Future perspectives and new directions in chemosensitizing activities to reverse drug resistance in gynecologic cancers: Emphasis on challenges and opportunities

Abstract Resistance to treatment is an unmet challenge in cancer treatment. Gynecologic cancers (cervical, endometrial/uterine, ovarian, vaginal, and vulvar cancers) originate in the female reproductive system tissues. Drug resistance is well established in many of these cancers. Gynecologic cancers are the fourth most common tumors diagnosed in women; as such, it is imperative to understand and address resistance to treatment. During the past decades, the gynecologic oncology field has evolved from radical en-bloc surgical procedures to more limited resections with systematic lymphadenectomy procedures. Cancer treatment has historically been developed through clinical trials; treatment is now determined based on tumor histology and demographic factors, leading to percentages of response for various groups of patients. With advent of the human genome project, tumors can now be categorized on genomic and proteomic signatures while drugs and treatments can be developed/tailored based on specific targets from these bioinformatics analyses (also referred to as personalized medicine approach). Disrupted apoptotic pathways, increased efflux of therapeutic agents, and modulation of the expression of tumor suppressors are major causes for drug resistance in gynecologic cancers. Current and upcoming research is focused to strategize and counteract the mechanisms of drug resistance. The heterogenic nature of tumors, genetic variability, and mutations are major setbacks in addressing the resistance to gynecologic cancers treatment. Information on critical biomarkers, signaling cascades, genes, and transcription factors associated with gynecologic cancers that are potentially involved in acquiring tumor resistance to better standard chemotherapeutic is emphasized. While several strategies are under testing to reverse resistance to chemotherapy, the major focus of this chapter is on chemosensitizers. The ongoing development of immunotherapy in the treatment of gynecologic cancers is promising due to its ability to manipulate the patients’ own immune system as a therapy against cancer. Oncolytic virus therapy is another promising approach of evading the tumor immune suppressive environment for heavily pretreated patients with gynecologic malignancies. Chemosensitization-focused research includes the prospects of using phytochemicals and nanomedicine coupled immunotherapy in gynecological cancer treatment; preclinical/translational and clinical trials of these techniques are highlighted herein.