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  PI3K-Akt expression in dysplastic oral lesions and implications for recurrence and malignant transformation


   Dental School

  , , ,  Thursday, October 31, 2024  Self-Funded PhD Students Only

About the Project

There are around 12,400 new head and neck cancer cases in the UK every year, that's 34 every day (2016-2018) with 4,143 deaths each year. It is the 8th most common cancer in the UK, accounting for 3% of all new cancer cases. Between 19% and 59% of people diagnosed with head and neck cancers in England survive their disease for ten years or more (Cancer Research UK 2018). In the UK, oral cancer incidence rates have steadily risen since the 1980s. Mistry et al (2011) projected that cancers of the lip, mouth and pharynx will increase by 1% per year to 2030.

In 2010 the National Screening Committee review (NSC) stated that there is “good evidence that tobacco in all forms (both smoked and smokeless, including snuff) and betel quid are carcinogenic in the upper aerodigestive tract, which includes the mouth. There is also convincing evidence that alcoholic drinks are carcinogenic and act synergistically with tobacco” (Speight & Warnakulasuriya 2010).

The natural history of oral cancer is only partly understood, with reports of “it is clear that oral squamous cell carcinoma (OSCC) is preceded by changes in the oral mucosa, but the extent or nature of these changes is uncertain” (Speight & Warnakulasuriya 2010). However, it was also noted that “only about 5% of these lesions will progress to malignancy and although some clinical features are associated with higher risk (e.g. non-homogenous, speckled or red lesions) there are still no reliable ways to predict which individuals or lesions will develop OSCC” (Speight & Warnakulasuriya 2010). The difficulty in interpreting some of the published work on malignant progression is that many studies do not actually investigate biopsy proven dysplasias but leucoplakias and therefore these may not actually be potentially malignant. One study showed that follow up of biopsy proven dysplasias showed a malignant transformation rate of 25% and an estimated 76% of patients will have one or other event in 5 years (Ho et al 2013). Another issue with reported studies is that they are carried out in parts of the world where oral cancer is far more prevalent and not comparable to the UK.

A systematic review of biomarkers in oral dysplasia found loss of heterozygosity (LOH) and elevated expression of survivin, matrix metalloproteinase (MMP 9), and DNA content are potential markers for increased risk of progression from oral dysplasia to cancer (Smith et al 2009). Another review suggested that epigenetic events, cell cycle molecules, angiogenic regulators, and S100 protein expression could predict malignant progression (Nikitakis et al 2018).

The PI3K-Akt signalling pathway is a well-established driver of cancer progression. Previous immunohistochemical analysis of VEGF positive human head and neck tumour tissues showed a significant increase in Akt phosphorylation at the T308 residue, suggesting that pAkt T308 may be associated with tumour progression in vivo. In addition a higher phosphorylation of Akt at S473 was shown to be a prognostic factor for HNSCC (Islam et al 2014). Another immunohistochemical study reported no pAkt staining in normal tissue compared to positive staining in the basal and parabasal cell layers, and partially in the spinous layer of epithelial dysplasia tissues, and in the spinous layer of early cancer tissues suggesting that activation of the PI3K-Akt signal pathway is associated with oral carcinogenesis.(Watanabe et al 2009) The PI3K/Akt pathway has also been implicated in perineural spread of oral cancer by stimulation by nerve growth factor which induced oral and salivary tumour cell scattering and migration (Alkhadar e al 2020).

The aim is to determine whether there is an association between the expression on PI3K-Akt in oral dysplastic lesions with recurrence, field cancerisation and malignant transformation. Also determine the efficacy of potential biomarkers such as cell cycle molecules, angiogenic markers and S100 protein expression.

For informal enquiries about the project, contact Professor Michaelina Macluskey, 

For general enquiries about the University of Dundee, contact

Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research. We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.

