Targeted therapy involves the design of therapeutic drugs aimed at critical targets in the development and progression of tumors. These drugs selectively interfere with specific targets in the body to exert antitumor effects. Compared with conventional chemotherapy drugs, targeted therapy not only demonstrates antitumor activity but also reduces adverse effects on normal cells. Common targeted drugs for gynecological malignancies currently include anti-angiogenic agents, PARP inhibitors, antibody-drug conjugates (ADC), HER2 inhibitors, and various signaling pathway inhibitors.
Anti-Angiogenic Agents
Mechanism of Action
Malignant tumors require a sufficient blood supply to sustain their unrestricted growth, disrupting the balance between pro- and anti-angiogenic factors in the body. Vascular endothelial growth factor (VEGF), a highly specific endothelial cell mitogen secreted by the human pituitary gland, binds to VEGF receptors (VEGFR) and activates intracellular tyrosine kinase signaling pathways. These pathways enhance vascular permeability, degrade the extracellular matrix, and promote endothelial cell migration and proliferation, thereby facilitating angiogenesis. VEGF-A is the most critical member of the VEGF family in tumor angiogenesis.
Bevacizumab is the first FDA-approved anti-angiogenic drug for cancer treatment. It is a recombinant humanized monoclonal antibody that specifically binds VEGF-A, blocking its interaction with VEGFR and thereby inhibiting angiogenic signaling pathways. Additionally, other signaling pathways, such as those mediated by platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) and their receptors, interact with the VEGF-VEGFR pathway and collectively contribute to angiogenesis.
Multitarget anti-angiogenic agents, also known as small molecule tyrosine kinase inhibitors (TKIs), block the tyrosine kinase activity within multiple signaling pathways, including VEGF, PDGF, and FGF pathways.
Primary Indications
Bevacizumab is valuable in several scenarios, including first-line treatment for epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, as well as the treatment of platinum-sensitive and platinum-resistant recurrent disease. Bevacizumab can be combined with chemotherapy during treatment phases and used as maintenance therapy following chemotherapy, either as a monotherapy or in combination with PARP inhibitors.
In addition, bevacizumab combined with paclitaxel and cisplatin or with paclitaxel and topotecan is an option for treating recurrent, refractory, or metastatic cervical cancer. Bevacizumab combined with paclitaxel and carboplatin can be used as a first-line treatment choice for recurrent endometrial cancer. Currently, TKIs are not approved for the treatment of gynecological malignancies.
PARP Inhibitors
Mechanism of Action
Poly (ADP-ribose) polymerase (PARP) is an enzyme involved in the repair of single-strand DNA breaks. PARP inhibitors block the enzymatic activity of PARP and prevent its detachment from sites of single-strand DNA damage, leading to the sustained presence of single-strand breaks and collapse of replication forks. This, in turn, induces double-strand DNA breaks.
Double-strand breaks are primarily repaired through two pathways: homologous recombination repair (HRR) and nonhomologous end joining (NHEJ). HRR is highly accurate and specific, serving as the preferred repair mechanism, whereas NHEJ is error-prone. When HRR is defective, a condition known as homologous recombination deficiency (HRD), the repair of double-strand breaks is shifted to the error-prone NHEJ pathway. This results in the accumulation of genetic damage that ultimately leads to selective apoptosis of the tumor cells.
Patients with HRD tumors respond well to both platinum-based chemotherapy and PARP inhibitors. In ovarian cancer, more than 50% of patients have HRD, primarily due to BRCA1/BRCA2 mutations. For this reason, PARP inhibitors are regarded as a breakthrough treatment for gynecological tumors, particularly ovarian cancer. They have introduced a new paradigm of "surgery + chemotherapy + PARP inhibitor maintenance therapy," significantly extending patient survival.
Primary Indications
Conventional testing for BRCA mutations and HRD is recommended before the use of PARP inhibitors to enable precise treatment. PARP inhibitors are primarily indicated for the maintenance treatment of ovarian cancer following initial treatment or platinum-sensitive recurrence. Approved PARP inhibitors have slightly varying indications, which depend on the presence of BRCA1/BRCA2 mutations and HRD.
Antibody-Drug Conjugates (ADCs)
Antibody-drug conjugates combine small-molecule cytotoxic drugs with monoclonal antibodies. Through the ability of antibodies to recognize specific targets, these cytotoxic drugs are delivered directly to tumor cells, enabling selective destruction with minimal systemic toxicity. Tisotumab vedotin (TV), the first ADC approved internationally for gynecological malignancies, targets tissue factor (TF) expressed on the surface of cancer cells. It is conjugated with the cytotoxic agent MMAE (monomethyl auristatin E) and is used for the treatment of recurrent or metastatic cervical cancer in patients whose disease has progressed during or after chemotherapy. Mirvetuximab soravtansine (MIRV), an ADC targeting folate receptor alpha (FRα), is employed as a later-line therapy for FRα-positive platinum-resistant ovarian cancer.
Emerging Targeted Therapies for Gynecological Malignancies
HER2, a membrane protein essential for embryonic development, is typically low or absent in expression in normal adult tissues. The expression of HER2 is closely related to the onset and progression of various cancers, including breast cancer, ovarian cancer, and gastric cancer. In low-grade serous ovarian cancer, activation of the Ras/Raf/MEK/ERK pathway is observed, with KRAS mutations reported in 16%–44% of cases, BRAF mutations in 2%–20%, and NRAS mutations in approximately 26%. The MEK inhibitor trametinib has shown efficacy in treating recurrent low-grade serous ovarian cancer.
The PI3K/AKT/mTOR signaling pathway plays a critical role in regulating key cellular activities such as cell growth, proliferation, differentiation, metabolism, apoptosis, and angiogenesis. Abnormal activation of this pathway has been found in gynecological malignancies. Studies have confirmed that combining HER2 inhibitors with chemotherapy can benefit patients with advanced or recurrent HER2-positive serous endometrial carcinoma and carcinosarcoma.
Trastuzumab deruxtecan, an ADC that targets HER2 and conjugates with a topoisomerase I inhibitor, has been approved internationally for later-line treatment of HER2-positive cancers (immunohistochemistry 3+) across tumor types. It has shown promise as a later-line treatment option for gynecological malignancies.
PI3K/AKT/mTOR pathway inhibitors can be classified into four major categories:
- PI3K inhibitors,
- AKT inhibitors,
- mTOR inhibitors,
- Dual mTOR/PI3K inhibitors.
Among these, mTOR inhibitors have been the most extensively studied. Additionally, many inhibitors targeting various signaling pathways are currently in clinical trial stages.
In the 20th century, cancer treatment strategies largely focused on "seek and destroy," whereas the 21st century has shifted toward "target and control." Targeted therapy has represented a major breakthrough in cancer treatment, transforming therapeutic approaches for multiple tumor types, including gynecological malignancies. Currently, bevacizumab and PARP inhibitors are the most widely used targeted drugs in this domain. Numerous clinical trials in Phase II and III are underway to evaluate new targeted therapies and their combination with conventional chemotherapy drugs.