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The Current and Future Status of Personalized Medicine for Gynecologic Cancers

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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 (1 April 2021) | Viewed by 35942

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Special Issue Editors

Prof. Dr. Kimberly Leslie

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Guest Editor

Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA
Interests: targeted agents in endometrial and ovarian cancer; hormonal therapy for endometrial cancer and the impact of mutations in TP53 on drug response

Prof. Dr. David G. Mutch

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Guest Editor

Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
Interests: Clinical and translational studies in gynecologic oncology

Prof. Dr. Doris M. Benbrook

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Guest Editor

1. Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
2. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Interests: development of novel therapeutics for gynecologic cancers

Dr. Kristina W. Thiel

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Guest Editor

Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
Interests: Personalized medicine in gynecologic oncology

Special Issue Information

Dear colleagues,

Since the dawn of providing cancer therapy, clinicians have noted that response to treatment differs among different patients with the same histologic tumor diagnosis. The idea behind personalized or precision medicine is to use unique germline or somatic genetic/proteomic information about a patient’s tumor to improve response to treatment. The concept of offering treatments chosen not based upon a diagnosis but based upon unique patient or tumor characteristics is not a new, but it has been a challenge to implement broadly in gynecologic oncology. Nevertheless, recent advances in biotechnology have now made it possible to expand personalized, precision medicine in this field.

Our special issue will give both an historical and an up to the minute overview of the status of personalized medicine in gynecologic oncology. We will first review the current status of FDA-approved targeted therapies in gynecologic malignancies. Manuscripts will be solicited from top experts in the field covering (1) how big data has helped us define the unique characteristics of gynecologic malignancies that predict for response to treatments, (2) current precision agents in use, including anti-angiogenics, PARP inhibitors and hormonal therapy, and (3) new biomarkers that may enhance our ability to further personalize treatments. Finally, the use of novel, personalized patient avatars such as organoids will be described. We will emphasize that organoid cell cultures represent a new technology with the potential to become a powerful functional prediction model for treatment responsiveness that is unique to every patient.

Prof. Dr. Kimberly Leslie
Prof. Dr. David G. Mutch
Prof. Dr. Doris M. Benbrook
Dr. Kristina W. Thiel
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

endometrial cancer
ovarian cancer
gynecologic cancer
targeted agents
biomarkers
organoids
hormonal therapy
small molecule inhibitors
precision medicine
personalized medicine

Published Papers (10 papers)

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Editorial

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5 pages, 172 KiB

Open AccessEditorial

The Dawning of the Age of Personalized Medicine in Gynecologic Oncology

by Kimberly K. Leslie, Kristina W. Thiel, Doris M. Benbrook and David Mutch

Cancers 2020, 12(11), 3135; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113135 - 27 Oct 2020

Cited by 2 | Viewed by 1498

Abstract

It is an undeniable truth that every patient with cancer is unique. [...] Full article

(This article belongs to the Special Issue The Current and Future Status of Personalized Medicine for Gynecologic Cancers)

Research

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13 pages, 2189 KiB

Open AccessArticle

Successful Patient-Derived Organoid Culture of Gynecologic Cancers for Disease Modeling and Drug Sensitivity Testing

by Jianling Bi, Andreea M. Newtson, Yuping Zhang, Eric J. Devor, Megan I. Samuelson, Kristina W. Thiel and Kimberly K. Leslie

Cancers 2021, 13(12), 2901; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13122901 - 10 Jun 2021

