Episensitization: Defying Time's Arrow

Abstract

The development of cancer is driven by complex genetic and epigenetic changes that result in aberrant and uncontrolled cellular growth. Epigenetic changes, in particular, are implicated in the silencing or activation of key genes that control cellular growth and apoptosis and contribute to transformative potential. The purpose of this review is to define and assess the treatment strategy of "episensitization," or the ability to sensitize cancer cells to subsequent therapy by resetting the epigenetic infrastructure of the tumor. One important facet is resensitization by epigenetic mechanisms, which goes against the norm, i.e., challenges the long-held doctrine in oncology that the reuse of previously tried and failed therapies is a clinically pointless endeavor. Thus, episensitization is a hybrid term, which covers recent clinically relevant observations and refers to the epigenomic mechanism of resensitization. Among the many formidable challenges in the treatment of cancer, the most inevitable is the development of acquired therapeutic resistance. Here, we present the basic principles behind episensitization and highlight the evidence suggesting that epigenetically mediated histone hypoacetylation and DNA hypermethylation events may reverse clinical drug resistance. The potential reversibility of epigenetic changes and the microenvironmental impact of epigenetic control on gene expression may mediate a return to a baseline state of treatment susceptibility. Episensitization is a novel and highly practical management strategy both to prevent the practice of permanent treatment discontinuation with the occurrence of resistance, which rapidly exhausts remaining options in the pharmaceutical armamentarium and to significantly extend patient survival. Accordingly, this review highlights several epigenetic agents including decitabine, vorinostat, entinostat, 5-azacitidine, oncolytic viruses, and RRx-001.

Keywords: RRx-001; epigenetics; epigenomic; episensitization; oncology; resensitization.

Figure 1

A diagram conceptualizing Waddington’s epigenetic landscape. Drug resistance is at an energy maxima (peak), which tends to arrive spontaneously at an energy minima (trough).

Figure 2

A diagram showing four different dosing strategies. (1) MTD dosing – maximal doses with maximal resistance. (2) Metronomic dosing – less is more regularly. (3) Intermittent dosing –start and stop dosing theoretically leads to less resistance than continuous dosing. (4) Adaptive therapy – dosing level and frequency adapted for tumor stability.

Figure 3

A diagram depicting the ROCKET trial design. Patients with mCRC are randomized to RRx-001 or regorafenib. On progression, both arms are rechallenged with irinotecan-based therapies, if clinically appropriate. The primary endpoint is OS. Another endpoint is PFS measured as the sum of PFS (RRx-001 or regorafenib) + PFS (irinotecan therapies).

Figure 4

A diagram depicting the RRx-001 resensitization loop. In the ROCKET trial, RRx-001 patients are shuttled between RRx-001 and FOLFIRI in an iterative retreatment loop.

Figure 5

A diagram depicting the concept of proliferation- resistance trade-offs. Tumors allocate finite resources toward proliferation or resistance, depending on the presence or absence of specific stresses. This process is referred to as the proliferation-resistance trade-off.