Winners 2015

John Thomson, MRC Human Genetics Unit, Edinburgh

Analysis of DNA modification profiles in matched primary and metastatic human kidney tumours

"Metastasis to distant organs often occurs in malignant tumours. Cellular origin and invasion routes of metastatic growths determine not only the sites of tumour spread but also the severity of metastasis. The function of tissues and organs is defined by gene expression profiles that are, in part, orchestrated by epigenetic changes: chemical modification of the DNA and associated DNA binding proteins. I study how the epigenetic patterns relate to the cellular environment. We have previously shown that the genome wide pattern of a specific DNA modification, 5-hydroxymethlycytosine (5hmC), is highly tissue specific.
Furthermore, 5hmC patterns are precisely perturbed in several cancer types as well as following exposure to cancer causing agents. Thus, 5hmC patterns reflect cellular identities as well as molecular perturbation and reflect changes that occur during cancer progression. We will study the genome wide 5hmC patterns in a series of normal tissues as well as primary tumours and matched metastatic tumours using cutting edge DNA sequencing technology. From this study we aim to achieve a better understanding of the molecular events which lead to metastasis, and to test if the 5hmC profiles can identify the tissue of origin in these metastases."

Report 2017:
The unique identity of a particular cell type is in part regulated by a heritable chemical modification ("epigenetic") of DNA and associated proteins; these components are related to the regulation of gene expression. Miss-regulation of epigenetic states is a common observation in disease and cancer progression. As epigenetic marks are potentially reversible, the restoration of “normal” patterns may hold therapeutic potential as indicators of cell state. Study of the genome-wide patterns of epigenetic modifications which are placed directly on the DNA itself - such as the methylated (5mC) and hydroxymethylated (5hmC) cytosine bases – holds immense potential towards both understanding disease progression as well as acting as novel clinical tools to help diagnose precise cancer subtypes

Importantly, metastases are associated with ~90% of human cancer deaths whilst a number of patients present without an identified primary tumour, hindering optimal clinical intervention. As such there is an urgent need to understand the events associated with metastasis as well as develop new and early diagnostic screens. Through my work I have shown that the global patterns of 5hmC reflect the identity of the cell type and that these patterns change during development, ageing, in response to chemical toxins and in cancer formation. Through an award from the Beug foundation for metastasis research I have been able to investigate the 5hmC profiles in a number of human tissues including healthy kidney, primary kidney tumours and matched distal metastatic tumours. Through this work I find:
i. High levels of 5hmC pattern reproducibility between two distinct human samples
ii. Clearly reduced levels and patterns of 5hmC in the primary tumour compared to healthy kidney, with a further reduction in the metastatic tumour samples
iii. A number of loci displaying strong changes in genic 5hmC levels between healthy, primary and metastatic samples – many of which can be mechanistically linked to disease progression (i.e. sequential loss of 5hmC healthy > primary tumour > secondary tumour at the E-cadherin locus, the transcriptional downregulation of which has been associated with loss of cellular adhesion, increase in motility and thus increase metastatic potential)

Together this work highlights the utility of 5hmC profiling as a viable method to develop towards clinical assays (low intra-individual variance in healthy tissues, strong changes in disease states) and due to the fact that the secondary tumour retains some of the epigenetic changes also present in the primary tumour provides evidence that such an assay may be useful in cases of unknown primary tumour.

In addition to the scientific benefits of the funding the award has allowed me to be more competitive in securing a number of small research grants and strongly assists in my ongoing applications towards securing independent funding fellowships. I am extremely grateful to the Beug Foundation for their support in the project.

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Karin E. de Visser, Division of Immunology, The Netherlands Cancer Institute

Fighting metastatic breast cancer with cancer immunotherapy

"Breast cancer is the most common malignancy among women worldwide. Despite significant progress in treatment options for primary breast cancer, metastasis formation relentlessly drives mortality. The occurrence of distant metastases accounts for over 90% of breast cancer deaths and is currently the most common cause of death for women aged between 35 and 50 years. Clearly, there is an urgent need for novel therapies with efficacious anti-metastatic activity. Recently, clinical breakthroughs have been achieved in advanced cancer patients with cancer immunotherapy that activates the patients’ own immune system to attack cancer cells. It is unclear whether patients with metastatic breast cancer may also benefit from cancer immunotherapy.
The Beug Foundation Metastasis Prize will allow us to perform preclinical studies to assess whether immunotherapy can prevent and/or treat established metastatic breast cancer. Using our novel breast cancer metastasis model that faithfully recapitulates breast cancer metastasis in humans, we will study which therapy combination leads to successful activation of the immune system to fight metastatic disease, and which potential negative regulators of the efficacy of immunotherapy exist in metastatic disease. Knowledge obtained from these pioneering studies supported by this Metastasis Prize will set the stage for new studies aimed at maximizing success of immunotherapy for metastatic disease and ultimately facilitate implementation of immunotherapy in breast cancer patients."

Report 2017:
The recent breakthrough of immunotherapy has opened new treatment avenues for cancer patients, however, the objective response rates presented so far for breast cancer patients treated with immune checkpoint inhibitors range from 5–20%. Thus, although effective in some breast cancer patients, the majority does not respond to single-agent immunotherapy. The current challenge is to understand how the efficacy of cancer immunotherapy can be enhanced. Thanks to the Beug Foundation Metastasis Research Price, my laboratory was able to study the efficacy of different therapy combinations, including immunotherapy, against metastatic breast cancer, using a pre-clinical mouse tumor model that recapitulates human metastatic breast cancer. We discovered that immune checkpoint inhibitors induce effective –although modest- anti-tumor immunity against metastatic breast cancer when combined with cisplatin, which translated in a longer survival of the mice. Intriguingly, this therapeutic effect was drug dependent, since docetaxel did not synergize with dual immune checkpoint blockade. We observed that more activated CD8+ T cells were infiltrating the mouse breast tumors treated with cisplatin and immunotherapy compared to cisplatin or immunotherapy alone, or to docetaxel and immunotherapy. These findings illustrate the importance of matching immunotherapy with a carefully selected combination partner. In addition, these data are hopeful, since they show us that –despite the low immunogenicity of breast cancer- it is possible to activate effective anti-tumor immune responses. At the same time, these breast tumors eventually escaped the control by the immune system, thus we were not able to sure metastatic breast cancer. We observed that breast tumors activate neutrophils, which suppress the ability of T cells to inhibit metastatic disease. We are currently performing intervention studies in which we combine immunotherapy with cisplatin and neutrophil inhibitors, with the aim to assess whether this results in durable anti-tumor immune responses. In parallel, we have initiated a collaboration with the clinic, through which we are now involved in immunomonitoring of blood of metastatic breast cancer patients that are being treated with immunotherapy, to study whether similar immunosuppressive neutrophil responses are activated in these patients.
Using these preliminary data obtained through the Beug Foundation Metastasis Research Prize, we have recently obtained a large research grant (4-years funding) from the Dutch Cancer Society, to obtain deeper insights into the different sensitivities of metastases localized in different distant organs for cancer immunotherapy, and to understand which chemotherapeutic drugs are the best combination partners for immunotherapy in metastatic breast cancer. In parallel, together with medical oncologist Marleen Kok at the Netherlands Cancer Institute, we have received a Unique High Risk grant (2 years funding) to validate our pre-clinical findings in metastasized breast cancer patients. Needless to say that I am very grateful to the Beug FouFoundation. Without the Metastasis Research Price, we would not have initiated this important and clinically relevant research line in the lab.