Cited by 29 | Viewed by 4091

Abstract

Developing reliable experimental models that can predict clinical response before treating the patient is a high priority in gynecologic cancer research, especially in advanced or recurrent endometrial and ovarian cancers. Patient-derived organoids (PDOs) represent such an opportunity. Herein, we describe our successful creation of 43 tumor organoid cultures and nine adjacent normal tissue organoid cultures derived from patients with endometrial or ovarian cancer. From an initial set of 45 tumor tissues and seven ascites fluid samples harvested at surgery, 83% grew as organoids. Drug sensitivity testing and organoid cell viability assays were performed in 19 PDOs, a process that was accomplished within seven days of obtaining the initial surgical tumor sample. Sufficient numbers of cells were obtained to facilitate testing of the most commonly used agents for ovarian and endometrial cancer. The models reflected a range of sensitivity to platinum-containing chemotherapy as well as other relevant agents. One PDO from a patient treated prior to surgery with neoadjuvant trastuzumab successfully predicted the patient’s postoperative chemotherapy and trastuzumab resistance. In addition, the PDO drug sensitivity assay identified alternative treatment options that are currently used in the second-line setting. Our findings suggest that PDOs could be used as a preclinical platform for personalized cancer therapy for gynecologic cancer patients. Full article

(This article belongs to the Special Issue The Current and Future Status of Personalized Medicine for Gynecologic Cancers)

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16 pages, 7508 KiB

Open AccessArticle

Molecular Classification to Prognosticate Response in Medically Managed Endometrial Cancers and Endometrial Intraepithelial Neoplasia

by Allison M. Puechl, Daniel Spinosa, Andrew Berchuck, Angeles Alvarez Secord, Kerry E. Drury, Gloria Broadwater, Janice Wong, Regina Whitaker, Nicolas Devos, David L. Corcoran, Kyle C. Strickland and Rebecca A. Previs

Cancers 2021, 13(11), 2847; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112847 - 07 Jun 2021

Cited by 21 | Viewed by 3527

Abstract

Background: The aim of this study was to evaluate whether molecular classification prognosticates treatment response in women with endometrial cancers and endometrial intraepithelial neoplasia (EIN) treated with levonorgestrel intrauterine system (LNG-IUS). Methods: Patients treated with LNG-IUS for endometrial cancer or EIN from 2013 to 2018 were evaluated. Using immunohistochemistry and single gene sequencing of POLE, patients were classified into four groups as per the Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE): POLE-mutated, mismatch repair-deficient (MMRd), p53 wild type (p53wt), and p53-abnormal (p53abn). Groups were assessed relative to the primary outcome of progression or receipt of definitive treatment. Results: Fifty-eight subjects with endometrioid endometrial cancer or EIN treated with LNG-IUS were included. Of these, 22 subjects (37.9%) had endometrial cancer and 36 subjects (62.1%) had EIN. Per the ProMisE algorithm, 44 patients (75.9%) were classified as p53wt, 6 (10.3%) as MMRd, 4 (6.9%) as p53abn, and 4 (6.9%) as POLE-mutated. Of the 58 patients, 11 (19.0%) progressed or opted for definitive therapy. Median time to progression or definitive therapy was 7.5 months, with p53abn tumors having the shortest time to progression or definitive therapy. Conclusions: Molecular classification of endometrial cancer and EIN prior to management with LNG-IUS is feasible and may predict patients at risk of progression. Full article

(This article belongs to the Special Issue The Current and Future Status of Personalized Medicine for Gynecologic Cancers)

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19 pages, 43543 KiB

Open AccessFeature PaperArticle

Utility and Mechanism of SHetA2 and Paclitaxel for Treatment of Endometrial Cancer

by Vishal Chandra, Rajani Rai and Doris Mangiaracina Benbrook

Cancers 2021, 13(10), 2322; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102322 - 12 May 2021

