A mathematical theory of the transcription repression (TR) therapy of cancer - whether and how it may work

Abstract

Transcription repression (TR) therapy of cancer has been widely discussed. Here, TR refers to global repression of transcription rather than specific targeting of cancer-causing genes such as MYC. TR drugs inhibit transcription by binding to the transcribed DNA or to RNA polymerase; for example, actinomycin D has been extensively used in research and therapy to shut down transcription globally [1–7]. As proliferating cells demand a high rate of transcription, restricting transcript production could be effective in slowing down cell proliferation. However, TR also deprives other less proliferative cells of new transcripts, thus leading to substantial toxicity [1, 8, 9]. We now develop a mathematical theory to exploit the greater demand for transcription in highly proliferating cells. A new strategy, referred to as the TRR (transcript repression-recovery) model, would insert a recovery phase to allow the more slowly proliferating cells to recover. It is most effective to have strong blocking for a short period (a few hours) followed by a longer recovery phase in each cell cycle. Hence, TRR can potentially achieve selective killing of cells based on their global transcription needs but precise fine-tuning is necessary.

On the low reproducibility of cancer studies

“…The efficacy of rituximab may be due to the fact that it does not target a product of cellular evolution. Recent strategies that have targeted the basal transcription machinery [53,54] are compatible with this view favoring non-moving targets.…”

Heightened protein-translation activities in mammalian cells and the disease/treatment implications

“…In this Perspective, we will focus on the second approach, repressing protein translation by targeting the tRNA–ribosome interaction. (Although the first approach is likely to be more effective against cancers [ 19 ], the details are beyond the scope of a short Perspective such as this.) For viral infections, this second approach may be effective thanks to a key molecule, Homoharringtonine (HHT), a cytotoxic plant alkaloid extracted from Cephalotaxus species [ 20 ].…”

Evaluation of the Small-molecule BRD4 Degrader CFT-2718 in Small-cell Lung Cancer and Pancreatic Cancer Models

“…However, BRD4 is critical for global elongation, raising the question as to whether prolonged BRD4 degradation would be tolerated by normal tissues. Data from mathematical modeling to establish the optimal timepoint for drug inhibition of transcription suggests a brief exposure at maximum serum concentration (Cmax) to kill proliferating cells while allowing a recovery time to resting cells (22). Thus, in screening for novel BRD4 degraders, we focused on compounds that were highly potent and displayed pharmacokinetic (PK) properties consistent with high systemic exposure, ability to distribute to peripheral tissues, fast elimination, and a wide therapeutic index.…”