Chemoresistance and targeted therapies in ovarian and endometrial cancers

Abstract

Gynecological cancers are known for being very aggressive at their advanced stages. Indeed, the survival rate of both ovarian and endometrial cancers is very low when diagnosed lately and the success rate of current chemotherapy regimens is not very efficient. One of the main reasons for this low success rate is the acquired chemoresistance of these cancers during their progression. The mechanisms responsible for this acquired chemoresistance are numerous, including efflux pumps, repair mechanisms, survival pathways (PI3K/AKT, MAPK, EGFR, mTOR, estrogen signaling) and tumor suppressors (P53 and Par-4). To overcome these resistances, a new type of therapy has emerged named targeted therapy. The principle of targeted therapy is simple, taking advantage of changes acquired in malignant cancer cells (receptors, proteins, mechanisms) by using compounds specifically targeting these, thus limiting their action on healthy cells. Targeted therapies are emerging and many clinical trials targeting these pathways, frequently involved in chemoresistance, have been tested on gynecological cancers. Despite some targets being less efficient than expected as mono-therapies, the combination of compounds seems to be the promising avenue. For instance, we demonstrate using ChIP-seq analysis that estrogen downregulate tumor suppressor Par-4 in hormone-dependent cells by directly binding to its DNA regulatory elements and inhibiting estrogen signaling could reinstate Par-4 apoptosis-inducing abilities. This review will focus on the chemoresistance mechanisms and the clinical trials of targeted therapies associated with these, specifically for endometrial and ovarian cancers.

Keywords: PI3K; chemoresistance; estrogen; gynecological cancers; targeted therapies.

Figure 1. Ovarian and endometrial cancers statistics

A. Ovarian and B. endometrial cancers statistics for new cases, deaths and 5-year survival). Data for new cases and deaths are represented by the number per 100 000 females (1975 to 2013), the 5-year survival rate (%) is available for all diagnosed patients (1975-2008) in a table or specifically sorted by tumor stage (2006-2012) in a histogram. The tumor stage is a factor related the chemoresistance. Data were obtained from seer.cancer.gov.

Figure 2. Ovarian and uterine cancers major alterations

A. A histogram representing the frequency of alterations for genes from the PI3K pathway (PIK3CA, PIK3R1, PTEN, AKT1-2-3), specifically in ovarian and uterine cancers from 6 studies. B.-C. The histograms representing the frequency of alterations for B. PTEN or C. P53 in various cancer types from 126 studies. Only the first 30 studies are shown to first simplify the figure, but also to indicate the importance of these alterations in ovarian and uterine cancers. The studies shown in the histograms were sorted from those with the highest to the lowest frequency of alterations for the associated genes. Data were obtained using www.cbioportal.org database.

Figure 3. Summary of the diverse mechanisms/pathways involved in chemoresistance and their associated targeted treatments

A. Schematic representing most of the mechanisms/pathways (P-gp, MMR, PARP, aromatase, ER, EGFR, PI3K/AKT, MAPK, mTOR) discussed and their associated therapeutics molecules. B. Schematic of the P53 mechanisms discussed and the diverse targeted therapies previously tested on ovarian and endometrial cancers. C. Schematic of the Par-4 mechanisms and the targeted therapy approach suggested using recombinant proteins (Par-4 or SAC domain only) on cancer cells.

Figure 4. Estrogen implication in Par-4 regulation

A. Ishikawa cancer cells were treated with either 0,1μM or 1μM estradiol (E2) for 4h. The levels of Par-4 and ERα were determined in treated cells using western blot analysis. GAPDH was used as a loading control. Results shown are representative of three independent experiments. B. ChIP-seq tracks showing ERα binding location on PAWR gene (Par-4) in control cells (top lane) and E2 treated cells (bottom lane) for 30 minutes. Genomic locations were obtained using the integrated genomic viewer (IGV 2.0). Red arrows indicate a novel ERα binding enrichment profile in the proximal region of Par-4 gene that can potentially be involved in negative regulation of the gene. Geo accession number: GSE23893.