Facile and Accurate Diagnosis of Cancer

Cancer is one of the leading causes of death worldwide. According to the World Health Organization, cancer accounts for nearly 1 in 6 of all global deaths and costs about £16 billion a year for the UK healthcare system. One of the main strategies to lower the global burden of cancer is early diagnosis, due to significant higher rate for successful treatment and significant lower rate for recurrence. For example, improvement of diagnosis during the 1980s contributed to a decrease in breast cancer mortality rates in middle aged women. If the breast cancer is diagnosed and treated before it has spread to the lymph nodes or other organs, the five-year survival rate is 98 percent, as opposed to 23 percent once it has spread to other organs in the body (known as metastatic cancer). Hence, early diagnosis of cancer is of great importance for conquering the disease.

The aim of this project is to develop facile and reliable diagnostics for detection of tumours at the earliest possible stage. The strategy will rely on a specific cell surface receptor, HER2. HER2-positive breast cancer is aggressive and fast-growing. Approximately 25 percent of all breast cancers are HER2-positive, and this type of cancer has a significantly higher recurring rate. Since HER2 is overexpressed in HER2-positive cancer, we will utilise this unique feature to develop early diagnostics.

This strategy combines a targeting entity, which recognises HER2 specifically, a reporter, and a cleavable linker that joins both of these moieties. An anti-HER2 antibody will be used as the targeting entity. This approach has proven successful in the case of FDA-approved biotherapeutic agent trastuzumab emtansine for the treatment of HER2-positive cancer cells. The linker will enable facile cleavage of the conjugate once internalised inside cells, leading to the release of free reporters. The reporter has no detectable signal before linker cleavage, and a strong signal will be detectable after linker cleavage. For proof of concept, we will use a self-immolative dendrimer containing several reporter moieties. The system will initiate a fragmentation cascade upon linker cleavage, and the cascade will release the free reporters.

Due to the presence of targeting entity, the conjugate will only be internalised by HER2-positive cells, so that we will be able to distinguish between cancer and healthy cells. Theoretically, this approach can be generalised to detect other types of cancer by using different targeting entities, thereby providing an effective and accurate new tool for cancer diagnosis.