Effective preclinical activity of datopotamab deruxtecan (Dato-DXd), an ADC targeting trophoblast cell-surface antigen 2 (TROP2), against primary cervical carcinoma cell lines and xenografts.

Background: Cervical cancer is one of the most prevalent and deadly cancers worldwide. Here we demonstrate the preclinical pharmacology of Dato-DXd, a TROP2-targeting antibody-drug conjugate (ADC), against primary cervical cancer cell lines and xenografts.

Methods: Primary cervical cancer cell lines with differential TROP2 expression were identified by flow cytometry.

HER2/neu as a Signaling and Therapeutic Marker in Uterine Serous Carcinoma.

Research into aggressive gynecologic cancers such as uterine serous carcinoma (USC) has recently evolved from chemotherapy to the development of drugs targeting specific biomarkers differentially expressed/active in tumor cells. One such target is HER2/neu, which plays an important role in the coordination of cell growth and differentiation. Importantly, when overexpressed and/or amplified in tumor cells, the downstream tyrosine kinase of HER2/neu becomes constitutively activated, causing dysregulated gene transcription.

Preclinical activity of Datopotamab deruxtecan (Dato-DXd), an antibody-drug conjugate targeting TROP2, in poorly differentiated endometrial carcinomas.

Datopotamab deruxtecan (Dato-DXd) is a novel antibody-drug conjugate (ADC) targeting trophoblast antigen-2 (TROP2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver DXd, a potent topoisomerase I inhibitor. We evaluated TROP2 expression in primary endometrial cancer (EC) cell lines and the activity of Dato-DXd against EC cell lines with different TROP2 expression in vitro and in vivo. TROP2 expression was assessed in nine primary tumor cell lines by flow cytometry.

Preclinical activity of sacituzumab govitecan in TROP2-positive low-grade serous ovarian cancer patient-derived xenograft models.

Objective: Low-grade serous ovarian cancer is a rare epithelial ovarian cancer subtype characterized by high resistance to chemotherapy and an indolent disease course. The development of novel, effective, targeted treatments for recurrent, chemotherapy-resistant low-grade serous ovarian cancer remains an unmet medical need. We evaluated trophoblast cell-surface antigen 2 (TROP2) expression in a cohort of patients with low-grade serous ovarian cancer and assessed the preclinical activity of sacituzumab govitecan, an antibody-drug conjugate targeting TROP2, in vivo using a patient-derived xenograft (PDX) model.

Clinical pharmacologic considerations for antibody-drug conjugate in gynecologic cancers.

Introduction: The mainstay of treatment for gynecologic cancers includes surgical debulking followed in a subset of patients by chemotherapy, radiation, hormonal therapy, and immunotherapy. In the last 10 years, antibody-drug conjugates (ADCs) have provided new therapeutic options and significant promise for the treatment of patients with recurrent gynecologic tumors.

Areas Covered: Information for this review article was obtained by literature review on PUBMED using phrases such as 'antibody drug conjugates in gynecologic cancers,' 'FDA approval for antibody drug conjugates in gynecologic cancers,' 'tisotumab vedotin,' 'mirvetuximab soravtansine,' 'trastuzumab deruxitcan,' 'sacituzumab govitecan,' 'datopotamab deruxtecan,' and 'sacituzumab tirumotecan.

Efficacy and Safety of Avutometinib ± Defactinib in Recurrent Low-Grade Serous Ovarian Cancer: Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201.

Purpose: This study evaluated the efficacy and safety of avutometinib (rapidly accelerated fibrosarcoma/mitogen-activated extracellular signal-regulated kinase [MEK] clamp) alone or in combination with defactinib (focal adhesion kinase inhibitor) in patients with recurrent low-grade serous ovarian cancer (LGSOC).

Methods: In this phase II, open-label study, patients with recurrent, measurable LGSOC after ≥1 line of platinum chemotherapy were stratified by tumor Kirsten rat sarcoma virus homolog () mutation status and randomly assigned to oral avutometinib 4.0 mg two times per week monotherapy or avutometinib 3.

Datopotamab deruxtecan, a novel TROP2-tareting antibody-drug conjugate with a topoisomerase I inhibitor payload, shows preclinical activity against primary and metastatic uterine and ovarian TROP2 over-expressing carcinosarcoma.

