Here are details of the projects that Kent Cancer Trust scholars are working on in order to obtain their MSc.
Rosalba's Project:
I am part of Tim Fenton’s group at the University of Kent. My research focuses on a family of proteins called APOBEC3; there are 7 APOBEC3 proteins (A3A, A3B, A3C, A3D, A3F, A3G and A3H) and I am interested in APOBE3B. APOBEC3 are involved in innate immunity, helping the body to fight against viral infections. However, it has recently been discovered that high expression of APOBEC3B causes specific DNA mutations, referred to as kataegis, mostly found in breast cancers, as well as bladder, cervix, lung adenocarcinoma, lung squamous cell carcinoma and head and neck cancer. Surprisingly, many DNA mutations of this type are also seen in tumors from patients who lack the APOBEC3B gene due to natural deletion found at varying frequencies across the global population. The APOBEC3B deletion is found in 1% of Africans, ~6% of Europeans, ~37% of East Asians, ~58% of Amerindians and a very high fixed frequency of ~93% in Oceanic population. It has been shown that this deletion is associated with an increased cancer incidence, though the reason for this is unknown.
I am currently investigating this important question, specifically addressing whether APOBEC3B deletion affects the expression of the other APOBEC3 proteins and their deaminase activity; in addition, I am going to investigate how the deletion polymorphism affects cell growth and replication. APOBEC3 are mainly involved in restricting viral infection, therefore my longer term goal will be to investigate if and how the deletion affects HPV infection and HPV-associated cancers. In order to achieve my aims, I am working with natural immortalized keratinocytes (NIKS) as an isogenic model where I will generate this APOBEC3B deletion polymorphism by using a powerful new genome engineering technique called CRISPR/Cas9.
The ultimate aim of my research is to further elucidate and understand the role of APOBEC3 proteins in cancer development, whether these might represent yet another dysregulation affecting cancer progression and if it can be a new or additive target for therapeutics.
Timo's project:
Drug resistance is a pervasive issue in cancer treatment. Although there are a wide range of therapies with high initial efficacy available, tumours often become resistant to treatment over time, decreasing the potency of the drug and giving the cancer the upper hand. The Michaelis lab investigates how drug resistance in cancer can be overcome by using a cellular model; we take cancer cells and make them resistant to different kinds of anti-cancer drugs, then investigate what other treatments are effective against these resistant cells to mimic the effect of the drug on a resistant tumour.
My project specifically is focussing on a type of lung cancer known as non-small cell lung cancer (NSCLC). This cancer often has a specific mutation that can be exploited by a group of targeted drugs called Epidermal Growth Factor Receptor (EGFR) inhibitors, which are initially very effective at killing NSCLC cells. However, the tumour rapidly becomes resistant to these agents, meaning that alternative lines of therapy must be investigated. My project involves screening resistant NSCLC cells against various anti-cancer drugs that work in different ways, so that we can find out which drug is the most effective to use once resistance to EGFR inhibitors occurs. This data can hopefully allow us to inform effective treatment plans for patients with resistant NSCLC in the future, giving them the best possible chance at beating their disease.
Natasha's project:
There were around 7,400 new cases of ovarian cancer in the UK for the years 2013-2015.
A major problem in the treatment of ovarian cancer is the development of resistance to chemotherapeutic drugs. DNA replication occurs during the cell cycle and is coordinated by DNA replication proteins; which form the replication fork. Impaired fork progression leads to a type of DNA damage termed replication stress. Cyclin E, a regulator of cell cycle progression, has been associated with enhanced replication stress when overexpressed in cancerous cells. In response to replication stress, cells initiate the DNA damage response leading to DNA repair or apoptosis. Deficiency in DNA repair leads to genomic instability which is a defining characteristic of cancer. This provides opportunities to use inhibitors complementary to aspects of the DDR pathway on which the cancers have become dependent. One such target is checkpoint kinase 1 (Chk1) for which there are inhibitors for, such as CCT245737, currently in clinical trial that have the potential to become available for the treatment of ovarian cancer.
The aim of this research project is therefore to; (i) generate a Chk1-resistant ovarian cancer model (ii) predict mechanisms of resistance and (iii) consider strategies to overcome drug resistance. This could allow for the identification of new drug targets for novel therapeutic therapies.
All of these studies are important in the search for new cancer therapies that will make a difference to patients. We wish our scholars well in their important studies!