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Cancer Grand Challenges - The dark proteome

Cancer Grand Challenges

This is a new challenge, which we announced in March 2025. It is open for Expressions of Interest, with the successful team(s) being awarded up to £20m ($25m) to tackle it. Submissions are due by 18 June 2025.

Context

Recent data indicate that cancer cells express proteins that are not derived from known open reading frames as well as proteins with alterations in amino acid sequences without corresponding DNA mutations. The origins of this ‘dark proteome’ remain elusive.

This challenge aims to define the mechanisms underlying the induction of these dark proteome products and understand their relationship with the oncogenic state of the cancer cell. It is also an opportunity to use them as therapeutic targets and understand whether the dark proteome is a source of non-mutated tumour-selective antigens and synthetic lethalities and determine whether these products can be targeted by immunologic or small molecule-based therapies that could be adapted to become ‘off the shelf’ treatments.

The focus of the challenge is on understanding the mechanisms giving rise to non-standard protein products (the dark proteome) and their impact on cancer.

Vision and impact

This challenge will reveal the fundamental molecular mechanisms leading to the expression and regulation of the dark proteome and determine their role in cancer versus normal cells. Based on this understanding, strategies to manipulate the expression of these unconventional protein products could be developed. Defining how this process is perturbed in cancer cells may uncover new opportunities to target tumours with immunologic or small molecule-based therapies, exploiting this selective vulnerability in cancer.

Specialties

Cancer

Oncology

Eligibility Requirements

Current examples of the dark proteome (including many so-called microproteins) may be the tip of the iceberg. More work is needed to understand how these proteins are generated and to elucidate the role that they play in oncogenesis. A key question could be whether these products give rise to non-mutated antigens and whether they are universally expressed between individuals and across tumour types. Dark proteome products may be immunogenic, but it is unclear if they undergo the same immuno-editing as conventional antigens.

Similarly, understanding how the dark proteome functions in tumours could then be applied to the selective disadvantage of the tumour cell or to the advantage of the immune system.

Addressing this challenge may require integrating fields such as but not limited to immunology, cell biology, genetics, RNA and protein biology, mass spectrometry, synthetic and analytical chemistry as well as oncology.

Note: Applications that focus on non-coding RNAs, RNA editing/ mutations and retroelements that do not produce a protein product as well as applications that focus on alterations in RNA splicing will not be considered responsive to this challenge.

Sponsor Details

Sponsor Institute/Organizations: Cancer Grand Challenges

Sponsor Type: Corporate

Address: 2 Redman Place London, E20 1JQ United Kingdom

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