Urological Cancer Biology

Research highlights

There are three main overlapping themes:

1. Immune Heterogeneity in Prostate Cancer

Prostate cancer is the second most common malignancy in men leading to an estimated 307,000 deaths worldwide. The majority of patients that present with prostate cancer in the western world have prostate confined, low risk disease with a 98.8% 10-year survival. However, the patients that present with high-risk prostate cancer have significant mortality rates despite radical treatments.

A key challenge in prostate cancer is being able to identify with certainty patients with high-risk and treat them, while avoiding overtreatment in the low-risk group. The UCBG aims to tackle this by investigating the prostate cancer heterogeneity through high coverage genomic sequencing, proteomics and immune infiltrate analysis.

Key trials underpinning this effort include Prostate TRACERx, PEACE and NEPTUNES.

2. Signalling Heterogeneity in Prostate Cancer

Even morphologically normal regions of the prostate have been shown to contain possible cancer drivers. When evaluating whether a prostate tumour is potentially lethal, an understanding of the activated oncogenic signalling networks within that region could be key. Using multi-regional mass spectrometry techniques, array based kinase assays and computational biology we aim to identify activated signalling nodes and test their functional relevance as potential therapeutic targets.

3. Early Phase Clinical Trials of Targeted Therapy

Immune checkpoint inhibition in prostate cancer has so far been of limited success. Bladder cancer has yielded notable successes but the majority of patients still gain limited benefit. This may be in part due to low mutational burdens, low neoepitope presentation or impaired T-cell migration. We are conducting a number of Early Phase Clinical trials of small molecule inhibitors, vaccines, immune checkpoint inhibitors and Bispecific T-cell engagers (BITEs) within the UCLH/NIHR Clinical Research Facility. We are the lead site for the BioNTech Prostate Cancer Vaccine study called Pro-MERIT and are exploring peptide vaccines in combination with checkpoint inhibitors in early bladder cancers (DURANCE study). Using clinical samples generously donated from patients enrolled in these trials, we are studying the immune landscape to help better understand responses and resistance to these exciting new treatments and to develop rational therapeutic combinations.

Urological Cancer Biology Group

Current group members

• Dr Mazlina Ismail, Postdoctoral Scientist
• Dr Andrea Castro, Postdoctoral Scientist
• Dr Gianmarco Leone, Clinical Fellow
• Dr Charles Parker, Clinical Fellow
• Dr Saquib Raza, Clinical Fellow
• Miss Emily Moore, PhD Student
• Mr Sam Gamble, PhD Student
• Mr Ali Shokri, Research Assistant
• Miss Hanna Mohamed, Research Assistant

Group alumni

• Dr Gerald Goh, Postdoctoral Scientist
• Dr Helen King, Postdoctoral Scientist
• Dr Sophia Wong, Clinical Fellow
• Dr Anu Jayaram, Clinical Fellow
• Dr Mahaz Kayani, Clinical Fellow
• Dr Parry Sawhney, Clinical Fellow
• Dr Jasmin Waterhouse, Clinical Fellow
• Mr Morgan Jones, PhD Student
• Ms Helena Vincentelli, Research Fellow

Publications

1. Linch M*, Goh G*, Hiley C, Shanmugabavan Y, et al. Intratumoural evolutionary landscape of high risk prostate cancer: The PROGENY study of genomic and immune parameters. Ann Oncol. 2017 Oct; 28(10): 2472-2480.
2. Wong S, Joshi K, Pule M, Peggs K, Swanton C, Quezada S, Linch M. Evolving adoptive cellular therapies in urological malignancies. Lancet Oncology. 2017 Jun;18(6):e341-e353. 
3. Soriano EV, Ivanova ME, Fletcher G ... Linch M, et al. aPKC Inhibition by Par3 CR3 Flanking Regions Controls Substrate Access and Underpins Apical-Junctional Polarization. Dev Cell. 2016 Aug 22;38(4): 384-98.
4. Yousaf N, Harris S, Martin J, Stanway S, Ifijen M, Linch M, Al Muderis Omar, Fisher C, Judson I, Benson C. First line palliative chemotherapy in elderly patients with advanced soft tissue sarcoma. Clin Sarcoma Res. 2015 Mar 24;5:10.
5. Martin-Liberal J, Cameron A, Claus J, Parker PJ, Linch M. Targeting protein kinase C in sarcoma. Biochim Biophys Acta. 2014 Dec; 1846(2): 547-559.
6. Linch M, Hayes A. PDT with a glucose-conjugated chlorin for GIST-Letter. Mol Cancer Ther 2014 Nov;13(11): 2763. 
7. Linch M, Gennatas S, Kazikin S, et al. Mesothelin is a prognostic indicator for patients with malignant mesothelioma in routine clinical practice. BMC Cancer. 2014 Sep 17;14(1):674.
8. Rossé C, Lodillinsky C, Fuhrmann L ... Linch M, et al. Control of MT1-MMP transport by atypical PKC during breast-cancer progression. Proc Natl Acad Sci U S A. 2014 May 6; 111(18): E1872-1879.
9. Linch M, Miah A, Thway K, Judson IR, Benson C. Systemic treatment of soft tissue sarcoma: current gold standard and novel therapies. Nat Rev Clin Oncol. 2014 Apr;11(4):187-202. 
10. Gough N, Miah A, Linch M. Oncological management of cancer pain. Curr Opin Support Palliat Care. 2014 Jun;8(2): 102-111.
11. Linch M, Riou P, Claus J, et al. Functional implications of assigned, assumed and assembled PKC structures. Biochem Soc Trans. 2014 Feb; 42(1):35-41.
12. Linch M, Sanz-Garcia M, Rosse C, Riou P, et al. Regulation of polarized morphogenesis by protein kinase C iota in oncogenic epithelial spheroids. Carcinogenesis. 2014 Feb;35(2):396-406. 
13. Linch M, Sanz-Garcia M, Soriano E, Zhang Y, et al. A cancer-associated mutation in atypical protein kinase C iota occurs in a substrate-specific recruitment motif. Sci Signal. 2013 Sep;6(293):ra82.