Dual-Liquid Biomarker Profiling to Predict Drug Resistance in Triple-Negative Breast Cancer.

The studentship is available to UK applicants only.

Supervisors:

• Dr Emmanuel Acheampong ea335@leicester.ac.uk
• Professor Jacqui Shaw
• Dr Roberto Feuda

Project:

TNBC represents 15-20% of all breast cancers and is the most aggressive subtype [1,2]. TNBC lacks hormone receptors (oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), resulting in the absence of effective targeted therapies. Chemotherapy has been the primary treatment until the recent introduction of immunotherapy /oncology (IO) [3-6]. Consequently, metastatic TNBC (mTNBC) patients have limited treatment options and worse overall survival. Reliable biomarkers for prognosis and treatment monitoring are lacking [2, 7], highlighting a clear unmet need. While new treatment like chemo-immunotherapy (chemo-IO) have improved outcomes, development of drug resistance remains a significant issue. 

Liquid biopsies (LB) offer an attractive alternative approach for disease monitoring, with circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) the current ‘cornerstones’ of LB analysis [8,9]. Circulating tumour DNA (ctDNA) mutation analysis often fails to detect resistance early due to low abundance, however CTCs, which are responsible for cancer metastasis, have shown promise in determining treatment resistance and guiding treatment. As aberrations are tumour-specific and reflect disease progression [10-12], epigenetic analysis of cfDNA and CTC transcriptomics are two attractive alternative analytes to explore metastatic progression through liquid biopsy analytes. 

This project aims integrate epigenetic profiling of plasma-derived cfDNA and transcriptomic analysis of CTCs to identify robust biomarkers of disease progression and therapy resistance.

The student will receive interdisciplinary training include microfluidic liquid biopsy workflows for CTC isolation, CTC transcriptomics techniques, whole-genome methylation sequencing (Oxford Nanopore Technologies), bioinformatics, biostatistics, machine learning for muti-omics integration (eg. Seurat DESeq2, Random Forest/SVM), scientific writing, data visualisation and presentation skills.

This project is hosted at the University of Leicester within the Cancer Research Centre and NIHR BRC Cancer Theme. The student will work in a multidisciplinary team with access to state-of-the-art facilities, including single-cell and methylation sequencing platforms, informatics and the University Cancer Research Biobank. Collaborators include experts in single-cell biology, computational genomics, and translational oncology.

References

1) Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA. Triple-negative breast cancer: clinical features and patterns of recurrence. Clinical cancer research. 2007 Aug 1;13(15):4429-34.
2) Almansour NM. Triple-negative breast cancer: a brief review about epidemiology, risk factors, signaling pathways, treatment and role of artificial intelligence. Frontiers in Molecular Biosciences. 2022 Jan 25;9:836417
3) Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M. Pembrolizumab for early triple-negative breast cancer. New England Journal of Medicine. 2020 Feb 27;382(9):810-21.
4) Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R. Sacituzumab govitecan in metastatic triple-negative breast cancer. New England journal of medicine. 2021 Apr 22;384(16):1529-41.
5) Emens LA, Adams S, Barrios CH, Diéras V, Iwata H, Loi S, Rugo HS, Schneeweiss A, Winer EP, Patel S, Henschel V. First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis. Annals of Oncology. 2021 Aug 1;32(8):983-93
6) Cortes J, Rugo HS, Cescon DW, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Perez-Garcia J, Iwata H, Masuda N. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. New England Journal of Medicine. 2022 Jul 21;387(3):217-26.
7) Obidiro, Onyinyechi, Gantumur Battogtokh, and Emmanuel O. Akala. "Triple negative Obidiro O, Battogtokh G, Akala EO. Triple negative breast cancer treatment options and limitations: future outlook. Pharmaceutics. 2023 Jun 23;15(7):1796.
8) Lone SN, Nisar S, Masoodi T, Singh M, Rizwan A, Hashem S, El-Rifai W, Bedognetti D, Batra SK, Haris M, Bhat AA. Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments. Molecular cancer. 2022 Mar 18;21(1):79
9) Alix-Panabières C, Pantel K. Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy. Cancer discovery. 2016 May 1;6(5):479-91.
10) Palanca-Ballester C, Rodriguez-Casanova A, Torres S, Calabuig-Farinas S, Exposito F, Serrano D, Redin E, Valencia K, Jantus-Lewintre E, Diaz-Lagares A, Montuenga L. Cancer epigenetic biomarkers in liquid biopsy for high incidence malignancies. Cancers. 2021 Jun 16;13(12):3016.
11) Lianidou E. Detection and relevance of epigenetic markers on ctDNA: recent advances and future outlook. Molecular Oncology. 2021 Jun;15(6):1683-700
12) Zeng C, Stroup EK, Zhang Z, Chiu BC, Zhang W. Towards precision medicine: advances in 5-hydroxymethylcytosine cancer biomarker discovery in liquid biopsy. Cancer communications. 2019 Dec;39:1-9.