Cited by 12 | Viewed by 2467

Abstract

Endometrial cancer patients with advanced disease or high recurrence risk are treated with chemotherapy. Our objective was to evaluate the utility and mechanism of a novel drug, SHetA2, alone and in combination with paclitaxel, in endometrial cancer. SHetA2 targets the HSPA chaperone proteins, Grp78, hsc70, and mortalin, which have high mutation rates in endometrial cancer. SHetA2 effects on cancerous phenotypes, mitochondria, metabolism, protein expression, mortalin/client protein complexes, and cell death were evaluated in AN3CA, Hec13b, and Ishikawa endometrial cancer cell lines, and on growth of Ishikawa xenografts. In all three cell lines, SHetA2 inhibited anchorage-independent growth, migration, invasion, and ATP production, and induced G1 cell cycle arrest, mitochondrial damage, and caspase- and apoptosis inducing factor (AIF)-mediated apoptosis. These effects were associated with altered levels of proteins involved in cell cycle regulation, mitochondrial function, protein synthesis, endoplasmic reticulum stress, and metabolism; disruption of mortalin complexes with mitochondrial and metabolism proteins; and inhibition of oxidative phosphorylation and glycolysis. SHetA2 and paclitaxel exhibited synergistic combination indices in all cell lines and exerted greater xenograft tumor growth inhibition than either drug alone. SHetA2 is active against endometrial cancer cell lines in culture and in vivo and acts synergistically with paclitaxel. Full article

(This article belongs to the Special Issue The Current and Future Status of Personalized Medicine for Gynecologic Cancers)

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17 pages, 4339 KiB

Open AccessArticle

Fallopian Tube-Derived Tumor Cells Induce Testosterone Secretion from the Ovary, Increasing Epithelial Proliferation and Invasion

by Jose A. Colina, Katherine E. Zink, Kanella Eliadis, Reza Salehi, Emma S. Gargus, Sarah R. Wagner, Kristine J. Moss, Seth Baligod, Kailiang Li, Brenna J. Kirkpatrick, Teresa K. Woodruff, Benjamin K. Tsang, Laura M. Sanchez and Joanna E. Burdette

Cancers 2021, 13(8), 1925; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081925 - 16 Apr 2021

Cited by 4 | Viewed by 2959

Abstract

The fallopian tube epithelium is the site of origin for a majority of high grade serous ovarian carcinomas (HGSOC). The chemical communication between the fallopian tube and the ovary in the development of HGSOC from the fallopian tube is of interest since the fimbriated ends in proximity of the ovary harbor serous tubal intraepithelial carcinoma (STICs). Epidemiological data indicates that androgens play a role in ovarian carcinogenesis; however, the oncogenic impact of androgen exposure on the fallopian tube, or tubal neoplastic precursor lesions, has yet to be explored. In this report, imaging mass spectrometry identified that testosterone is produced by the ovary when exposed to tumorigenic fallopian tube derived PTEN deficient cells. Androgen exposure increased cellular viability, proliferation, and invasion of murine cell models of healthy fallopian tube epithelium and PAX2 deficient models of the preneoplastic secretory cell outgrowths (SCOUTs). Proliferation and invasion induced by androgen was reversed by co-treatment with androgen receptor (AR) antagonist, bicalutamide. Furthermore, ablation of phosphorylated ERK reversed proliferation, but not invasion. Investigation of two hyperandrogenic rodent models of polycystic ovarian syndrome revealed that peripheral administration of androgens does not induce fallopian proliferation in vivo. These data suggest that tumorigenic lesions in the fallopian tube may induce an androgenic microenvironment proximal to the ovary, which may in turn promote proliferation of the fallopian tube epithelium and preneoplastic lesions. Full article

(This article belongs to the Special Issue The Current and Future Status of Personalized Medicine for Gynecologic Cancers)

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18 pages, 4099 KiB

Open AccessArticle

Bacterial, Archaea, and Viral Transcripts (BAVT) Expression in Gynecological Cancers and Correlation with Regulatory Regions of the Genome

by Jesus Gonzalez-Bosquet, Silvana Pedra-Nobre, Eric J. Devor, Kristina W. Thiel, Michael J. Goodheart, David P. Bender and Kimberly K. Leslie

Cancers 2021, 13(5), 1109; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13051109 - 05 Mar 2021

