The path to prevention is paved with biological insight

Professor Walid Khaled and Dr Sara Pensa, Epithelial cell fate and tumour development laboratory, University of Cambridge

Despite major advances in the development of immune and targeted-therapies, the molecular and cellular complexity of late-stage tumours remain a major barrier to developing a ‘silver bullet’ cancer cure.

This makes a strong case for focusing on identifying those at risk of developing cancer and intervening prophylactically to prevent tumour development.

One of the major hurdles for the early detection of premalignant disease is our poor understanding of tumour initiating events. Historically, cancer research has focused on the identification of putative cancer driver genetic alterations and mutations. However, more recent studies find cancer driver mutations in healthy tissues suggesting that mutational events are not the sole drivers of tumour initiation.

These findings highlight how little we understand the impact of such genetic alterations on the cellular dynamics of the tissue, including changes in the immune and stromal microenvironment during the early stages of transformation. By identifying the early cellular and molecular changes that occur in the tissue, we could develop effective early detection and intervention strategies.

There are several challenges to applying a biological approach to prevention, and I hope the new Biology-Prevention Award from CRUK will allow researchers to address over the coming years. Here’s how our lab see some of those challenges:

• As a society, generally, we are happy to take Statins to prevent and minimise the chances of heart disease based on a blood test showing high cholesterol. However, this is not accepted for cancer yet. This is probably because of the lack of non-invasive early detection methods.
• We need to go beyond genetic screening and leverage our understanding of early tumour biology to improve our identification of those at imminent risk. This is a technical and clinical challenge – but I think we can meet it with investment and new modes of operating in the clinic. Importantly, these assays need to have very low false discovery rates otherwise we increase patients’ anxiety unnecessarily.
• Once you identify individuals that are at imminent risk of developing cancer how do you treat them? Traditionally, cancer drugs are designed to be toxic and as such have multiple side effects. However, if targeted prevention is to become a reality, we need to change our target profile for drug development as well as our treatment regimen. This could mean using smaller doses of existing drugs or developing new ones. In either case, most treatments will need to be guided by a biomarker.
• Perhaps the biggest challenge, and certainly one that requires innovation, is running a clinical trial that assesses the benefit of preventative treatments.

Cancer is, of course, a global disease. As such, no approach will be effective in tackling it if we don’t address the inequalities preventing interventions to be effective worldwide. A focus on prevention will be one of the most cost-effective approaches to balance inequalities and improve disease outcome. Detailed biological understanding of premalignancy and tumour initiating events can lead to prophylactic approaches to cancer and improve early detection not only in high-income countries but also those with fewer resources.

Our science

In our laboratory, we focus on studying breast tumour initiation with the aim of developing novel early detection methods and therapeutic interventions.

We have used single cell RNA sequencing (scRNAseq) to map the precancerous cellular changes that occur in BRCA1 mouse and human samples. This allowed us to identify 6 putative targets for preventative therapies. In this proposal we will test the efficacy of these FDA approved, or near approved compounds, in preventing tumour development in the mouse. We will also assess utility of a blood biomarker we have identified to see if it could help guide such preventive treatments.

At the end of the project, we hope to be armed with more information to justify testing some of these compounds in a pilot clinical trial.

Dr Elise Rees is postdoctoral scientist in Professor Kwee Yong’s Multiple Myeloma Laboratory at the UCL Cancer Institute, and co-investigator on a project to investigate the role of NK cells in the development of MM

Our ability to detect, treat and even prevent cancer has made great progress over the last couple of decades but sadly, cancer remains a frequent and debilitating disease.

Whilst our treatment options are vastly improved, unresponsiveness or relapse remains a major issue. This may be in part due to the idea that frank malignancy represents the endpoint of a series of molecular steps and is therefore often difficult, or even impossible, to reverse. Understanding the complex biological systems that underlie its development is essential if we are to identify new ways of treating the disease and even more so if we hope to prevent development in the first place.

It is now well accepted that virtually all malignancies are preceded by clinically silent precursor states, where characteristic cancer molecular lesions emerge. These precursor states provide a unique opportunity to investigate the biological features that influence cancer development. The factors that drive or delay a precursor along the path to malignancy are mechanistically and clinically important, as well as potential targets for early interventions. With an understanding of the key molecular lesions that drive progression – and an understanding of how the surrounding environment is altered – treatment options could be specifically targeted and rationally based.

Our science

Our group is interested in multiple myeloma, a cancer of antibody producing plasma cells that expand in the bone marrow. More common in the elderly, the disease leads to multi-organ failure and, despite considerable therapeutic advances, remains incurable.

Myeloma is preceded by clinically defined precursor conditions called monoclonal gammopathy of uncertain significance (MGUS) and smouldering myeloma (SMM). Progression through these states is generally associated with increasing tumour burden, acquisition of secondary or additional genetic events and, ultimately, increasing risk of progression to symptomatic malignant multiple myeloma.

Importantly, whilst all patients with malignant multiple myeloma are thought to have progressed through precursor states, not all patients with MGUS or SMM will go on to develop multiple myeloma. If we hope to intervene, then it is crucial that we can select those patients that are most likely to progress to prevent the over – and possibly unnecessary – treatment of patients.

We urgently need a deeper understanding of the determinants of progression, to identify those at greatest risk, and design appropriate interception strategies.

Both precursor states share many genomic features with MM, with MGUS and SMM clones already harbouring chromosomal alternations that define MM. Progression is thought to be, in part, influenced by tumour extrinsic factors.

There is accumulating evidence for a role of the immune system in disease progression, but studies thus far have focused on adaptive immune responses and T cell dysfunction. The importance of innate immune responses, however, is underscored by markers of inflammation observed in both animal models and patients. Natural killer (NK) cells are key players in the innate immune response against tumours. NK cell dysfunction has been described in MM; however, no clear picture has emerged of the way in which NK cell function is altered in precursor disease and how this might influence the progression to frank malignancy.

The aim of this project is to investigate the role of NK cells in the development of MM from SMM. This project will utilise MGUS, SMM and MM patient samples our national prospective study in SMM, COSMOS. Studying serial longitudinal samples from cohorts of individuals will allow us to determine if NK cell function is perturbed in SMM patients and how this relates to malignant transformation. Specifically, we aim to investigate the possibility of targeting known high risk SMM patients with a myeloma treatment approved anti-CD38 antibody, Isatuximab, on delaying or preventing disease progression to frank malignancy.

Utilising the expertise of new collaborations both within UCL and at Cambridge University, we hope to comprehensively understand the determinants of progression and response to intervention.

Improved clinical outcome will depend on a thorough understanding of patient tumour and NK cell biology. We hope to elucidate and identify features associated with how well a patient will respond to anti-CD38 antibody therapy in precursor condition and with the ultimate aim of investigating whether early immunological intervention can prevent the development of this malignant, incurable disease.