QUALIFICATIONS

Applicants must have obtained, or expect to obtain, a Batchelor of Dental Surgery (BDS) degree (or equivalent for non-UK qualifications), and/or a Masters degree in a relevant discipline. For international qualifications, please see equivalent entry requirements here: www.dundee.ac.uk/study/international/country/.

English language requirement: IELTS (Academic) overall score must be at least 6.5 (with not less than 5.5 in reading, listening, speaking or 6.0 in writing). The University of Dundee accepts a variety of equivalent qualifications and alternative ways to demonstrate language proficiency; please see full details of the University’s English language requirements here: www.dundee.ac.uk/guides/english-language-requirements.

APPLICATION PROCESS

Step 1: Email Professor Michaelina Macluskey,  to (1) send a copy of your CV and (2) discuss your potential application and any practicalities (e.g. suitable start date).

Step 2: After discussion with Prof Macluskey, formal applications can be made via our direct application system. When applying, please follow the instructions below:

Candidates must apply for the Doctor of Philosophy (PhD) degree in Dentistry (3 Year Non-Clinical) using our direct application system: apply for a PhD in Dentistry.

Please select the study mode (full-time/part-time) and start date agreed with the lead supervisor.

In the Research Proposal section, please:

-         Enter the lead supervisor’s name in the ‘proposed supervisor’ box

-         Enter the project title listed at the top of this page in the ‘proposed project title’ box

In the ‘personal statement’ section, please outline your suitability for the project selected.

Biological Sciences (4) Medicine (26)

Funding Notes

There is no funding attached to this project. The successful applicant will be expected to provide the funding for tuition fees and living expenses, via external sponsorship or self-funding.

References

Head and neck cancers statistics Cancer Research UK 2018
https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/head-and-neck-cancers
Moyer VA , Screening for oral cancer: U.S. Preventive Services Task Force recommendation statement..Ann Intern Med. 2014 Jan 7;160(1):55-60. doi: 10.7326/M13-2568.PMID: 24276469
M Mistry, D M Parkin, A S Ahmad, P Sasieni.Cancer Incidence in the United Kingdom: Projections to the Year 2030. Br J Cancer. 2011 Nov 22;105(11):1795-803. doi: 10.1038/bjc.2011.430. Epub 2011 Oct 27.
Speight, P.M. and Warnakulasuriya, S. (2010) Evaluation of Screening for Oral Cancer against National Screening Committee Criteria. UK National Screening Committee Publications. http://www.screening.nhs.uk/oralcancer

Biomarkers in dysplasia of the oral cavity: a systematic review.
Smith J, Rattay T, McConkey C, Helliwell T, Mehanna H.Oral Oncol. 2009 Aug;45(8):647-53. doi: 10.1016/j.oraloncology.2009.02.006. Epub 2009 May 12.
Nikitakis NG, Pentenero M, Georgaki M et sl. Molecular markers associated with development and progression of potentially premalignant oral epithelial lesions: Current knowledge and future implicationsOral Surgery, Oral Medicine, Oral Pathology and Oral Radiology Volume 125, Issue 6, June 2018, Pages 650-669
Islam M.R , Jones S.J, Macluskey M, Ellis I.R. Is There a pAkt Between VEGF and Oral Cancer Cell Migration? Cell Signal. 2014 Jun;26(6):1294-302. doi: 10.1016/j.cellsig.2014.02.004. Epub 2014 Feb 19.

Watanabe S1, Sato K, Okazaki Y, Tonogi M, Tanaka Y, Yamane GY.Activation of PI3K-AKT pathway in oral epithelial dysplasia and early cancer of tongue. Bull Tokyo Dent Coll. 2009 Aug;50(3):125-33.
Alkhadar H, Macluskey M, White S, & Ellis I. Perineural Invasion in Oral Squamous cell Carcinoma: Incidence, prognostic Impact and Molecular Insight 12 Jun 2020, In : Journal of Oral Pathology and Medicine.

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