Background: Uterine and ovarian carcinosarcomas (CS) are rare gynecologic tumors with a high recurrence rate and poor prognosis. Datopotamab-deruxtecan (Dato-DXd) is a novel antibody-drug-conjugate (ADC) targeting TROP2. We evaluated the preclinical activity of Dato-DXd in vitro against primary and metastatic CS cell lines with various TROP2 expression and in vivo against CS xenografts in mice.

Co-expression of tissue factor, TROP2, and NECTIN4 in primary and matched metastatic cervical cancer lesions.

Background: Early detection of cervical cancer (CC) generally leads to favorable prognosis; however, survival rates drop significantly for late-stage or recurrent disease with limited treatment options. Antibody-drug conjugates (ADCs) show promise across multiple cancers but remain sparsely explored in CC.

Objective: This study evaluates ADC target expression in primary and metastatic CC to identify potential ADC responders.

The VEGF/VEGFR2 system in ovarian cancer: From functional to pharmacological significance.

The vascular endothelial growth factor receptor 2 (VEGFR2) is a tyrosine kinase receptor regulating a variety of biological processes, including embryonic development, angiogenesis, tissue homeostasis and cancer. VEGFR2 is activated by canonical VEGFs and non-canonical ligands, triggering intracellular signaling cascades that mediate its biological activity. Preclinical studies show that VEGFR2 plays a complex yet pivotal role in the progression of ovarian cancer (OC), a deadly disease with a global burden of more than 320,000 women in 2022.

Personalized Treatment in Ovarian Cancer: A Review of Disease Monitoring, Biomarker Expression, and Targeted Treatments for Advanced, Recurrent Ovarian Cancers.

: Ovarian cancer is the most lethal gynecologic malignancy due to its late diagnosis, aggressive disease course, and high likelihood of recurrence. In the last few years, with the advent of high-throughput genomic methodologies, our understanding of ovarian cancer genetics and biology has grown. In this review, we discuss current monitoring techniques, as well as biomarker-directed therapies, recently developed for ovarian cancer treatment.

A phase 2 trial of pembrolizumab for recurrent Lynch-like versus sporadic endometrial cancers with microsatellite instability (NCT02899793): Updated survival and response analyses.

Objective: Microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR) is a biomarker for response to immune checkpoint inhibitors. We report updated results including objective response rate, progression free survival, and overall survival data with 5-year follow-up in recurrent platinum-resistant, MSI-H, endometrial cancer (EC) patients fully sequenced using whole exome sequencing (WES) and treated within a prospective phase II study with pembrolizumab (NCT02899793).

Methods: Tumors from patients with measurable MSI-H/dMMR endometrial cancer confirmed by immunohistochemistry, polymerase chain reaction, and MLH-1 methylation assays were sequenced using whole exome sequencing and the FoundationOne platform for the identification of Lynch, Lynch-like, and MLH-1 methylated characteristics before receiving pembrolizumab 200 mg every 3 weeks for up to 24 months.

Preclinical Activity of Datopotamab Deruxtecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2, in Uterine Serous Carcinoma.

Unlabelled: Uterine serous carcinoma (USC) is a rare subset of endometrial cancer with a poor prognosis and high recurrence rate. Datopotamab deruxtecan (Dato-DXd) is a novel antibody-drug conjugate (ADC). The objective of this study was to evaluate the preclinical activity of Dato-DXd in USC in vitro against primary USC cell lines with various trophoblast cell-surface antigen 2 (TROP2) expression and in vivo in TROP2-overexpressing cell line-derived mice xenografts.

N-acetylcysteine (NAC) supplementation improves dyspnea and may normalize von Willebrand plasma levels in gynecologic patients with Post-Acute-COVID-Sequela (PASC)/Long COVID.

Objectives: A subset of COVID-infected cancer patients may develop post-acute sequelae of COVID-19 (PASC), also known as Long COVID (LC). While LC is considered multifactorial in its pathogenesis, growing evidence suggests that persistent microvascular inflammation (ie, spike-induced endotheliosis) causing chronically elevated levels of clotting factors including von Willebrand factor (vWF), clumping/clotting of red blood cells and platelets, and thrombotic complications may be at the root of PASC/LC symptoms. N-Acetylcysteine (NAC), a precursor of glutathione, is an inexpensive FDA-approved drug/supplement endowed with mucolytic, antioxidant, anti-inflammatory and thrombolytic properties.

