issue Targeted Therapy for Ovarian Cancer)

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26 pages, 740 KiB

Open AccessSystematic Review

Circulating Cell-Free DNA Methylation Profiles in the Early Detection of Ovarian Cancer: A Scoping Review of the Literature

by Xiaoyue M. Guo, Heather Miller, Koji Matsuo, Lynda D. Roman and Bodour Salhia

Cancers 2021, 13(4), 838; https://doi.org/10.3390/cancers13040838 - 17 Feb 2021

Cited by 12 | Viewed by 2997

Abstract

Epithelial ovarian cancer is the most lethal gynecologic malignancy and has few reliable non-invasive tests for early detection or diagnosis. Recent advances in genomic techniques have bolstered the utility of cell-free DNA (cfDNA) evaluation from peripheral blood as a viable cancer biomarker. For multiple reasons, comparing alterations in DNA methylation is particularly advantageous over other molecular assays. We performed a literature review for studies exploring cfDNA methylation in serum and plasma for the early diagnosis of ovarian cancer. The data suggest that serum/plasma cfDNA methylation tests have strong diagnostic accuracies for ovarian cancer (median 85%, range 40–91%). Moreover, there is improved diagnostic performance if multiple genes are used and if the assays are designed to compare detection of ovarian cancer with benign pelvic masses. We further highlight the vast array of possible gene targets and techniques, and a need to include more earlier-stage ovarian cancer samples in test development. Overall, we show the promise of cfDNA methylation analysis in the development of a viable diagnostic biomarker for ovarian cancer. Full article

(This article belongs to the Special Issue Targeted Therapy for Ovarian Cancer)

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7 pages, 906 KiB

Open AccessBrief Report

Utility of Comprehensive Serum Glycopeptide Spectra Analysis (CSGSA) for the Detection of Early Stage Epithelial Ovarian Cancer

by Koji Matsuo, Kazuhiro Tanabe, Masaru Hayashi, Masae Ikeda, Miwa Yasaka, Hiroko Machida, Masako Shida, Kenji Sato, Hiroshi Yoshida, Takeshi Hirasawa, Tadashi Imanishi and Mikio Mikami

Cancers 2020, 12(9), 2374; https://doi.org/10.3390/cancers12092374 - 21 Aug 2020

Cited by 5 | Viewed by 1945

Abstract

Comprehensive serum glycopeptide spectra analysis (CSGSA) evaluates >10,000 serum glycopeptides and identifies unique glycopeptide peaks and patterns via supervised orthogonal partial least-squares discriminant modeling. CSGSA was more accurate than cancer antigen 125 (CA125) or human epididymis protein 4 (HE4) for detecting early stage epithelial ovarian cancer. Combined CSGSA, CA125, and HE4 had improved diagnostic performance. Thus, CSGSA may be a useful screening tool for detecting early stage epithelial ovarian cancer. Full article

(This article belongs to the Special Issue Targeted Therapy for Ovarian Cancer)

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