NEIL3 as a new target for cancer therapy.

NEIL3 is a DNA glycosylase that has activity in vitro by releasing oxidised bases from DNA. Of interest to the field of cancer research, NEIL3 has been found to be highly expressed in cancer cell lines and metastatic tumour tissue, while normally expression is strictly limited, both temporally during development, and in a tissue specific manner. Recently, it has been confirmed that NEIL3 is highly expressed in cells from a number of paediatric malignancies, including solid tumours (T32, primitive neuroectodermal tumour; Saos-2 & HOS, osteosarcomas) and glucocorticoid resistant and sensitive acute lymphoblastic leukaemia (CEM-C1, CEM-C7). Evidence suggest that NEIL3 is indeed a valid target for anticancer treatments has come from experiments that show that HCT116 human colorectal cells were sensitised to oxaliplatin treatment following siRNA knockdown of NEIL3. Therefore, a lack of NEIL3 protein has a significant effect on inhibiting the growth of the HT116 cells, even at the lowest dose of oxaliplatin used. This project will investigate the therapeutic potential of these observations.

 

Investigating n-3 PUFAs for potential adjuvant therapy in acute lymphoblastic leukaemia.

Treatments for acute lymphoblastic leukaemia (ALL) typically involve chemotherapy, usually in combination with steroids. There remains a need to develop novel therapies or enhance existing approaches to treatment, especially in patients with relapsed disease.

A link between inflammation and cancer is established. Whereas acute inflammation is perceived as a physiologic protective response to injury, chronic inflammation has been found to mediate a wide range of diseases, including cancers. Chronic inflammation is known to be important as a moderator of tumorigenesis, affecting cellular processes of survival, proliferation, invasion, angiogenesis, metastasis and influencing responses to chemo- and radio-therapies. In addition, inflammation is considered to be a risk factor for the development of many types of cancers. Thus, there is a potential to employ anti-inflammatory agents to suppress NFκB or NFκB-regulated products for the adjuvant treatment of cancers.

Marine n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), typically derived by humans from consuming fish oils have received much attention for their anti-inflammatory properties and completely safe adjuvant therapeutic potential. There is already strong epidemiological evidence linking fish oil consumption with low incidence of cancers. Anticancer actions of n-3 PUFAs are poorly understood but a number of studies have demonstrated synergistic effects of n-3 PUFAs, particularly DHA, delivered as conjugates with a variety of anticancer drugs, improving drug efficacy by enhancing cellular uptake. The broad aim of the project is to investigate cytotoxic effects in human leukaemic cells of the n-3 PUFAs, EPA, DHA and a key metabolite Resolvin D1, alone and in combination with chemotherapeutic agents used for ALL treatment.

 

Novel role of Calreticulin in haematological malignancies like Acute Myeloid Leukaemia

Recently mutations in the calreticulin (CALR) gene in human cases of Acute Myeloid Leukaemia (AML) and Myeloproliferative neoplasms (MPS) were identified. This study used FLAG tagged Calr protein to identify the sub-cellular localisation of mutant Calreticulin. In addition Co-immunoprecipitation techniques will be used to search for binding partners of mutant Calreticulin relative to WT Calreticulin. As Calreticulin is known to act as calcium buffer in the endoplasmic reticulum, this project analysed calcium signalling changes with mutant calreticulin

 

Selective targeting of the Ras oncogene family as a novel treatment for Ras mutated children cancers

Mutations in the DNA play an important role in the development of cancer; the Ras gene family produces proteins that help cells to survive and presents mutations in at least 15% of all human cancers and 6-20% of children cancers. These mutations appear in paediatric cancers such as melanoma of the central nervous system, neuroblastoma, juvenile myelomonocytic leukaemia, acute lymphoblastic lymphoma (ALL) and rhabdomyosarcoma). Ras is an important cancer target and for the last 25-years different inhibitors have been developed with little success as they target the genes protein products. The goal of this project is to study the Ras family as cancer targets by attacking at the DNA level. The second goal is to produce the foundations for the development of Ras inhibitors that can develop into new therapies to treat ALL and other childhood cancers.

