Ultimate Precision: Targeting Cancer but Not Normal Self-replication

American Society of Clinical Oncology Educational Book
Vamsidhar VelchetiYogen Saunthararajah

Abstract

Self-replication is the engine that drives all biologic evolution, including neoplastic evolution. A key oncotherapy challenge is to target this, the heart of malignancy, while sparing the normal self-replication mandatory for health and life. Self-replication can be demystified: it is activation of replication, the most ancient of cell programs, uncoupled from activation of lineage-differentiation, metazoan programs more recent in origin. The uncoupling can be physiologic, as in normal tissue stem cells, or pathologic, as in cancer. Neoplastic evolution selects to disengage replication from forward-differentiation where intrinsic replication rates are the highest, in committed progenitors that have division times measured in hours versus weeks for tissue stem cells, via partial loss of function in master transcription factors that activate terminal-differentiation programs (e.g., GATA4) or in the coactivators they use for this purpose (e.g., ARID1A). These loss-of-function mutations bias master transcription factor circuits, which normally regulate corepressor versus coactivator recruitment, toward corepressors (e.g., DNMT1) that repress rather than activate terminal-differentiation genes. Pharmacologic inhibition of the corep...Continue Reading

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Citations

Nov 19, 2019·British Journal of Haematology·Hassan AwadaYogen Saunthararajah
Apr 3, 2019·Cancer Discovery·Vamsidhar VelchetiYogen Saunthararajah
Jan 30, 2021·Seminars in Hematology·Babal K Jha, Yogen Saunthararajah
Mar 26, 2021·Blood·Yogen Saunthararajah
Sep 24, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Phaedon D ZavrasYogen Saunthararajah

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