The MYC oncogene is thought to be involved in more than half of all human tumors and hence has great potential as a targeted therapy. However, despite the well appreciated role of oncogenes in the pathogenesis and maintenance of tumors, the ability to directly target them has proven elusive save a few examples, such as imatinib for chronic myelogenous leukemia. Recently, Carter et al. reported a way to circumvent the necessity to directly target MYC in neuroblastoma, a MYC-driven pediatric cancer, by identifying a downstream factor that was essential for the high expression of MYC-targeted genes in these tumors (1).
The authors began their search for targets downstream of MYC-driven transcription by filtering the gene-expression profiles of close to 650 neuroblastoma tumors through a MYC activation signature. This was followed by the application of multiple additional filters related to the level of prognostic significance as well as the current availability of a small molecule inhibitor to narrow the field down to one gene, suppressor of Ty 16 (SUPT16H). This gene encodes for SPT16, which along with SSRP1, forms the facilitated chromatin transcription (FACT) complex. FACT serves to remodel histones at sites of active transcription to enable processivity of the RNA polymerase (2). Using neuroblastoma cell lines, the authors revealed a previously unappreciated interdependence between MYC and FACT whereby MYC directly drives transcription of SUPT16H and SSRP1 and FACT then feeds back to positively drive both MYC expression and protein stability. In support of this model, the cell lines with the highest levels of MYC expression were also the most sensitive to perturbation of FACT.
As mentioned previously, a main criteria that led the authors to focus on FACT was the current availability of an inhibitor. Specifically, an indirect inhibitor to FACT, CBL0137, has been developed and is currently in clinical trials for cancer (NCT01905228) (3). CBL0137 binds to DNA but, unlike conventional DNA intercalating agents, it is non-mutagenic and hence was shown not to induce a DNA damage response (3). Instead, CBL0137 binding to DNA causes a prevalence of alternative DNA structures and destabilized nucleosomes which FACT recognizes and consequentially becomes trapped at (4). This leads to cell death via FACT-dependent activation of p53 as well as downregulation of a subset of NF-κB-dependent genes (3). Using animal models, the authors demonstrate that neuroblastoma tumors treated with CBL0137 undergo increased apoptosis as a result of inhibition of the FACT/MYC positive feedback loop. This translated into a significant increase in survival for mice treated with CBL0137. Furthermore, combining CBL0137 with DNA damaging chemotherapeutics routinely used for neuroblastoma showed even greater in vivo efficacy versus any drug used as a monotherapy.
The synergy with DNA damaging agents is particularly interesting as it likely highlights a therapeutic efficacy of FACT perturbation independent from deregulation of MYC. FACT has been directly implicated in aspects of the DNA damage response so it is plausible that chromatin trapping by CBL0137 would preclude the ability of FACT to contribute to this process (5-9). Alternatively, the DNA intercalation of CBL0137 in combination with another DNA-damaging agent may synergize to grossly alter DNA integrity and trigger cell death. It is somewhat surprising that CBL0137 is not genotoxic as a single agent despite its mechanism of action of directly binding DNA. Its ability to increase DNA double strand breaks was ruled out by the authors and others, by using markers for this event as well as by evaluating direct DNA laddering which is indicative of DNA breaks (3). The recent evidence that CBL0137 drives the formation of alternative DNA structures which FACT can bind and directly trigger a p53-dependent response, hence circumventing the need to activate the DNA damage response, sheds some light as to why there are not direct DNA breaks with CBL0137 treatment alone. However, this model may need to be modified in the context of combination treatment whereby Carter et al. demonstrated that efficacy was independent of p53 status.
Another area that would be of interest to explore further is the impact of CBL0137 on putative cancer stem-like cells in neuroblastoma. These cells represent a subpopulation in these tumors that harbor stem cell-like characteristics with a high tumorigenic potential. They were identified in both neuroblastoma cell lines and from primary tumors with more recent studies elucidating gene expression signatures unique to these cells (10-13). In previous studies, CBL0137, as a monotherapy, had a preferential impact on the cancer stem cell component in pancreatic cancer and glioblastoma and the same may hold true for neuroblastoma (14,15). FACT itself is more highly expressed in developmental tissues and likely is crucial for the regulation of stem-specific gene signatures that cancer stem-like cells are dependent on and hence more susceptible to cell death upon FACT disruption by CBL0137. It is thought that neuroblastomas are embryonal tumors that arise from a differentiation defect of multipotent embryonic neural crest cells. In support of the previously stated critical role for FACT in the undifferentiated state, Carter et al. confirmed that FACT was highly expressed in neuroblastoma precursor cells in a mouse model and showed that CBL0137 treatment could promote differentiation.
These studies provide new options for clinical paradigms that can be used to target MYC-driven tumors. They also independently shine a light on FACT disruption, via CBL0137, as a promising therapeutic modality. The author’s data hold promise for the clinical application of this approach for neuroblastoma, which remains difficult to treat in advanced stages. More broadly, with MYC alterations so common in numerous tumor types, these findings provide rational to test this treatment strategy for other cancers.
Conflicts of Interest: The author has no conflict of interest to declare.
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