Cancer dynamics

A PhD project for the 2022 doctoral clinical fellows programme with Samra Turajlic (primary supervisor, Crick) and James Larkin (The Institute of Cancer Research/Royal Marsden).

Project description

James Larkin

Reader, Institute of Cancer Research & Consultant Medical Oncologist, The Royal Marsden

We are looking for a doctoral clinical fellow to join the Cancer Dynamics laboratory - a multi-disciplinary team of cancer biologists and translational research clinicians concerned with both basic evolutionary principles and application of evolutionary rules in the clinic, as well as emergent clinical questions such as the bases of anti-tumour immunity and immunotherapy benefit. We collaborate nationally and internationally and there will be ample opportunities for training at the Crick and beyond. 

We have two potential projects that may be of interest to clinical fellows:

Project 1: Resolving the evolutionary dynamics of renal cancer metastases and therapy resistance 

Evolutionary principles are increasingly applied to help us understand cancer initiation and progression as evidence by our work to date (1) (2) (3, 4).

In the context of renal cancer, we observe that the mode of evolution can determine the growth of the primary tumour and the patterns of metastatic progression. Renal cancer in particular exhibits a wide range of metastatic phenotypes- from very latent metastases with predilection for endocrine tissues; oligometastases where metastases are confined to a single organ; and widespread/rapid metastases. To build on this we will decipher the evolutionary dynamics of renal cancer metastases, characterizing the sources of selection that lead to emergence of metastasis-competent clones at the site of the primary tumour;  understand the patterns and timing of metastatic spread; identify novel/common vulnerabilities within the metastatic process, that may inform new strategies for therapeutic targeting; and understand the mechanisms of resistance to targeted and immune-oncology agents. This is very pertinent in the context of renal cancer because the therapies used to treat the disease target the tumour microenvironment (angiogenesis or immune cells). 

Through established research studies: TRACERx Renal and a post-mortem (PEACE) Study, there is a unique opportunity to sample a whole range of metastatic sites. The TRACERx Renal study has complete recruitment and we have already performed 20 renal cancer post-mortem with both studies contributing 100s of samples that undergo whole exome, genome and RNA sequencing, generating the largest dataset of this type worldwide. This is an opportunity to work with this dataset to provide unprecedented insights into patterns of renal cancer spread and the variation in evolutionary patterns between cases. There is also an opportunity to contribute to mathematical modelling to predict cancer evolution (5).

On this project we will also collaborate with Kevin Litchfield, PI in immune-genomics at the UCL Cancer Institute.

Understanding evolutionary dynamics in renal cancer also has the potential to inform design of future clinical trials with regards to the timing of therapy. The current paradigm rests upon an assumption of linear progression and will be challenged in this project.
This project would suit a candidate with a background in mathematics, physics, statistics, bioinformatics, evolutionary biology who has an interest in cancer evolution, cancer biology and translational research. Prior experience of computational methods especially in cancer genomics and cancer evolution is useful, but ample opportunities for training will be provided to those without such experience. Candidates from any clinical background and at any stage of clinical training are encouraged to apply.

Project 2: Understanding immunE-related toXicities to uncover mechanisms of autoimmunity and inflammation induced by immune checkpoint blockade 

Immune-related adverse events (IrAEs) are a significant cause of discontinuation of checkpoint inhibitor (CPI) therapy and patient morbidity. IrAEs are common, largely unpredictable in timing and organ systems affected, and range from manageable endocrinopathies to potentially fatal pneumonitis, colitis, neurological and cardiac toxicities. Their impact is increasingly relevant as CPIs are tested and approved for an expanding number of indications (5), including the adjuvant setting. The management of irAEs remains crude involving high-dose steroids, which cause profound morbidity and could impact anti-cancer immunity. There is very limited understanding of the biology underlying irAEs and potentially multiple mechanisms implicated including host factors such as pre-existing sub-clinical autoimmunity, germline polymorphisms and the immune landscape of the tumour itself. At the same time, they present an ideal model of induction and understanding of autoimmune disease, given the opportunity to obtain samples before autoimmunity/autoinflammation set in. Over the last decade our group has extensively clinically phenotyped irAEs (6) and established treatment algorithms (7,8), and more recently begun to define the mechanisms of irAEs (9). We have already established the bases of liver inflammation driven by CPI. We have established a study EXACT – understanding immunE-related toXicities by multifACeT profiling. We will study a cohort of 200 patients with cancer treated with combination anti-PD-1/anti-CTLA4 therapy, collecting peripheral blood throughout and affected tissue samples, especially skin and gut. We will use flow cytometry and cytoff as well as multiplex immunohistochemistry to characterise the immune and signalling changes associated with these phenomena and incorporate information on the microbiome, and germline   variation, especially in known loci associated with autoimmune disease. Ultimately, the aim is to develop a multiparametric biomarker to predict irAEs and provide mechanistic insights and thereby therapeutic targets for prevention and/or management of irAEs. The candidate will have the opportunity to train in flow cytometry, mass cytometry, cutting-edge imaging techniques, and cancer biology and immunology.

On this project we will also collaborate with Anne O’Garra, PI in Immunoregulation at the Francis Crick Institute and Andrew Furness, PI in Adoptive therapy at the Royal Marsden/The Institute of Cancer Research.

This project would suit a candidate with a background in immunology, immunotherapy and translational research, but candidates without prior experience and from any clinical background and at any stage of clinical training are encouraged to apply. 

The partner institution for these potential projects is The Institute of Cancer Research.

References

 

Project 1

  1. Turajlic S, Larkin J, Swanton C. SnapShot: Renal Cell Carcinoma. Cell. 2015;163(6):1556- e1.
  2. Turajlic S, Xu H, Litchfield K, Rowan A, Chambers T, Lopez JI, et al. Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal. Cell. 2018;173(3):581-94 e12.
  3. Turajlic S, Xu H, Litchfield K, Rowan A, Horswell S, Chambers T, et al. Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal. Cell. 2018;173(3):595-610 e11.
  4. Zhao et al, Selection of metastasis-competent subclone in the tumour interior, Nature Evolution and Ecology 2021 PMID: 34002049

Project 2

  1. Larkin J, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma, NEJM 2019 Oct 17;381(16):1535-1546.
  2. Lyon et al. Immune checkpoint inhibitors and cardiovascular toxicity,
  3. Spain et al. How we treat neurological toxicity from immune checkpoint inhibitors.ESMO Open. 2019
  4. Rzeniewicz  et al. Immunotherapy use outside clinical trial populations: never say never? Ann Oncol. 2021 Jul;32(7):866-880.
  5. Gudd et al. Activation and transcriptional profile of monocytes and CD8 + T cells are altered in checkpoint inhibitor-related hepatitis J Hepatol 2021 Jul;75(1):177-189.