For a cell to become cancerous, it needs to acquire a series of mutations in the genes encoded within its DNA. These mutations are specific to the cancer cell, and so are not found in the surrounding healthy cells. Certain mutations will trigger the transformation of a healthy cell into a cancer cell, which will begin to divide and grow. The mutations occurring before this transformation event will be carried by all of the cells of the growing cancer. We refer to these as ‘truncal’ mutations, akin to the trunk of a growing tree. As the cancer grows, its cells will accumulate further mutations, which may enhance the ability of the cancer cells to proliferate or disseminate. These later mutations are referred to as ‘branch’ mutations, as they are like the branches of a growing tree, and they will not be carried by all the cells that make up the whole cancer cell population in an individual.
Many of the mutations in the DNA of the cancer cell will lead to changes in the proteins encoded by the mutated genes, which can then be recognised by the immune system as ‘foreign’. As a consequence, these cancer-specific ‘neo-antigens’ can be targeted by immunotherapies, which will attack the tumour but not the healthy cells. However, if the therapy targets only the branch mutations, this will not result in the elimination of the whole cancer population, akin to pruning of specific branches, but not felling the entire tree. In order to attack the entire cancer, Achilles Therapeutics’ therapy will target the truncal mutations. This is the ‘clonal architecture’ of the cancer.
By understanding the clonal architecture of individual tumours, Achilles Therapeutics will exploit the unique aspect of each tumour, targeting multiple truncal mutations present in every tumour cell. This approach will reduce the risk that new mutations can induce therapeutic resistance, as occurs with many conventional therapies.