 

Investigation of the anticancer activity of PBN derivatives on selected paediatric cancer cell lines.

Nitrones are compounds with the general formula R1R2C=N(O)R3 which were originally developed to allow the trapping of highly reactive free radicals at room temperature. The resulting adducts being sufficiently stable for detection by electron paramagnetic resonance spectroscopy (EPR). Their ability to react rapidly with free radicals has also encouraged researchers to investigate their antioxidant capabilities and potential therapeutic properties. More recently, it has been demonstrated that nitrones, such as a-phenyl-t-butyl-nitrone (PBN), have specific anticancer activity. Studies have clearly shown that PBN, hydroxylated PBN (PBN-4OH) and 2,4-disulfoPBN have antitumour effects on glioma and hepatocellular carcinoma models.

Previously, this research group has investigated the spin trapping properties of a-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) using GC-MS and MALDI-TOF mass spectrometry. These studies unexpectedly demonstrated that the major product of methyl radical trapping is the dimethyl adduct. These dimethyl adducts have not been synthesized previously and thus no studies on their anticancer activity have been conducted. The aim of this project is to investigate the anticancer activity of selected PBN derivatives and their dimethyl radical adducts on a panel of paediatric cancer cell lines.

 

Studies towards the asymmetric synthesis of novel antimitotic agents

A number of compounds are known that bind to the colchicine binding site on tubulin, effectively preventing the assembly of microtubules and thus preventing cancer cells from dividing. The project set out to establish methodologies for the synthesis of new compounds related to the known inhibitor phenstatin.

 

Understanding and development of a new class of cancer drug targeting proteins involved in angiogenesis.

These agents do not directly kill tumour cells – instead they destroy the blood supply to the tumour whilst not interfering with the normal blood supply in the healthy parts of the body. Unfortunately, the first examples of this type of compound have been shown to cause damage to the heart and children may be particularly sensitive to this type of toxicity. By altering the chemical structure of this new type of drug we aim to reduce or eliminate this heart toxicity. One part of this project will be to monitor the effects of our new drugs on heart muscle tissue. The project aims to improve the existing drug, to show little or no heart toxicity that would be suitable for further clinical development.

 

Synthesis and evaluation of novel analogues of emetine as antileukemics

Emetine is a naturally-occurring drug used for many years to treat amoebiasis. It also has very useful activity against many cancers including leukaemia but has side-effects which have prevented its development. We propose to make a range of new compounds slightly different in structure to emetine which can be tested for anti-cancer activity and developed into possible new treatments for childhood leukaemia. The intention is that new compounds made would have the activity of the natural product, or more, without the side-effects.

 

Studies of relapses within the central nervous system (CNS) in children with acute lymphoblastic leukaemia (ALL)

ALL is the most common cancer in childhood and treatment related toxicity and relapse are important therapeutic challenges. To further improve outcome new, non-toxic, targeted therapies need to be developed. These may be targeted to the leukemic population in general or to the sub-population thought to give rise to relapse. Relapsed disease is characterised by an increased involvement of sites other than the bone marrow. This has led to the suggestion that chemo-resistance and invasion may be linked.

 

Establishing the factors that determine quality of life, health status, psychological wellbeing and self-esteem for children undergoing treatment for central nervous system (CNS) tumours.

The personal response of children to treatment for cancer is important for their wellbeing during treatment and can impact on outcomes such as health-related quality of life, health status and psychological wellbeing afterwards. This study will establish the factors that determine quality of life, health status, psychological wellbeing and self-esteem for children undergoing treatment for central nervous system (CNS) tumours. The families of sixty children within three years following diagnosis will be surveyed using measurement questionnaires about child health-related quality of life, health status, psychological functioning, self-esteem, and family functioning. This will result in mapping of key factors and their influence on these patients during different treatments and follow-up. These issues will be explored in greater detail with up to twenty families to establish how these factors exert their effect on children and their family. The researcher will follow each family for one year through more or less challenging times, and employing child-friendly methods of data collection. The result will be a deeper understanding of the relationship between key factors and their impact on self-esteem, quality of life, health status, psychological wellbeing and family functioning. This will help to optimise the psychosocial and other support for these families throughout the cancer journey.

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