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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - TRACT (Training in Cancer Mechanisms and Therapeutics)

Teaser

Summary

There is an urgent need for researchers trained in next-generation technologies for improved detection and treatment of oral and oesophageal cancers. The number of oral cancers diagnosed in the EU has increased by over 75% in the last 30 years, with long-term survival rates of only 50%. This is typically due to the late diagnosis of the disease and resistance to current therapies. Through the â€˜TRAining in Cancer mechanisms & Therapeuticsâ€™ (TRACT) project, eleven PhD Fellows are completing research projects in three critical thematic areas; biomarker discovery, molecular resistance mechanisms and metabolic transformation mechanisms. TRACT will enable these PhD Fellows to discover novel insights into the molecular and cellular basis of oral and oesophageal cancer and generate new diagnostic tools and therapeutics that will improve patient response and survival. Through a number of SME/industrial partners, the PhD Fellows are being exposed to next-generation technologies in areas such as cancer diagnosis, metabolism, biomarker identification and drug development. As well as attending a range of bespoke research training courses in the partner universities and within industry, the Fellows are also taking courses on how to commercialize research discovery. Thus, Fellows trained through the TRACT network will be uniquely positioned for careers in academia, industry or as entrepreneurs.

Work performed

One of the TRACT research objectives is to identify novel biomarkers at the molecular level to enable early detection of oral and oesophageal cancer and to predict response to therapy. Tests to measure inflammatory and glycan markers in human saliva have been established. Furthermore, these salivary markers are currently being correlated with stages of oral cancer and before and after radiotherapy in patient samples. In addition, analysis of biopsies taken from early stage oesophageal cancer patients has been undertaken to try to identify gene profiles that will help to predict the response of patients to chemotherapy. Another objective of the project is to better understand the molecular basis of drug resistance in oral and oesophageal cancer. A study of frequently altered or mutated genes in oesophageal cancer biopsy samples has been completed. A protein involved in glucose transport has been identified as a potential marker of prognosis in oesophageal cancer. Furthermore, certain inflammatory proteins are strongly expressed in early stage oesophageal cancer suggesting that their inflammatory role may be involved in the progression of oesophageal cancer. A series of novel drugs that target cell death pathways have also been designed and synthesised and are currently being tested in oral and oesophageal cancer models. Finally, altered metabolism may also play an important role in the development of oral and oesophageal cancer OOC. A high-resolution test to examine, in real time, the metabolism of oral cancer cells has been developed and metabolic profiling of oral cancer cells is underway.

Final results

The past decade has witnessed a renewed appreciation of the complexity of cancer cell metabolism, survival and therapeutic resistance. These characteristics are especially important in the context of oral and oesophageal cancer (OOC), which is difficult to detect, is frequently diagnosed late, has few therapeutic options and has poor survival rates. Current state of the art in clinical diagnosis is limited to visual/endoscopic examination of the oral/oesophageal region and histological analysis of tumour biopsies. In addition, the predominant treatment approach is chemotherapy/radiotherapy followed by surgery. The TRACT project is focusing on developing original and innovative solutions to key challenges in OOC diagnosis and treatment through the development of methods for early and accurate diagnosis, methods for monitoring patients during therapy, approaches for prognostic stratification of patients, novel therapeutics to overcome resistance and novel target pathways, including metabolic transformation pathways.
TRACT is carrying out discovery research into biomarkers associated with OOC to develop state-of-the-art diagnostic assays for 1) earlier, more reliable detection, and 2) therapeutic response prediction. This research will improve OOC survival rates by developing biomarker-based assays for earlier, more reliable disease diagnosis and stratification of individual patients to more effective chemotherapeutic regimes. This comprehensive patient profiling provides essential information to the clinician, enabling earlier and more accurate diagnosis and the potential to administer more appropriate treatment. This approach will not only benefit the patient, with the potential for improved quality of life, disease control and minimize side-effects by administering more targeted treatment, but will also potentially lead to reduced costs for healthcare providers.
TRACT is also uncovering the molecular basis of drug resistance mechanisms in OOC and of metabolic transformation with the aim of 1) improving the efficacy of existing therapies, 2) identifying new drug targets, and 3) developing novel therapies. Initial pre-clinical testing will be carried out to support future translation to clinical studies. A greater understanding of the cellular mechanisms that contribute to chemotherapeutic resistance in OOC and that lead to metabolic transformation will enable the development of combination therapies with greater efficacy than current chemotherapeutic regimes. Targeted combination therapies hold the promise of improved response rates, decreased chemotherapeutic toxicity and enhanced survival rates.
A novel pre-clinical model of oesophageal adenocarcinoma is also being developed. These model system should better mimic the environment of the tumour within the body and tumour drug-response than traditional oesophageal cancer cell line models thus advancing the state-of-the-art.