Dr. Niamh O'Boyle

Summary

The aim of this project is to evaluate the biochemical effects of novel, enantiomerally pure β-lactams on breast cancer cells. Specific assays will investigate effects on breast cancer cell proliferation, cell cycle, apoptosis and tubulin polymerisation. This will enable us to identify the best drug candidate for progression to pre-clinical experiments, e.g. in vivo assessment.

Funding Agency

Wellcome Trust Institutional Strategic Support Fund

Programme

Start-Up Funding for Newly Independent Investigators

Person Months

12

Summary

Funding Agency

CAMS-UK and Royal Society of Chemistry

Programme

Analytical Chemistry Trust Fund CAMS Fellowships

Person Months

6

Summary

Cancer is a disease that affects thousands of people and their families every year. The aim of cancer research is to understand what happens in the body to cause cancer, enabling us to prevent it or treat it. This project will investigate new ways to treat cancer, using chemicals called 'oxygen free radicals' that are found in tumors. The research will be based on a natural product known as piperlongumine and the effect that it has on the response of cancer cells to oxygen free radicals. Piperlongumine is found in the fruit plant Piper longum ('Long pepper'). It was recently discovered that piperlongumine can selectively kill cancer cells without harming normal, healthly cells. It is thought that this is because piperlongumine raises the levels of reactive oxygen free radicals in cancer cells, which causes them to die. I will investigate if piperlongumine and other related chemicals have additional biochemical effects in cancer cells that contribute to their anti-cancer effects. In particular the research will focus on a protein called tubulin that is extremely important for cell replication, both in cancer cells and healthy cells. The overall, long-term goal of this research is to design new anti-cancer drugs that will selectively kill cancer cells by manipulating oxygen free radicals and tubulin.

Funding Agency

Irish Research Council

Programme

Government of Ireland Postdoctoral Fellowship

Person Months

24

Summary

Triple-negative breast cancer (TNBC) is the most aggressive and lethal form of breast cancer. The most successful drugs target three receptors common to most breast cancers (estrogen receptors, progesterone receptors and HER2 receptors). TNBC does not express any of these receptors and, despite many advances in cancer treatment, remains difficult to treat. This project aims to address an unmet clinical need by developing drugs to treat TNBC. With an increasing incidence of cancer and an ageing population, we need to address this problem now to improve future outcomes for the individual and for society. The development of new drugs to treat TNBC will improve quality-of-life for patients and alleviate the economic burden of cancer on society. Tubulin is a protein that is essential for tumour cell replication. Drugs targeting tubulin, e.g. paclitaxel, are used to treat a wide range of cancers and have saved countless lives. Unfortunately drug resistance and side-effects are common, hence development of new drugs is necessary. A large library of anti-tumour β-lactams that interact with tubulin and halt the growth of cancer cells, including TNBC cells, have been developed by our research group. These compounds are amongst the most potent tubulin-targeting agents ever reported. The β-lactams were initially evaluated as a racemic mixture of two isomers known as enantiomers. It is common that one enantiomer of a drug has a better therapeutic profile, although many drugs are still produced as racemates. The next critical step in this project involves chemical synthesis of the enantiomers of our β-lactams. The most biologically active compounds from our series of over 250 analogues have been chosen for synthesis as single enantiomers. Upon completion of synthesis, biological evaluation of their relative potencies in TBNC cells will allow us to determine which has superior activity. The most promising compounds will be progressed for preclinical development to establish a clinical drug candidate with the potential to save lives. The three overall aims of this research project are: 1. Development of efficient methods for chemical synthesis of enantiomerically pure β-lactams. 2. Evaluation of the anti-tumour effects of the β-lactams in breast cancer cells. 3. Development of the best β-lactams as potential clinical drug candidates for treatment of TNBC. The outcomes of the project will be twofold: firstly, advances in the design of novel anti-cancer drugs to treat TNBC and secondly, development of more efficient methods to synthesise enantiomerically pure β-lactams. The methodology developed from the latter can potentially be applied to the synthesis of number of commercially available β-lactam-containing drugs, e.g. ezetimibe.

Funding Agency

University of Dublin, Trinity College

Programme

Provost's PhD Project Awards

Person Months

48

Summary

Breast cancer is the most common cancer amongst Irish women and its incidence is predicted to rise. The most common subtype is estrogen-receptor positive (ER+) breast cancer, comprising nearly four out of every five cases (79%). Long-term (5 years) hormone treatment such as use of tamoxifen and raloxifene has revolutionised the treatment of ER+ breast cancer and improved the lives of millions of women worldwide. Tamoxifen and raloxifene are selective-estrogen receptor modulators (SERMs), modifying the effects of estrogen in female reproductive tissues. They act as antagonists of the ER in some tissues, such as the breast, and agonists in other tissues, e.g. bone. Tamoxifen is the first-line treatment and is also under investigation for the prophylaxis of breast cancer in high-risk women. Unfortunately, long-term use of tamoxifen significantly increases the risk of endometrial cancer whilst raloxifene has a protective effect. The reasons for this are still unclear and there are likely to be a number of contributing factors. Interferon-epsilon (IFNε) is recently discovered type I interferon that is constitutively expressed in the female reproductive tract (FRT), including the endometrium. IFNε expression is under hormonal control and IFNε levels fluctuate depending on the relative concentrations of estrogen and progesterone. Our preliminary data strongly indicates that IFNε also acts as a tumour suppressor in the FRT. We propose that SERMs modify expression levels of IFNε in endometrial and breast cells and tissues. This would contribute to altered immunity in the endometrium, potentially leading to increased risk of developing cancerous cells. Given the current widespread use of tamoxifen and its potential prophylactic use in the future, unravelling the mechanisms leading to tamoxifen-associated endometrial cancer is of paramount importance. Such knowledge could influence patient treatment, cancer strategies and prescribing guidelines in the future.

Funding Agency

Trinity St. James's Cancer Institute

Programme

Cancer Immunology Stimulus Awards