Company: NCNA
Filing Date: 2025-03-20
Form Type: 20-F
Source: 0000950170-25-042709
Chunk: 119

Company: NuCana plc
Filing Date: 2025-03-20
Form: 20-F
Item: Item 4
Chunk 119
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 treatment of colorectal and breast cancer, had worldwide sales of $1.5 billion in 2012, before the market launch of generic competitors. We believe the number of patients receiving capecitabine represents a small proportion of the overall number of patients treated with 5-FU.

Shortcomings of Nucleoside Analogs
 
 Despite the widespread uses of nucleoside analogs, their efficacy and safety are severely limited by major shortcomings, including breakdown, poor pharmacokinetic properties, requirement for uptake by transporters, and inefficient metabolic pathways to generate the active anti-cancer metabolite.
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 Nucleoside analogs block the replication of cancer cells by providing faulty DNA and RNA building blocks during the cell replication process or by blocking enzymes necessary for the production of these DNA and RNA building blocks. These processes lead to disruption of DNA and RNA replication resulting in cancer cell death, known as apoptosis. However, there are several major shortcomings that limit the efficacy of existing nucleoside analogs including:
 •Breakdown and Toxic Byproducts. Multiple enzymatic processes can break down nucleoside analogs, resulting in their degradation prior to phosphorylation. For example, 3’-dA, the parent nucleoside analog of NUC-7738 is rapidly broken down by the enzyme adenosine deaminase, or ADA, preventing the generation of the active anti-cancer metabolite, 3’-dATP. Breakdown can also result in the generation of catabolites that can lead to off-target toxicity. For example, the breakdown of 5-FU is known to result in the generation of a toxic byproduct called FBAL, which has been associated with off-target toxicity including “hand-foot syndrome”, a debilitating side effect that commonly causes dose reductions or discontinuation of therapy. Breakdown can take place either inside or outside the cancer cell.
 •Uptake by transporters. Nucleoside analogs require specific active-transport proteins in the cell membrane to enter cancer cells. If these proteins are missing or down-regulated, nucleoside analogs cannot enter the cancer cell to exert their anti-cancer effect. Transport proteins are often not expressed at sufficient levels in many solid tumor cancers which can result in poorer outcomes for patients treated with nucleoside analogs. 
 •Inefficient metabolic activation pathways. Nucleoside analogs