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Drugs Oct 2023Ovarian cancer is the leading cause of gynecological cancer death. Improved understanding of the biologic pathways and introduction of poly (ADP-ribose) polymerase... (Review)
Review
Ovarian cancer is the leading cause of gynecological cancer death. Improved understanding of the biologic pathways and introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) during the last decade have changed the treatment landscape. This has improved outcomes, but unfortunately half the women with ovarian cancer still succumb to the disease within 5 years of diagnosis. Pathways of resistance to PARPi and chemotherapy have been studied extensively, but there is an unmet need to overcome treatment failure and improve outcome. Major mechanisms of PARPi resistance include restoration of homologous recombination repair activity, alteration of PARP function, stabilization of the replication fork, drug efflux, and activation of alternate pathways. These resistant mechanisms can be targeted to sensitize the resistant ovarian cancer cells either by rechallenging with PARPi, overcoming resistance mechanism or bypassing resistance pathways. Augmenting the PARPi activity by combining it with other targets in the DNA damage response pathway, antiangiogenic agents and immune checkpoint inhibitors can potentially overcome the resistance mechanisms. Methods to bypass resistance include targeting non-cross-resistant pathways acting independent of homologous recombination repair (HRR), modulating tumour microenvironment, and enhancing drug delivery systems such as antibody drug conjugates. In this review, we will discuss the first-line management of ovarian cancer, resistance mechanisms and potential strategies to overcome these.
Topics: Female; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Drug Resistance, Neoplasm; Ovarian Neoplasms; DNA Repair; Recombinational DNA Repair; Tumor Microenvironment
PubMed: 37737434
DOI: 10.1007/s40265-023-01934-0 -
Science Advances Nov 2023BMP15 is a conserved regulator of ovarian development and maintenance in vertebrates. In humans, premature ovarian insufficiency is caused by autoimmunity and genetic...
BMP15 is a conserved regulator of ovarian development and maintenance in vertebrates. In humans, premature ovarian insufficiency is caused by autoimmunity and genetic factors, including mutation of BMP15. The cellular mechanisms underlying ovarian failure caused by BMP15 mutation and immune contributions are not understood. Using zebrafish, we established a causal link between macrophage activation and ovarian failure, which, in zebrafish, causes sex reversal. We define a germline-soma signaling axis that activates macrophages and drives ovarian failure and female-to-male sex reversal. Germline loss of zebrafish Bmp15 impairs oogenesis and initiates this cascade. Single-cell RNA sequencing and genetic analyses implicate ovarian somatic cells that express conserved macrophage-activating ligands as mediators of ovarian failure and sex reversal. Genetic ablation of macrophages or elimination of Csf1Rb ligands, Il34 or Csf1a, delays or blocks premature oocyte loss and sex reversal. The axis identified here provides insight into the cells and pathways governing oocyte and ovary maintenance and potential therapeutic targets to preserve female fertility.
Topics: Humans; Animals; Male; Female; Zebrafish; Macrophage Activation; Oocytes; Primary Ovarian Insufficiency
PubMed: 37992158
DOI: 10.1126/sciadv.adg7488 -
Clinical Medicine Insights. Oncology 2023Ovarian cancer is the second leading cause of death from gynecologic malignancies worldwide. Management of platinum-resistant disease is challenging and clinical... (Review)
Review
Ovarian cancer is the second leading cause of death from gynecologic malignancies worldwide. Management of platinum-resistant disease is challenging and clinical outcomes with standard chemotherapy are poor. Over the past decades, significant efforts have been made to understand drug resistance and develop strategies to overcome treatment failure. Antibody drug conjugates (ADCs) are a rapidly growing class of oncologic therapeutics, which combine the ability to target tumor-specific antigens with the cytotoxic effects of chemotherapy. Mirvetuximab soravtansine is an ADC comprising an IgG1 monoclonal antibody against the folate receptor alpha (FRα) conjugated to the cytotoxic maytansinoid effector molecule DM4 that has shown promising clinical activity in patients with FR-α-positive ovarian cancer. This review summarizes current evidence of mirvetuximab soravtansine in platinum-resistant ovarian cancer, focusing on clinical activity, toxicity, and future directions.
PubMed: 37528890
DOI: 10.1177/11795549231187264