Targeted Drugs for Cervical Cancer
What is cervical cancer?
Cervical cancer is a type of cancer that occurs in the cells of the cervix. According to the World Health Organization, cervical cancer is the fourth most common cancer among women worldwide. It is estimated that there were 530,000 new cases in 2012, accounting for 7.5% of all cancer deaths. More than 85% of the 270,000 cases of cervical cancer deaths occur in underdeveloped areas each year.
There are plans in developed countries to screen cervical cancer so that most precancerous lesions are discovered at a very easy stage of treatment. Cervical cancer is slow-growing, so its progression through precancerous changes provides opportunities for prevention, early detection, and treatment. Better means of detection have meant a decline in cervical cancer in the U.S. over the decades.
What causes cervical cancer?
Cervical cancer begins with abnormal changes in the cervical tissue. The risk that cause the disease is usually related to:
- Infection with human papillomavirus (HPV)
- Early sexual contact
- Multiple sexual partners
- Taking oral contraceptives (birth control pills), etc.
HPV is estimated to be the most common sexually transmitted infection in the United States. In fact, by age 50 approximately 80% of women have been infected with some type of HPV.
How to treat cervical cancer?
Surgery and concurrent chemoradiotherapy can cure 80%-90% of patients with early stage cervical cancer, but there is no satisfactory treatment for locally advanced and recurrent metastatic cervical cancer.
In recent years, the vigorous development of molecular targeted drugs has provided a new way for the treatment of advanced malignant tumors, and has also achieved certain results in the treatment of cervical cancer.
Targeted therapy for cervical cancer
- Angiogenesis inhibitors
Vascular endothelial growth factor (VEGF) secreted by different tumor cells can induce angiogenesis and lymphangiogenesis, and promote the progression of cervical precancerous lesions to invasive carcinoma. It has become an important therapeutic target for inhibiting tumor angiogenesis.
- Bevacizumab,recombinant humanized monoclonal antibody
- Sunitinib,small molecule tyrosine kinase inhibitor
- Pazopanib,inhibits VEGFR-1,2,3, PDGFR-a,b, fibroblast growth factor receptor (FGFR)-1,3, c-kit
- Imatinib, inhibitor of PDGFR the nucleus to promote cell division and proliferation.
- Epidermal growth factor receptor (EGFR) inhibitors
EGFR is a transmembrane glycoprotein with tyrosine kinase activity. Once combined with epidermal growth factor (EGF), it activates genes involved in the nucleus to promote cell division and proliferation. The EGFR signaling pathway is involved in controlling cell survival, proliferation, angiogenesis, cell movement, cell invasion and metastasis, and overexpression in most tumors.
- Cetuximab, IgG1 monoclonal antibody
- Panitumumab, specific binding to normal and tumor cell EGFR
- Gefitinib, selectively inhibits the signal transduction pathway of EGFR-TKI and blocks cancer cell growth
- Erlotinib, an EGFR-specific inhibitor with tyrosine kinase activity
- Lapatinib, with anti-HER2 activity, anti-angiogenesis
- Mammalian target of rapamycin (mTOR) inhibitors
In invasive cervical cancer, HPV infection is associated with decreased regulation of the PI3K-AKT-mTOR signaling pathway. mTOR inhibitors can reduce the expression of mTOR/4EBP1 in cells, reduce the mTOR activity of HPV-positive cervical cancer cells and the tumor burden of transplanted tumors.
- Cyclooxygenase (COX-2) inhibitiors
Cyclooxygenase is the rate-limiting enzyme in the synthesis of prostaglandins from arachidonic acid. COX-2 is an inducible enzyme that is up-regulated when cells are stimulated by various inducing factors. Celecoxib is a COX-2 inhibitor, but there is no significant advantage in clinical treatment of cervical cancer and side effects are higher than expected.
- Histone deacetylase inhibitors(HDACIs)
HDACIs inhibit the proliferation of tumor cells, induce cell differentiation and/or apoptosis by increasing the degree of acetylation of intracellular histones and increasing the expression levels of tumor suppressor genes p21, p53, etc.