Cited by 7 | Viewed by 3957

Abstract

Bacteria, archaea, and viruses are associated with numerous human cancers. To date, microbiome variations in transcription have not been evaluated relative to upper female genital tract cancer risk. Our aim was to assess differences in bacterial, archaea, and viral transcript (BAVT) expression between different gynecological cancers and normal fallopian tubes. In this case-control study we performed RNA sequencing on 12 normal tubes, 112 serous ovarian cancers (HGSC) and 62 endometrioid endometrial cancers (EEC). We used the centrifuge algorithm to classify resultant transcripts into four indexes: bacterial, archaea, viral, and human genomes. We then compared BAVT expression from normal samples, HGSC and EEC. T-test was used for univariate comparisons (correcting for multiple comparison) and lasso for multivariate modelling. For validation we performed DNA sequencing of normal tubes in comparison to HGSC and EEC BAVTs in the TCGA database. Pathway analyses were carried out to evaluate the function of significant BAVTs. Our results show that BAVT expression levels vary between different gynecological cancers. Finally, we mapped some of these BAVTs to the human genome. Numerous map locations were close to regulatory genes and long non-coding RNAs based on the pathway enrichment analysis. BAVTs may affect gynecological cancer risk and may be part of potential targets for cancer therapy. Full article

(This article belongs to the Special Issue The Current and Future Status of Personalized Medicine for Gynecologic Cancers)

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17 pages, 1540 KiB

Open AccessArticle

Modification of Homologous Recombination Deficiency Score Threshold and Association with Long-Term Survival in Epithelial Ovarian Cancer

by Jeffrey A. How, Amir A. Jazaeri, Bryan Fellman, Molly S. Daniels, Suzanna Penn, Cara Solimeno, Ying Yuan, Kathleen Schmeler, Jerry S. Lanchbury, Kirsten Timms, Karen H. Lu and Melinda S. Yates

Cancers 2021, 13(5), 946; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13050946 - 24 Feb 2021

Cited by 27 | Viewed by 4321

Abstract

New therapies, such as poly-ADP ribose polymerase inhibitors (PARPi), and immunotherapy treatments have generated great interest in enhancing individualized molecular profiling of epithelial ovarian cancer (EOC) to improve management of the disease. In EOC patients, putative biomarkers for homologous recombination deficiency (HRD), microsatellite instability (MSI), and tumor mutational burden (TMB) were characterized and correlated with survival outcomes. A series of 300 consecutive EOC patients were enrolled. Patients underwent neoadjuvant chemotherapy (n = 172) or primary cytoreductive surgery (n = 128). Molecular profiling and survival analyses were restricted to the primary cytoreductive surgery cohort due to tissue availability. All patients underwent germline testing for HRD- and MSI-related gene mutations. When sufficient tissue was available, screening for somatic BRCA1/2 mutations, BRCA1 promoter methylation, HRD score (a measure of genomic instability), MSI, and TMB testing were performed. HRD score ≥33 was associated with improved overall survival on multivariable analysis. In the era of biomarker-driven clinical care, HRD score ≥33 may be a useful adjunctive prognostic tool and should be evaluated in future studies to predict PARPi benefits. Full article

(This article belongs to the Special Issue The Current and Future Status of Personalized Medicine for Gynecologic Cancers)

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Review

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23 pages, 1740 KiB

Open AccessReview

Targeting Wnt Signaling in Endometrial Cancer

by Iram Fatima, Susmita Barman, Rajani Rai, Kristina W. W. Thiel and Vishal Chandra

Cancers 2021, 13(10), 2351; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102351 - 13 May 2021

Cited by 36 | Viewed by 5558

Abstract

This review presents new findings on Wnt signaling in endometrial carcinoma and implications for possible future treatments. The Wnt proteins are essential mediators in cell signaling during vertebrate embryo development. Recent biochemical and genetic studies have provided significant insight into Wnt signaling, in particular in cell cycle regulation, inflammation, and cancer. The role of Wnt signaling is well established in gastrointestinal and breast cancers, but its function in gynecologic cancers, especially in endometrial cancers, has not been well elucidated. Development of a subset of endometrial carcinomas has been attributed to activation of the APC/β-catenin signaling pathway (due to β-catenin mutations) and downregulation of Wnt antagonists by epigenetic silencing. The Wnt pathway also appears to be linked to estrogen and progesterone, and new findings implicate it in mTOR and Hedgehog signaling. Therapeutic interference of Wnt signaling remains a significant challenge. Herein, we discuss the Wnt-activating mechanisms in endometrial cancer and review the current advances and challenges in drug discovery. Full article

