Promising new drugs and therapeutic approaches for treatment of ovarian cancer-targeting the hallmarks of cancer

Abstract

Ovarian cancer remains the most lethal gynecological malignancy. Despite the approval of promising targeted therapy such as bevacizumab and PARP inhibitors, 5-year survival has not improved significantly. Thus, there is an urgent need for new therapeutics. New advancements in therapeutic strategies target the pivotal hallmarks of cancer. This review is giving an updated overview of innovative and upcoming therapies for the treatment of ovarian cancer that focuses specific on the hallmarks of cancer. The hallmarks of cancer constitute a broad concept to reenact complexity of malignancies and furthermore identify possible targets for new treatment strategies. For this purpose, we analyzed approvals and current clinical phase III studies (registered at ClinicalTrials.gov (National Library of Medicine, National Institutes of Health; U.S. Department of Health and Human Services, 2024)) for new drugs on the basis of their mechanisms of action and identified new target approaches. A broad spectrum of new promising drugs is currently under investigation in clinical phase III studies targeting mainly the hallmarks "self-sufficiency in growth signals," "genomic instability," and "angiogenesis." The benefit of immune checkpoint inhibitors in ovarian cancer has been demonstrated for the first time. Besides, targeting the tumor microenvironment is of growing interest. Replicative immortality, energy metabolism, tumor promoting inflammation, and the microbiome of ovarian cancer are still barely targeted by drugs. Nevertheless, precision medicine, which focuses on specific disease characteristics, is becoming increasingly important in cancer treatment.

Keywords: Hallmarks of cancer; Ovarian cancer; Therapy.

Fig. 1

Sustaining proliferative signaling. Alterations in growth factors such as EGFR, FRα, ALK, AXL, and IGFR lead to constitutive activity in downstream signaling pathways. Most frequently affected are RAS/RAF/MAPK, PI3K/AKT/mTOR, and JAK/STAT pathway. Constitutive activity leads to dysregulated cell proliferation, cell survival, and cell cycle progression. Currently ongoing and recently completed phase III trials targeting those molecules are displayed in the table. This figure was created using Biorender.com [, , , , , –52]

Fig. 2

Inducing or accessing vasculature. In cancer, angiogenesis is stimulated by proangiogenic factors such as vascular endothelial growth factor (VEGF), tumor growth factor β (TGF β), and fibroblast growth factor (FGF), interacting with their receptors VEGFR, TGFR, and FGFR. Binding of angiopoietin to Tie2 receptor inhibits vascular maturation and platelet-derived growth factor (PDGF) promotes proliferation of pericytes. Increased activity of depictured signaling pathways leads to leaky neovasculature with high levels of apoptosis and excessive vessel branching. Currently ongoing and recently completed phase III trials targeting those pathways are listed in the table. This figure was created using Biorender.com [–85]

Fig. 3

Evading growth suppressors. Cell cycle progression is strictly regulated by checkpoints controlled by cyclin-dependent kinases (CDKs)/cyclin-complexes. Due to frequent aberrations in checkpoint control, as well as alterations in critical gatekeepers, uncontrolled cell cycle progression is a common feature in OC. Current strategies in phase III studies targeting evasion of growth suppressors are listed in the table. This figure was created using Biorender.com [85, 98]

Fig. 4

Resisting cell death. With regard to apoptosis induction, extrinsic and intrinsic pathways are differentiated. Several mechanisms of cancer cells are known to circumvent apoptosis. Treatment strategies to inhibit resistance to cell death are listed in the table. TNF, tumor necrosis factor; TRADD, TNFR1-associated death domain protein; FADD, Fas-associating protein with death domain. This figure was created using Biorender.com [112]

Fig. 5

Avoiding immune destruction. Expression of immune checkpoint molecules and programmed cell death ligands compromise immunostimulatory interaction of tumor, T, and dendritic cells. In addition, OC is characterized by highly immunosuppressive tumor microenvironment, which further attenuates antitumoral immune response by secretion of cyto- and chemokines. Current endeavors fighting immune evasion encompass immune checkpoint inhibitors, cancer vaccines, viro-immunotherapy, and interleukin application. Recently completed and currently ongoing phase III trials targeting immune evasion of OC are listed in the table. This figure was created using Biorender.com [, , , , –149]

Fig. 6

Genome instability and mutation. High quality repair of DNA damage is crucial to maintain genomic stability. In case of DNA damage repair defects, as homologous repair deficiency or artificially induced defects by PARP inhibition, DNA damage leads to genomic instability or cell death due to synthetic lethality. Recently completed and currently ongoing phase III trials targeting genome instability of OC are listed in the table. SSB, single-strand breaks; DSB, double-strand breaks. This figure was created using Biorender.com [, , –180]

Fig. 7

Tissue invasion and metastasis. Tissue invasion and metastasis are complex processes, modulated by various signaling pathways. Epithelial-mesenchymal transition and expression of its regulating transcription factors, which are controlled by TGF β, Wnt, and growth factor signaling, is pivotal. Recently completed and currently ongoing phase III studies targeting tissue invasion and metastasis are listed in the table. EMT, epithelial-mesenchymal transition. This figure was created using Biorender.com [40, 41]

Fig. 8

Further hallmarks to target. The hallmarks deregulating cellular metabolism, unlocking phenotypic plasticity and the enabling characteristics tumor-promoting inflammation offer broad possibilities of altered pathways to target by cancer treatment. Auspicious targets are displayed in the boxes. CSC, cancer stem cells; CAF, cancer-associated fibroblasts; TCA, tricarboxylic acid cycle; TERT, telomerase reverse transcriptase; HMT, histone methylases; HDMS, histone demethylases; HAT, histone acetyltransferases; HDAC, histone deacetylase; DNMT, DNA methyltransferase. This figure was created using Biorender.com

Fig. 9

Further hallmarks to target. Other promising targets for treatment are the reprogramming of glucose metabolism in cancer cells and the cellular senescence of cancer by stimulating the senescence-associated secretory phenotype, which consists of proinflammatory cytokines, chemokines and matrix-reforming factors. MCT4, monocarboxylate transporter 4; ATP, adenosine triphosphate; GLUT, glucose transporter; TCA, tricarboxylic acid cycle; PDH, pyruvate dehydrogenase; HIF, hypoxia-inducible factor; ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype; SA-β-gal, senescence-associated beta-galactosidase. This figure was created using Biorender.com

Fig. 10

Targeted transport—overexpressed cell surface markers. Antibody drug conjugates (ADC) are composed by a carrier, a payload, and a linker. Common carrier molecules include carbohydrates, proteins, small molecules, peptides, and aptamers. FRα, HER2, TROP2, CDH6, and NaPi2b represent overexpressed surface molecules of OC, which are possible targets for ADCs. Recently completed and currently ongoing studies investigating ADC for OC are listed in the table. This figure was created using Biorender.com [–310]