In addition to the above drugs, there are many types of inhibitors in clinical research. Although molecular targeted therapy has a good effect in the treatment of some solid cancers such as lung cancer, the clinical evaluation of cervical cancer treatment has just started. With the deepening of research on the molecular targets of cervical cancer, new targeted therapies will continue to emerge, bringing new hope to patients.
|Celecoxib||169590-42-5||A highly selective COX-2 inhibitor.|
|Lapatinib||231277-92-2||Lapatinib, used in the form of Lapatinib Ditosylate, is a potent EGFR and ErbB2 inhibitor with IC50 of 10.8 and 9.2 nM, respectively.|
|Erlotinib||183321-74-6||Erlotinib is an EGFR inhibitor with IC50 of 2 nM, >1000-fold more sensitive for EGFR than human c-Src or v-Abl.|
|Gefitinib||184475-35-2||Gefitinib effectively inhibits all tyrosine phosphorylation sites on EGFR in both the high and low-EGFR-expressing cell lines including NR6, NR6M and NR6W cell lines. The phosphorylation sites Tyr1173 and Tyr992 are less sensitive requiring higher concentrations of Gefitinib for inhibition.|
|Panitumumab||339177-26-3||Panitumumab is a humanized monoclonal antibody that binds to epidermal growth factor receptor (EGFR), which is often overexpressed in colorectal cancers. Combination of Panitumumab and EGFR reduces cell proliferation therefore inhibits colorectal cancers. It was approved for the treatment of EGFR-expressing metastatic colorectal cancer.|
|Cetuximab||205923-56-4||Cetuximab, a novel molecular-targeted agent,is an inhibitor of EGFR monoclonal humanized antibody interacting with the extracellular binding site of EGFR to block ligand stimulation.|
|Bevacizumab||216974-75-3||Bevacizumab is an angiogenesis inhibitor, a drug that slows the growth of new blood vessels. It is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A). It has since been approved for use in certain lung cancers, renal cancers, ovarian cancers, and glioblastoma multiforme of the brain. It is listed for its use in treating certain eye diseases.|
|Imatinib||152459-95-5||Imatinib inhibits the SLF-dependent activation of wild-type c-kit kinase activity with a IC50 for these effects of approximately 0.1 μM, which is similar to the concentration required for inhibition of PDGFR.|
|Sunitinib||557795-19-4||Sunitinib is a multi-targeted RTK inhibitor targeting VEGFR2 (Flk-1) and PDGFRβ with IC50 of 80 nM and 2 nM, and also inhibits c-Kit.|
|Pazopanib||444731-52-6||Pazopanib is a novel multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit and c-Fms with IC50 of 10 nM, 30 nM, 47 nM, 84 nM, 74 nM, 140 nM and 146 nM, respectively.|
|VEGFR||Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis (the formation of the circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature).|
|HDAC||Histone deacetylases (HDACs), that may be called protein deacetylases (PDAC) as some of their targets are non-histone proteins, are a family of eleven zinc-dependent enzymes that have gained major interest as therapeutic targets, mainly in cancer research. Their abnormal expression in many cancer cells modifies the expression of tumour suppressor genes (TSG) and genes involved in normal cellular functions.|
|Cox-2||Cyclooxygenase (COX) catalyses the first committed step in the synthesis of prostanoids, a large family of arachidonic acid metabolites comprising prostaglandins, prostacyclin, and thromboxanes. COX-2 is the inducible isoform, rapidly expressed in several cell types in response to growth factors, cytokines, and pro-inflammatory molecules.|
|mTOR||The mechanistic target of rapamycin (mTOR), also known as mammalian target of rapamycin and FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a protein that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.|
|EGFR||EGFR (The epidermal growth factor receptor; ErbB-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factorfamily (EGF-family) of extracellular protein ligands. The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases.|