Long-Term Follow-Up and Overall Survival in NRG258, a Randomized Phase III Trial of Chemoradiation Versus Chemotherapy for Locally Advanced Endometrial Carcinoma.

This randomized phase III trial aimed to determine whether treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel for four cycles (chemoradiotherapy [C-RT]) increased recurrence-free survival (RFS) and overall survival (OS) when compared with carboplatin and paclitaxel for six cycles (chemotherapy [CT]) in locally advanced endometrial cancer (UC). Previously reported results showed that C-RT did not improve RFS compared with CT. Here we report the final OS analysis.

Utility of next generation sequencing to unequivocally establish clonality in synchronous vs metastatic endometrial and ovarian carcinomas.

Background: Synchronous endometrial and ovarian carcinomas represent up to 10% of all endometrial and ovarian tumors. These are diagnostically challenging cases to determine if they represent dual primary tumors or related metastatic tumors.

Case: A 48-year-old was diagnosed with synchronous primary ovarian and endometrial malignancies on pathology based on traditional morphological parameters.

Unmet needs in cervical cancer - can biological therapies plug the gap?

Introduction: Cervical cancer remains one of the most common gynecologic malignancies worldwide. A disproportionate burden of cases occurs in developing countries due to inadequate screening and treatment. Even among patients adequately treated, in the presence of locally advanced or recurrent disease, outcomes tend to be poor.

Sacituzumab govitecan in heavily pretreated, platinum-resistant high grade serous ovarian cancer.

Background: Treatment of recurrent platinum-resistant high grade serous ovarian cancer (HGSOC) remains a challenge. Novel treatment options for recurrent disease are an unmet need.

Case: A 69-year-old with recurrent, metastatic, platinum-resistant HGSOC overexpressing TROP2 experienced a significant response to the antibody-drug conjugate (ADC) sacituzumab govitecan after multiple failed lines of chemotherapy and targeted treatment.

Efficacy and Safety of Sacituzumab Govitecan in Patients With Advanced Solid Tumors (TROPiCS-03): Analysis in Patients With Advanced Endometrial Cancer.

Purpose: Patients with advanced endometrial cancer (EC) who progress on or after platinum-based therapy and immunotherapy have poor prognosis. We report efficacy and safety of sacituzumab govitecan (SG), a trophoblast cell-surface antigen 2 (Trop-2)-directed antibody-drug conjugate, in patients with advanced EC.

Methods: TROPiCS-03 (ClinicalTrials.

Preclinical activity of datopotamab deruxtecan, a novel TROP2 directed antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (TROP2) in ovarian carcinoma.

Introduction: Epithelial ovarian cancer (EOC) is associated with the highest gynecologic cancer mortality. The development of novel, effective combinations of targeted therapeutics remains an unmet medical need. We evaluated the preclinical activity of datopotamab deruxtecan (Dato-Dxd), a novel TROP2 targeting antibody drug conjugate (ADC) in ovarian cancer cell lines and xenografts with variable TROP2 expression.

Targetable ERBB2/HER2 Mutations in Gynecologic Malignancies: Clinicopathological, Immunohistochemical, and Molecular Correlations.

Targeted anti-HER2 therapy has been recently added to the standard treatment recommendations in endometrial serous carcinoma. Current eligibility requires testing for HER2 overexpression and/or gene amplification by immunohistochemistry and by fluorescence in situ hybridization. However, clinical trials have also demonstrated the efficacy of anti-HER2 drugs against activating ERBB2/HER2 mutations in a variety of solid tumor types, and fam-trastuzumab deruxtecan is now approved by the US Food and Drug Administration for HER2 -mutant non-small cell lung cancer.

Microtubule-Targeting Agents: Disruption of the Cellular Cytoskeleton as a Backbone of Ovarian Cancer Therapy.

Microtubules are dynamic polymers composed of α- and β-tubulin heterodimers. Microtubules are universally conserved among eukaryotes and participate in nearly every cellular process, including intracellular trafficking, replication, polarity, cytoskeletal shape, and motility. Due to their fundamental role in mitosis, they represent a classic target of anti-cancer therapy.