Targeting Tyrosine Kinases in Ovarian Cancer: Small Molecule Inhibitor and Monoclonal Antibody, Where Are We Now?

Ovarian cancer is one of the most lethal gynaecological malignancies worldwide. Despite high success rates following first time treatment, this heterogenous disease is prone to recurrence. Oncogenic activity of receptor tyrosine kinases is believed to drive the progression of ovarian cancer. Here we provide an update on the progress of the therapeutic targeting of receptor tyrosine kinases in ovarian cancer. Broadly, drug classes that inhibit tyrosine kinase/pathways can be classified as small molecule inhibitors, monoclonal antibodies, or immunotherapeutic vaccines. Small molecule inhibitors tested in clinical trials thus far include sorafenib, sunitinib, pazopanib, tivantinib, and erlotinib. Monoclonal antibodies include bevacizumab, cetuximab, pertuzumab, trastuzumab, and seribantumab. While numerous trials have been carried out, the results of monotherapeutic agents have not been satisfactory. For combination with chemotherapy, the monoclonal antibodies appear more effective, though the efficacy is limited by low frequency of target alteration and a lack of useful predictive markers for treatment stratification. There remain critical gaps for the treatment of platinum-resistant ovarian cancers; however, platinum-sensitive tumours may benefit from the combination of tyrosine kinase targeting drugs and PARP inhibitors. Immunotherapeutics such as a peptide B-cell epitope vaccine and plasmid-based DNA vaccine have shown some efficacy both as monotherapeutic agents and in combination therapy, but require further development to validate current findings. In conclusion, the tyrosine kinases remain attractive targets for treating ovarian cancers. Future development will need to consider effective drug combination, frequency of target, and developing predictive biomarker.

Therapeutic Inducers of Apoptosis in Ovarian Cancer.

Ovarian cancers remain one of the most common causes of gynecologic cancer-related death in women worldwide. The standard treatment comprises platinum-based chemotherapy, and most tumors develop resistance to therapeutic drugs. One mechanism of developing drug resistance is alterations of molecules involved in apoptosis, ultimately assisting in the cells' capability to evade death. Thus, there is a need to focus on identifying potential drugs that restore apoptosis in cancer cells. Here, we discuss the major inducers of apoptosis mediated through various mechanisms and their usefulness as potential future treatment options for ovarian cancer. Broadly, they can target the apoptotic pathways directly or affect apoptosis indirectly through major cancer-pathways in cells. The direct apoptotic targets include the Bcl-2 family of proteins and the inhibitor of apoptotic proteins (IAPs). However, indirect targets include processes related to homologous recombination DNA repair, micro-RNA, and p53 mutation. Besides, apoptosis inducers may also disturb major pathways converging into apoptotic signals including janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), wingless-related integration site (Wnt)/ß-Catenin, mesenchymal-epithelial transition factor (MET)/hepatocyte growth factor (HGF), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K)/v-AKT murine thymoma viral oncogene homologue (AKT)/mammalian target of rapamycin (mTOR) pathways. Several drugs in our review are undergoing clinical trials, for example, birinapant, DEBIO-1143, Alisertib, and other small molecules are in preclinical investigations showing promising results in combination with chemotherapy. Molecules that exhibit better efficacy in the treatment of chemo-resistant cancer cells are of interest but require more extensive preclinical and clinical evaluation.

Relationship between ovarian cancer stem cells, epithelial mesenchymal transition and tumour recurrence.

Investigating the biological processes that occur to enable recurrence and the development of chemoresistance in ovarian cancer is critical to the research and development of improved treatment options for patients. The lethality of ovarian cancer is largely attributed to the recurrence of disease with acquired chemoresistance. Cancer stem cells are likely to be critical in ovarian cancer progression, contributing to tumour malignancy, metastasis and recurrence by persisting in the body despite treatment with anti-cancer drugs. Moreover, cancer stem cells are capable of mediating epithelial-to-mesenchymal transition traits and secrete extracellular vesicles to acquire therapy resistance and disease dissemination. These attributes merit in depth research to provide insight into the biological role of ovarian cancer stem cells in disease progression and chemotherapy response, leading to the development of improved biomarkers and innovative therapeutic approaches.

Mechanisms underlying acquired platinum resistance in high grade serous ovarian cancer - a mini review.

BACKGROUND: Advanced epithelial ovarian cancer is one of the hardest human malignancies to treat. Standard treatment involves cytoreductive surgery and platinum-based chemotherapy, however, median progression-free survival for patients diagnosed with advanced stage disease (FIGO stages III and IV) is approximately 18 months. There has been little improvement in overall survival over the past decade and less than half of women with advanced stage disease will be living 5 years after diagnosis. A majority of patients initially have a favourable response to platinum-based chemotherapy, but most will eventually relapse and their disease will become platinum resistant. SCOPE OF REVIEW: Here, we review our current understanding of mechanisms that promote recurrence and acquired resistance in epithelial ovarian cancer with particular focus on studies that describe differences observed between untreated primary tumors and recurrent tumors, post-first-line chemotherapy. Multiple molecular mechanisms contribute to recurrence in patients following initial treatment for advanced epithelial ovarian cancer including those involving the tumor microenvironment, tumor immune status, cancer stem cells, DNA repair/cell survival pathways and extracellular matrix. MAJOR CONCLUSIONS: Due to the adaptive nature of recurrent tumors, the major contributing and specific resistance pattern may largely depend on the nature of the primary tumor itself. GENERAL SIGNIFICANCE: Future work that aims to elucidate the complex pattern of acquired resistance will be useful for predicting chemotherapy response/recurrence following primary diagnosis and to develop novel treatment strategies to improve the survival of patients with advanced epithelial ovarian cancer, especially in tumors not harbouring homologous DNA recombination repair deficiencies.

Ovarian cancer stem cells and their role in drug resistance.

Ovarian cancer is typically diagnosed at advanced stages (III or IV), with metastasis ensuing at stage III. Complete remission is infrequent and is not achieved in almost half of the women diagnosed with ovarian cancer. Consequently, management and treatment of this disease is challenging as many patients are faced with tumour recurrence disseminating to surrounding organs further complicated with acquired chemo-resistance. The cancer stem cell theory proposes the idea that a drug resistant subset of tumour cells drive tumour progression, metastasis and ultimately, recurrent disease. In the ovarian cancer field, cancer stem cells remain elusive with significant gaps in our knowledge. The characteristics and specific role of ovarian cancer stem cells in recurrence still requires further research since different studies often arrive at contradictory conclusions. Here we present a review and critical analysis of current research conducted in the field of ovarian cancer stem cells and their potential role in drug resistance including several signalling pathways within these cells that affect the viability of targeted therapies.

Role of epigenetic modulation in cancer stem cell fate.

A sub-population of the tumor micro-environment consists of cancer stem cells (CSCs), which are responsible for the initiation and recurrence of cancer. Recently, epigenetic processes such as DNA methylation, histone modification, and chromatin remodeling have been found to be involved in inducing epigenetic factors in CSCs. Most of these processes, such as DNA methylation, generally occur in the genome that is rich in Cytosine-Guanine repeat sequences, also known as CpG islands, which are distributed throughout the human genome. The Polycomb gene (PcG) complex is a chromatin modifier facilitating the maintenance of embryonic and adult stem cells. Recent evidence suggests that the PcG is also involved in maintaining CSC stemness. We have presented various aspects and examples of how epigenetic modulation may drive or promote tumorigenesis and metastasis by alteration of key transcriptomic programs and signaling pathways in CSCs.