Chasing the personalized medicine dream through biomarker validation in colorectal cancer.

Colorectal cancer (CRC) is a major health burden worldwide. The optimal approach to the diagnosis, management, and treatment of CRC involves multidisciplinary and integrated management practices. The field is rapidly changing because of recent advancements in delineating the molecular basis of tumorigenesis, introduction of targeted therapy, varied patient response to mainstay chemotherapeutics, biological drugs, and the effective combination regimes being used for treatment. Recent meta-analysis studies, which tend to establish few clinically useful predictor biomarkers, identify inconsistent results and limitations of the trials. Therefore, molecular pathological epidemiology discipline initiatives are promising. Here, we provide an overview of the potential of biomarker validation for personalized medicine by focusing largely on metastatic (m)CRC. We also highlight new candidate predictive and prognostic biomarkers.

Primary systemic therapy in HER2-amplified breast cancer : a clinical review

Primary systemic therapy (PST) in early breast cancer is utilized in locally advanced breast tumors and when breast-conserving surgery is desirable. In addition, the PST setting provides an opportunity to monitor response including histopathological and biomarker examination of the tumor and host tissues before and after systemic therapy. Trastuzumab is a monoclonal antibody targeting the hEGF receptor that is overexpressed in 15–20% of breast tumors. Trastuzumab is effective in prolonging survival when used to treat women with hEGF receptor overexpressed tumors, both in adjuvant and metastatic disease settings. Trastuzumab has also shown promising activity in PST/neoadjuvant studies by achieving high rates of complete pathologic response. This is a review of clinical studies that incorporated trastuzumab in PST and/or neoadjuvant chemotherapy, including the results of recently reported studies using trastuzumab in combination with other novel therapies such as lapatinib or pertuzumab.

Selection of DNA aptamers against epithelial cell adhesion molecule for cancer cell imaging and circulating tumor cell capture

Epithelial cell adhesion molecule (EpCAM) is overexpressed in most solid cancers and is an ideal antigen for clinical applications in cancer diagnosis, prognosis, imaging, and therapy. Currently, most of the EpCAM-based diagnostic, prognostic, and therapeutic strategies rely on the anti-EpCAM antibody. However, the use of EpCAM antibody is restricted due to its large size and instability. In this study, we have successfully identified DNA aptamers that selectively bind human recombinant EpCAM protein. The aptamers can specifically recognize a number of live human cancer cells derived from breast, colorectal, and gastric cancers that express EpCAM but not bind to EpCAM-negative cells. Among the aptamer sequences identified, a hairpin-structured sequence SYL3 was optimized in length, resulting in aptamer sequence SYL3C. The Kd values of the SYL3C aptamer against breast cancer cell line MDA-MB-231 and gastric cancer cell line Kato III were found to be 38±9 and 67±8 nM, respectively, which are better than that of the full-length SYL3 aptamer. Flow cytometry analysis results indicated that the SYL3C aptamer was able to recognize target cancer cells from mixed cells in cell media. When used to capture cancer cells, up to 63% cancer cell capture efficiency was achieved with about 80% purity. With the advantages of small size, easy synthesis, good stability, high binding affinity, and selectivity, the DNA aptamers reported here against cancer biomarker EpCAM will facilitate the development of novel targeted cancer therapy, cancer cell imaging, and circulating tumor cell detection.

Development of microfluidic-based analytical methodology for studying the effects of chemotherapy agents on cancer tissue

Whilst a multitude of techniques have been employed to study the biology of tumour tissue and its response to chemotherapeutic reagents, most current methodologies do not capture the sophistication of the in vivo environment. Microfluidics however offers the ability to maintain and interrogate primary tissue samples in an environment with biomimetic flow characteristics. In this study head and neck squamous cell carcinoma (HNSCC) tumour biopsies have been used to investigate the performance of a microfluidic device for generating clinically-useful information. The response of fresh and cryogenically-frozen primary HNSCC or metastatic lymph node samples to chemotherapy drugs (cisplatin, 5-flurouracil or docetaxel), alone and in combination, were monitored for both proliferation (water-soluble tetrazolium salt metabolism) and cell death biomarker release (lactate dehydrogenase, LDH) “off-chip”. The frozen tissue showed no significant difference in terms of either proliferation or LDH release in comparison with the matched fresh samples. Administration of all drugs caused cell death, in a dose-response manner, with the combination showing the greatest amount of cytotoxicity particularly at days 8 and 9; correlating well with published clinical data. The system described here offers an innovative method for studying the tumour microenvironment in vitro and, through incorporation of relevant analytical modules, provides the basis of a pre-clinical device that can be used to define personalised treatment regimens.

Microfluidic platforms for biomarker analysis

Biomarkers have been described as characteristics, most often molecular, that provide information about biological states, whether normal, pathological, or therapeutically modified. They hold great potential to assist diagnosis and prognosis, monitor disease, and assess therapeutic effectiveness. While a few biomarkers are routinely utilised clinically, these only reflect a very small percentage of all biomarkers discovered. Numerous factors contribute to the slow uptake of these new biomarkers, with challenges faced throughout the biomarker development pipeline. Microfluidics offers two important opportunities to the field of biomarkers: firstly, it can address some of these developmental obstacles, and secondly, it can provide the precise and complex platform required to bridge the gap between biomarker research and the biomarker-based analytical device market. Indeed, adoption of microfluidics has provided a new avenue for advancement, promoting clinical utilisation of both biomarkers and their analytical platforms. This review will discuss biomarkers and outline microfluidic platforms developed for biomarker analysis.

Genomics based biomarker discovery in oral squamous cell carcinoma

 The present thesis showed signaling mechanisms and pathways essential for oral cancer progression through genomics approach. It has identified markers that are of diagnostic, prognostic and therapeutic importance. It has also shown that aspirin is a potential drug in oral cancer treatment.

Mass spectrometry-based proteomic data for cancer diagnosis using interval type-2 fuzzy system

An interval type-2 fuzzy logic system is introduced for cancer diagnosis using mass spectrometry-based proteomic data. The fuzzy system is incorporated with a feature extraction procedure that combines wavelet transform and Wilcoxon ranking test. The proposed feature extraction generates feature sets that serve as inputs to the type-2 fuzzy classifier. Uncertainty, noise and outliers that are common in the proteomic data motivate the use of type-2 fuzzy system. Tabu search is applied for structure learning of the fuzzy classifier. Experiments are performed using two benchmark proteomic datasets for the prediction of ovarian and pancreatic cancer. The dominance of the suggested feature extraction as well as type-2 fuzzy classifier against their competing methods is showcased through experimental results. The proposed approach therefore is helpful to clinicians and practitioners as it can be implemented as a medical decision support system in practice.