Molecular Oncology - Richard Marais

Richard obtained his BSc in Genetics and Microbiology from the University College London in 1985, after which he undertook his PhD on Protein Kinase C Isotypes at the Ludwig Institute for Cancer Research in London, which he completed in 1989. He then worked as a Postdoctoral Research Fellow at the Imperial Cancer Research Fund, London, until 1993. Richard then moved to The Institute of Cancer Research (ICR) in London as an Independent Postdoctoral Research Fellow. It was at the ICR where Richard spent the next 19 years of his career focusing on cell signalling in melanoma, developing a particular interest in the role of oncogenic BRAF. During his time at the ICR, Richard progressed to Team Leader of the Signal Transduction Team in 1998, then to Professor of Molecular Oncology in 2007, to Deputy Chair, Section of Cell and Molecular Biology, in 2008, and finally to the Division Head, Division of Cancer Biology, in 2011.

Throughout his career, Richard has received numerous accolades for his contributions to cancer research. In 2007, he was elected Fellow of the Academy of Medical Sciences. In 2009, he was elected Fellow of the European Academy of Cancer Sciences and became an EMBO member. In 2011, he received the Society for Melanoma Research Estella Medrano Memorial Award for outstanding contributions to melanoma research. Richard became Director of the CRUK Manchester Institute in February 2012 where he also continues to head his Molecular Oncology Group. Richard was elected to the Academia Europaea in 2015. In 2016, he received a University of Manchester Researcher of the Year award, as well as The Colin Thomson Memorial Medal from Worldwide Cancer Research and the Fritz Anders medal from the European Society for Pigment Cell Research. In 2017, Richard was awarded the prestigious ARC Foundation Léopold Griffuel Award in Translational and Clinical Research, and the Society for Melanoma Research Outstanding Research Award for major discoveries in melanoma in the last five years. In 2018, he was elected Fellow of the Royal Society.

Introduction

Over the last decade, we have made great strides into understanding the biology of melanoma. The BRAF gene is mutated in about half of melanoma cases, and the NRAS gene is mutated in about 20% of cases. These proteins are part of a conserved signalling pathway that regulates cell proliferation and survival, and the mutant proteins drive uncontrolled cell growth and tumour progression.

Our laboratory focuses on melanoma biology, as well as the biology of other cancers, and we use a combination of approaches, including biochemistry, cell and molecular biology, structural biology, transgenic models and next generation signalling.

Section of healthy skin highlighting the different cell types that develop into melanoma (pink) or squamous cell carcinoma (green and red). Candelaria Bracalente, Molecular Oncology.


We are developing new anti-cancer drugs, and are developing precision medicine protocols to tailor treatments to individual patients. In collaboration with Professor Caroline Springer, now Director of our Drug Discovery Unit, we currently have clinical trials with panRAF drugs that overcome resistance in melanoma to BRAF drugs at The Royal Marsden Hospital and The Christie NHS Foundation Trust. Working with Professor Caroline Dive, our lab has brought whole exome sequencing of patient melanoma samples, and sequencing of naked DNA in plasma, to the clinic to facilitate a new approach to monitoring of disease and response to therapy.

Our aim is to develop multi-disciplinary teams of scientists and clinicians to develop new diagnostic tools and new treatments for cancer patients. 

Overview

 

Our multidisciplinary group studies cancer biology, from the basic causes of cancer to how patients respond to treatment. Over the past year, we described how patient blood can be used to monitor which patients will respond to immunotherapy, studies that have improved our understanding of the human immune system and provided new methods to identify which patients are likely to respond to therapy and which patients are unlikely to respond. We also identified new prognostic markers and new therapeutic targets in prostate cancer. Together, these studies provide new possible ways of monitoring cancer so that their treatment can be tailored for individual patients.

 

Immunotherapy

 

Immunotherapy has been transforming the melanoma treatment paradigm over the past decade, affording sustained survival benefit in some patients. However, we do not yet fully understand the mechanisms that determine response to immunotherapy and most patients with malignant melanoma still die of their disease. Our group has previously shown that in patients who respond to immunotherapy a small subset of circulating T cells that we have called immune effector T cells (TIE) expand within 3 weeks of starting treatment. In the same study, we showed that changes in clonality (expansion of one or a small number of predominant T cell clones) or diversity (expansion of many T cell clones) of circulating T cells in response to immunotherapy also provided an indication of whether a patient would go on to respond to immunotherapy.

