Precision targeted therapy of ovarian cancer

Abstract

The review is aimed at describing modern approaches to detection as well as precision and personalized treatment of ovarian cancer. Modern methods and future directions of nanotechnology-based targeted and personalized therapy are discussed.

Keywords: Genetic profiling; Nanotechnology; Personalized medicine; Targeted therapy; siRNA.

Figure 1

Systems biology approaches in cancer therapy. Reproduced with permission from [9].

Figure 2

An integrative, iterative and model-based strategy for personalized cancer medicine. After initial diagnosis, a series of molecular profiling measurements are carried out for the patient for extensive characterization of the individual cancer. The results of the profiling are used to build computational. Based on the results of the measurements and modeling, an optimal therapeutic strategy is developed and applied for the specific patient. The process can be repeated during the treatment in order to account for possible cancer adaptation to therapy. Reproduced with permission from [9].

Figure 3

The PARE (personalized analysis of rearranged ends) approach. The method is based on novel mate-paired analysis of resected tumor DNA to identify individualized tumor-specific rearrangements. Such alterations are used to develop PCR-based quantitative analyses for personalized tumor monitoring of plasma samples or other bodily fluids. Modified from [24].

Figure 4

Different analytical methodologies that have been used to build functional modules or enriched gene sets. (A) The binomial distribution was used to calculate the chance probability that a gene set would show a given degree of enrichment in a cancer signature. Gene set enrichment scores were computed for several types of gene sets (Gene Ontology, KEGG, Biocarta) across hundreds of cancer signatures from the Oncomine database. (B). Two functional modules (mitosis and the Y branching of actin filaments modules) enriched in a metastatic breast cancer signature. The modules showed significant enrichment, suggesting that these processes are important for the development of metastases in breast cancer. Modified from [25].

Figure 5

The epigenetic transcriptional machinery. BET, SEC: representative reader (proteins that bind modifications and facilitate epigenetic effects); HATs, DOT1L, DNMT, EZH2: representative writers (enzymes that establish DNA methylation or histone modifications); histone deacetylases, JmjC–KDMs, LSDs, DNA demethylase: representative erasers (proteins that remove DNA methylation or histone modification marks). Reproduced with permission from [29].

Figure 6

Enhancement in ovarian cancer MRI sensitivity and specificity by ovarian cancer-targeted Mn₃O₄ nanoparticles. (A) Representative bioluminescence IVIS optical imaging. (B-C) Representative magnetic resonance imaging. (B) MRI without a contrast agent. (C) MRI after injection of biocompatible cancer-targeted Mn₃O₄ nanoparticles. Modified from [41].

Figure 7

Receptor targeted drug loaded liposomes. Targeted Targeting ligands coupled to the distal end of poly(ethylene glycol), which are anchored to the liposome surface in order to generate a targeted PEGylated liposome system specific to upregulated cell surface receptors. Reproduced with permission from [44].

Figure 8

Development of cancer in a complex and dynamic tumor microenvironment (TME). Cancer cells are in close relationship with diverse non-cancer cell types within the TME, forming a functional nexus that facilitates tumor initiation, survival, and exacerbation. Cytotoxicity generated by treatments including chemotherapy, radiation, and targeted therapy eliminates many malignant cells within the cancer cell population; however, surviving cells are frequently retained in specific TME niches. Reproduced with permission from [7].

Figure 9

Schematic diagram illustrating core molecular pathways driving ovarian cancer that represent therapeutic targets. Reproduced with permission from [75].

Figure 10

Personalized cancer treatment. Modified from [153].

Figure 11

Expression of genes (A, B, C, qPCR) in tumors of mice bearing xenografts of drug resistant malignant ascites obtained from a patient with ovarian carcinoma. The selected targeted genes for this patient are denoted in the table by red squares. Nude mice were inoculated with cancer cells. After tumors reached a size of about 0.4 cm³, mice were treated 8 times twice per week within 4 weeks with LHRH-Dendrimer-PTX (B) and LHRH-Dendrimer-PTX + LHRH- Dendrimer –siRNAs (C). Means ± SD are shown, n=4.

Figure 12

Expression of targeted proteins (Western blotting) in tumors of mice bearing xenografts of drug resistant malignant ascites obtained from a patient with ovarian carcinoma. Nude mice were inoculated with cancer cells. After tumors reached a size of about 0.4 cm³, mice were treated 8 times twice per week within 4 weeks with LHRH-Dendrimer-PTX and LHRH-Dendrimer-PTX + LHRH-Dendrimer-siRNAs. Representative images of Western blots are shown.

Figure 13

Tumor volume (A) and mass of intraperitoneal ascites (metastases, B) in mice bearing xenografts of drug resistant malignant ascites obtained from patients with ovarian carcinoma. After tumor reached a size of about 0.4 cm³, mice were treated 8 times twice per week within 4 weeks with substances indicated. Means ± SD are shown, n=4.

Figure 14

A Typical Flowchart for Single-Cell Data Analysis. Reproduced with permission from [60].

Figure 15

Algorithm for predictive BRCA testing in tumor tissue. Patients with recurrent, high-grade serous ovarian, tubal, or primary peritoneal carcinoma may be considered for an olaparib maintenance therapy. For patients with unknown BRCA status or patients who have previously been tested negative for a BRCA germline mutation BRCA status should be determined in tumor tissue, which enables the detection of germline and somatic mutations (green). Patients in whom a tumoral BRCA mutation is detected are eligible for therapy. Patients who have previously been tested positive for a germline BRCA mutation are eligible for therapy and do not need further testing (red). Reproduced with permission from [23].