Analytical Challenges in Development of Chemoresistance Predictors for Precision Oncology

Abstract

Chemoresistance, i.e., tumor insensitivity to chemotherapy, shortens life expectancy of cancer patients. Despite the availability of new treatment options, initial systemic regimens for solid tumors are dominated by a set of standard chemotherapy drugs, and alternative therapies are used only when a patient has demonstrated chemoresistance clinically. Chemoresistance predictors use laboratory parameters measured on tissue samples to predict the patient’s response to chemotherapy and help to avoid application of chemotherapy to chemoresistant patients. Despite thousands of publications on putative chemoresistance predictors, there are only about a dozen predictors that are sufficiently accurate for precision oncology. One of the major reasons for inaccuracy of predictors is inaccuracy of analytical methods utilized to measure their laboratory parameters: an inaccurate method leads to an inaccurate predictor. The goal of this study was to identify analytical challenges in chemoresistance-predictor development and suggest ways to overcome them. Here we describe principles of chemoresistance predictor development via correlating a clinical parameter, which manifests disease state, with a laboratory parameter. We further classify predictors based on the nature of laboratory parameters and analyze advantages and limitations of different predictors using the reliability of analytical methods utilized for measuring laboratory parameters as a criterion. Our eventual focus is on predictors with known mechanisms of reactions involved in drug resistance (drug extrusion, drug degradation, and DNA damage repair) and using rate constants of these reactions to establish accurate and robust laboratory parameters. Many aspects and conclusions of our analysis are applicable to all types of disease biomarkers built upon the correlation of clinical and laboratory parameters.

Necessity and Challenges of Sample Preconcentration in Analysis of Multiple MicroRNAs by Capillary Electrophoresis

“…The lack of a rugged quantitative method for analysis of multiple miRNAs contributes to the fact that none of the thousands of putative miRNA fingerprints has been approved by the Food and Drug Administration to guide cancer therapy. A very similar situation with the difficulties of validation and approval can be found for other types of cancer biomarkers …”

“…A very similar situation with the difficulties of validation and approval can be found for other types of cancer biomarkers. 9 There is an ongoing effort to find an alternative to RT-PCR for validation of miRNA fingerprints. [10][11][12][13][14][15][16] A promising approach is direct quantitative analysis of multiple miRNAs (DQAMmiR) by capillary electrophoresis with laser-induced fluorescence detection (CE-LIF).…”

Small Extracellular Vesicles and Their Involvement in Cancer Resistance: An Up-to-Date Review

“…However, the effectiveness of chemotherapy is significantly limited by the partial or total insensitivity of neoplastic cells to cytotoxic drugs. This common phenomenon is referred to as chemoresistance, and it is estimated to be responsible for treatment failure and for the deaths of over 90% of patients with cancer [ 21 , 22 ]. This alarming number urges researchers to understand the mechanisms of drug resistance, as combating it is undeniably crucial to successful treatment.…”

α‑hederin overcomes hypoxia‑mediated drug resistance in colorectal cancer by inhibiting the AKT/Bcl2 pathway

“…Currently, tumour cell resistance to chemotherapy is one of the leading causes of colorectal cancer (CRC)-related death (1). Therefore, a more comprehensive understanding of drug resistance mechanisms is required to better combat this disease.…”