 

Response of immune system to cancer and immunotherapy

 

In the past year, we continued to study the immune system’s response to cancer and immunotherapy. In one study, we sought to understand whether the extent of the TIE expansion we previously described in patients that responded to immunotherapy correlated in some way with observed tumour shrinkage. Comparing tumour measurements at the start of therapy and 12 weeks after therapy, we confirmed an inverse relationship between tumour size and TIE cell expansion, further validating TIE cell expansion as a biomarker for immunotherapy response. We examined if the expansion of TIE cells and the changes in T cell clonality and diversity were influenced by clinical variables such as sex, disease stage, BRAF mutation status, LDH levels or age. We found that whilst TIE cell expansion was not influenced by the first four clinical parameters, changes in the clonality and diversity of T cells in response to immunotherapy were influenced by age. Specifically, we observed that in patients younger than 70 years of age, T cells exhibited a trend towards increased diversity in response to immunotherapy, whereas in patients of 70 years and over, we observed a trend towards increased clonality. The increased diversity in younger patients but increased clonality in older patients is consistent with the reduction in thymus function as we age (thymus involution) and is important because it suggests that biological variation driven by age should be taken into account when developing immunotherapy approaches, new treatments or diagnostic tools.

Figure 1: Tumour infiltrating lymphocyte T cell (TIL/Tc) clonality is predictive of anti-PD1 response in melanoma Survival curves for a cohort of patients with metastatic melanoma treated with anti-PD1 immunotherapy drugs in Manchester or Italy, grouped according to the clonality of the tumour infiltrating T cells in their pre-treatment melanoma biopsy. Patients with high TIL/Tc clonality (purple) had a significantly longer survival (median not reached) compared to patients with low (blue, median survival=4.8 months) TIL/Tc clonality (n=16, cut-off calculated with optimalCutoff algorithm=0.06, log-rank P=0.0003). Image adapted from Valpione et al, The T cell receptor repertoire of tumour infiltrating T cells is predictive and prognostic of cancer survival, Nat Commun, 2021 Jul 2;12(1):4098.

 

Tumour T cells

 

In a separate study, we focused on the different types of T cells that reside within tumours, examining their clonality and diversity. We discovered that the diversity of T cell receptors in the tumour resident T cells is prognostic for survival not only in melanoma, but also in breast cancer, certain lung cancers, renal and testicular cancers, and thymoma, irrespective of whether patients received immunotherapy or not. This provides interesting new insight into the interactions between the immune system and tumour cells. Additionally, we discovered that the clonality of tumour resident T cells is predictive for response and survival after anti-PD1 based immunotherapy (Figure 1), providing a potential biomarker that can identify patients that are most likely to respond to these immunotherapies. There is a great need to identify markers of response to these therapies so they can be administered to the patients that will derive benefit from them, whilst sparing other patients the potential side effects of these therapies and affording them more time to explore other treatment options.

 

Basic biology of cancer

 

Alongside these translational studies focused on identifying markers of response to therapy, we also continue our studies of the basic biology of cancer, seeking out vulnerabilities that may be exploited therapeutically. One such study of prostate cancer (PCa), the fifth leading cause of cancer deaths worldwide, revealed a 7-microRNA (miR) signature that identifies PCa primary tumours that are more prone to metastasise, providing a mechanism to help clinicians to stratify patients more accurately for follow up and therapy (Figure 2a, b). MiRs are small RNA molecules that regulate many biological processes, and analysis of our signature has provided clues to novel therapeutic options because we discovered that one of the miRs in our signature, miR-378a, impairs the metabolism of glucose by PCa cells. This is because miR-378a blocks the expression of a protein called GLUT1 (glucose transporter 1) in PCa cells, reducing their ability to use glucose to support their proliferation (division) (Figure 2c, d). These studies reveal that metabolism could be an exciting therapeutic target in aggressive prostate cancer.

Figure 2. Identification of a 7-miR prognostic signature and metabolism therapeutic target in prostate cancer. (a) Unsupervised hierarchical clustering TCGA N0 PCa patients presenting Gleason 7 score using expression (log2 RPM) of 7-miR identified from miR RNAseq data. Columns: individual patients, rows: individual miRs. Centering and unit variance scaling are applied to rows, and rows and columns are clustered using correlation distance and average linkage. The dendrogram shows Gleason score for each patient (G7: green). (b) Kaplan–Meier plot of disease-free survival in Group 5 and Group 6 patients (from a). The number of patients (n) in each group is indicated. **p = 0.0053; HR 95% CI = 3.9 (1.5–10.3); Mantel–Cox test. Median survival Group 5: not reached; median survival Group 6: not reached. (c) Western blot for GLUT1 and ACTB as loading control in PC3 and LNCaP PCa cells after transfection with two concentrations (10 nM and 30 nM) of the miR-378a-mimic or a non-targeting control (Ctrl). (d) Quantification of the glyco-stress test parameters in PC3 cells. Cannistraci et al. (2022) MiR-378a inhibits glucose metabolism by suppressing GLUT1 in prostate cancer. Oncogene, 41(10), 1445–1455.