(This article belongs to the Special Issue The Current and Future Status of Personalized Medicine for Gynecologic Cancers)

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16 pages, 1905 KiB

Open AccessReview

Histopathologic, Genetic and Molecular Characterization of Endometrial Cancer Racial Disparity

by Pouya Javadian, Christina Washington, Shylet Mukasa and Doris Mangiaracina Benbrook

Cancers 2021, 13(8), 1900; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081900 - 15 Apr 2021

Cited by 12 | Viewed by 3065

Abstract

In contrast to the decline in incidence and mortality of most other cancers, these rates are rising for endometrial cancer. Black women with endometrial cancer have earlier diagnosis, more aggressive histology, advanced stage and worse outcomes compared with their White counterparts. Socioeconomic status, a higher incidence of aggressive histology, and comorbid conditions are known factors leading to racial disparity in patients with endometrial cancer; nevertheless, they do not account for the entire racial disparity; which emphasizes the roles of molecular, histopathological and genetic factors. We performed a comprehensive review of all published scientific literature up to January 2021 reporting histopathologic, genetic and molecular factors associated with racial disparities in patients with endometrial cancer. The interactions and pathways of molecules reported to have significant differential expression in endometrial cancers from Black and White patients were identified with Ingenuity Pathway Analysis. The majority of studies compared Black and White patients; however, limited data are available for other racial and ethnic groups. Reported differences that could account for the worse survival of Black endometrial cancer patients include more aggressive histopathologies and molecular alterations, including upregulation of molecules driving cell cycle progression, and p53 and HER2/NEU signaling. Several of these molecules are targeted by existing pharmaceuticals. These findings encourage further study and the development of race-specific treatment strategies. Full article

(This article belongs to the Special Issue The Current and Future Status of Personalized Medicine for Gynecologic Cancers)

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51 pages, 7107 KiB

Open AccessReview

Small Non-Coding-RNA in Gynecological Malignancies

by Shailendra Kumar Dhar Dwivedi, Geeta Rao, Anindya Dey, Priyabrata Mukherjee, Jonathan D. Wren and Resham Bhattacharya

Cancers 2021, 13(5), 1085; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13051085 - 03 Mar 2021

Cited by 18 | Viewed by 3371

Abstract

Gynecologic malignancies, which include cancers of the cervix, ovary, uterus, vulva, vagina, and fallopian tube, are among the leading causes of female mortality worldwide, with the most prevalent being endometrial, ovarian, and cervical cancer. Gynecologic malignancies are complex, heterogeneous diseases, and despite extensive research efforts, the molecular mechanisms underlying their development and pathology remain largely unclear. Currently, mechanistic and therapeutic research in cancer is largely focused on protein targets that are encoded by about 1% of the human genome. Our current understanding of 99% of the genome, which includes noncoding RNA, is limited. The discovery of tens of thousands of noncoding RNAs (ncRNAs), possessing either structural or regulatory functions, has fundamentally altered our understanding of genetics, physiology, pathophysiology, and disease treatment as they relate to gynecologic malignancies. In recent years, it has become clear that ncRNAs are relatively stable, and can serve as biomarkers for cancer diagnosis and prognosis, as well as guide therapy choices. Here we discuss the role of small non-coding RNAs, i.e., microRNAs (miRs), P-Element induced wimpy testis interacting (PIWI) RNAs (piRNAs), and tRNA-derived small RNAs in gynecological malignancies, specifically focusing on ovarian, endometrial, and cervical cancer. Full article

(This article belongs to the Special Issue The Current and Future Status of Personalized Medicine for Gynecologic Cancers)

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