Platform 2: Oncology, general and trauma
Despite significant advances being made in the treatment of patients with cancer, more needs to be done to improve outcomes. In oncology, the term precision medicine means giving the right treatment to the right patient at the right time. Although this sounds simplistic, in practice, it is actually hugely complex. In this theme, projects are offered to address this aspiration using cutting edge technologies that are available at the University of Leicester. Professor Shaw's group has spent more than 20 years investigating the use of the 'liquid biopsy' that can detect the DNA shed by tumour cells (ctDNA) into the blood of patients with a number of different cancers. Repeat blood tests can be taken for patients throughout their treatments to monitor circulating tumour derived DNA or ctDNA to detect disease progression as soon as possible, understand why some tumours eventually become resistant to treatments thereby personalising individual patient's treatment. We are also investing other markers in the blood as tools for detection and monitoring cancer including platelets and vesicles including their cargo of DNA RNA and proteins.
Each year millions of dollars are spent developing new drugs. Historically this process has involved taking a drug of interest, testing it on cancer cells in the laboratory and then animal models with cancer. Promising drugs then enter clinical trials. This process is expensive, both financially and in terms of time. Moreover, we now know that, based on results from sequencing the genome, a tumour type such as breast cancer comprises many different types of cancer cells, all of which have their own genetic signatures. Some of these cancer cells will respond to the new drugs but others will not. Professor Pritchard has developed a novel way of growing a tumour outside the body long enough to test new drugs on it. This means that we can effectively carry out an experiment using patient cancer tissue (biopsy) and find the most effective drug to kill the cancer cells on a patient-by-patient basis. This allows treatment to be individualised to a particular patient’s tumour. This technology is being developed further in Dr Royle’s laboratory in patients with soft tissue sarcoma. We know that the number of active treatments in this tumour is very small – by working with a commercial company, it potentially opens up the treatment opportunities available.
Within the Leicester Cancer Centre scientists work alongside clinicians to ensure we deliver the best lab to bedside cancer research. This model provides a rich environment for bright and up and coming academic doctors to flourish. The team has an excellent track record in supporting ACF trainees providing them with grant writing and funding opportunities, excellent laboratory skills training and opportunities for manuscript writing. All this is done while ensuring that trainees continue to develop their clinical skills with protected research time. To date we have successfully provided this excellent support network for both medical and surgical focused trainees.
Three projects available are:
ctDNA technology to monitor tumour evolution and emergence of resistance for clinical decision making in cancer
Professor Jacqui Shaw heads one of the leading international laboratories developing ctDNA technology. The ACF will join this well-established research team investigating the utility of circulating tumour DNA for detection and monitoring of cancers. There are ongoing projects in oesophago-gastric, breast, colorectal and endometrial cancers. The group was the first to show that monitoring acquired mutations in the ESR1gene through a blood test could help clinicians decide the optimum treatment for patients with breast cancer. Their recent work has highlighted the importance of CNV as well as somatic mutations for monitoring tumour evolution and emergence of resistance for clinical decision making in both breast and oesophago-gastric cancers. The overall aim is to determine whether ctDNA monitoring has value for detection of disease progression, emergence of resistance and for personalising individual patient's treatment. The ACF will focus on analysis of patient omic data generated from ultra deep sequencing of tumour and plasma DNA. Bioinformatic approaches will be used to determine the optimum panel of markers for evaluation of ctDNA and these will be applied to serial plasma samples from patients on follow up recruited through the Hope Clinical Trials Unit.
Evaluation of the power of breast cancer explants in predicting responses of patients to novel therapies in clinical trials.
Attrition is a major problem in anticancer drug development with up to 95% of drugs tested in Phase I trials not reaching the market. It is being increasingly recognised that there is a need to re-capitulate inter- and intra-tumour heterogeneity in pre-clinical cancer models in order to more robustly assess interventional strategies. Current model systems fail to take into account the diverse histopathological and molecular characteristics of tumours, leading to sub-optimal efficacy readouts. Although Patient-Derived Xenograft (PDX) mouse models allow the clonal architecture of tumours to be preserved they are limited by loss of supporting tumour microenvironment (TME) over time. To overcome these problems, we have invested in the development of a patient-relevant tumour “explant” platform. In this approach, tumour samples are obtained fresh from surgery and cultured ex vivo as small tumour fragments. The tumour architecture and TME are retained intact and drug responses can be assessed in situ. We are now developing the model in breast cancer. We have the opportunity to train an ACF in the laboratory of Professor Catrin Pritchard who is an outstanding record in the training of PhD students and has secured grant income in excess of £1M for this project.
Developing personalised treatments for patients with soft tissue sarcomas.
Soft tissue sarcomas (STSs) are a heterogeneous group of malignant solid tumours derived from mesenchymal origin. Presently the curative treatment of STSs revolves around surgical resection and peri-operative radiotherapy. The benefits of adjuvant chemotherapy remain controversial and are not usually recommended. Unfortunately following primary treatment 17%-24% of tumours will either recur locally or with metastatic disease. Recurrence is difficult to manage, the outcomes for patients are poor and have seen little improved over the past 30 years. STSs are genetically and histologically highly diverse and this has made development of alternative therapies challenging. Through the East Midlands Sarcoma Service and in collaboration with a commercial company we are exploring a novel, highly personalised approach to assess the response of each STS to a wide range of chemotherapeutic drugs, by directly testing STS tissue removed during surgery. The drug response data will be evaluated in relation to the genetic profile of each tumour. The ACF will join this project to collect STS tissue for immediate drug testing by our commercial partner company and they will work to increase STS collection and drug testing from other specialist services in the Midlands and North of England. In addition the ACF will conduct laboratory experiments, using a model organism, to identify genes and pathways that are involved in the development of resistance to chemotherapeutic drugs or drug combinations commonly used to treat metastatic STS disease.