 

Early detection

 

In addition to understanding and developing therapeutic options for advanced cancer, we continue to seek ways in which cancer can be prevented or detected at earlier stages. Especially in the context of rare cancer types, such as melanoma of the eye, identifying their underlying drivers can be a key factor in preventing their development. Our studies of conjunctival melanoma, set in the context of a series of recent studies focused on the genetic changes that drive ocular melanomas, suggest that whilst different genetic events drive melanoma at specific sites (the skin, the eye, mucosal membranes), ultraviolet radiation (UVR) imposes additional events over these specific processes to accelerate melanoma development. It is generally accepted that this is particularly important for the skin, but our data show it is very important to remember that is can also happen in the eyes (particularly the conjunctiva and iris) and mucosal membranes that are sun-exposed, such as the lips. Our findings emphasise the importance of promoting UVR protection with sunblock for the skin, UVR protective lip balm for the lips and sunglasses for the eyes. The data also suggest that therapies currently approved for skin melanoma should also be considered for melanomas at other sites, guided by their underlying genetics.

Selected Publications

 

Valpione S, Galvani E, Tweedy J, Mundra PA, Banyard A, Middlehurst P, Barry J, Mills S, Salih Z, Weightman J, Gupta A, Gremel G, Baenke F, Dhomen N, Lorigan PC, Marais R. (2020)
Immune-awakening revealed by peripheral T cell dynamics after once cycle of immunotherapy. 
Nature Cancer 1: 210-221. PubMed abstract

Galvani E, Mundra PA, Valpione S, Garcia-Martinez P, Smith M, Greenall J, Thakur R, Helmink B, Andrews MC, Boon L, Chester C, Gremel G, Hogan K, Mandal A, Zeng K, Banyard A, Ashton G, Cook M, Lorigan P, Wargo JA, Dhomen N, Marais R. (2020)
Stroma remodeling and reduced cell division define durable response to PD-1 blockade in melanoma.
Nature Communications 11: 853. PubMed abstract

Trucco LD, Mundra PA, Hogan K, Garcia-Martinez P, Viros A, Mandal AK, Macagno N, Gaudy-Marqueste C, Allan D, Baenke F, Cook M, McManus C, Sanchez-Laorden B, Dhomen N, Marais R. (2019)
Ultraviolet radiation-induced DNA damage is prognostic for outcome in melanoma.
Nature Medicine 25(2):221-224. PubMed abstract

Lee RJ, Gremel G, Marshall A, Myers KA, Fisher N, Dunn J, Dhomen N, Corrie PG, Middleton MR, Lorigan P, Marais R. (2018)
Circulating tumor DNA predicts survival in patients with resected high risk stage II/III melanoma.
Annals of Oncology 29(2):490-496. PubMed abstract

Tang H, Leung L, Saturno G, Viros A, Smith D, Di Leva G, Morrison E, Niculescu-Duvaz D, Lopes F, Johnson L, Dhomen N, Springer C, Marais R. (2017)
Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface.
Nature Communications 8:14909. PubMed abstract

Gremel G, Lee RJ, Girotti MR, Mandal AK, Valpione S, Garner G, Ayub M, Wood S, Rothwell DG, Fusi A, Wallace A, Brady G, Dive C, Dhomen N, Lorigan P, Marais R. (2016)
Distinct subclonal tumour responses to therapy revealed by circulating cell-free DNA.
Annals of Oncology 27(10):1959-65. PubMed abstract

Viros A, Sanchez-Laorden B, Pedersen M, Furney SJ, Rae J, Hogan K, Ejiama S, Girotti MR, Cook M, Dhomen N and Marais R. (2014)
Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53. 
Nature 511(7510):478-82. PubMed abstract

Furney SJ, Pedersen M, Gentien D, Dumont AG, Rapinat A, Desjardins L, Turajlic S, Piperno Neumann S, de la Grange P, Roman-Roman S, Stern M.-H., and Marais R. (2013)
SF3B1 mutations are associated with alternative splicing in uveal melanoma.
Cancer Discovery 3(10):1122-9. PubMed abstract

Su F, Viros A, Milagre C, Trunzer K, Bollag C, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, Chapman PB, Jung Kim M, Hayward F, Martin M, Yang H, Wang Q, Hilton H, Hang JS, Noe J, Lambros M, Geyer F, Dhomen N, Niculescu-Duvaz I, Zambon A, Niculescu-Duvaz D, Preece N, Robert L, Otte NJ, Mok S, Kee D, Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, Kockx M, Andries L, Lestini B, Nolop KB, Lee RJ, Joe AK, Troy JL, Gonzalez F, Hutson TE, Puzanov I, Chmielowski B, Springer CJ, McArthur GA, Sosman JA, Lo RS, Ribas A, Marais R. (2012)
RAS mutations in cutaneous squamous cell carcinomas with BRAF inhibitors.
The New England Journal of Medicine 366: 207-215. PubMed abstract

Associate Scientists
Nathalie Dhomen
Valeria Pavet

Postdoctoral Fellows
Daphné Brisard
Pauline Hascoët
Sjors Kas
Patricia Pacios-Centeno

Clinical Scientist
Sara Valpione

Clinical Fellow
Pablo Garcia Martinez

Graduate Student
Luke Chisholm

Scientific Officers
Christopher Chester
Darryl Coles
Megan Grant
Jessica Walker


 

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