Discovery and Development of Mithramycin Analogs for Prostate Cancer Treatment by Direct Inhibition of the Oncogenic Transcription Factor ERG (TMPRSS2-ERG)
Abstract
Prostate cancers that resist treatment by castration have limited treatment options; therefore, innovative therapeutic strategies are needed to treat such cancers. As with other cancers, such treatments should ideally provide selectivity against cancer cells, sparing normal cells, thereby minimizing toxicity to the patients. Prostate cancers that are insensitive to androgen depletion contain an abnormal fusion protein, called TMPRSS2-ERG, where the ERG protein is a DNA binding transcription factor. This abnormal fusion is present only in cancer cells, but not in normal cells and is therefore an attractive target for cancer cell-selective drugs. Suppressing ERG in these cancer cells was shown to block tumor growth and invasiveness. Conversely, increase in ERG expression promotes tumor growth in mice. Recently, mithramycin (MTM), a DNA binding natural product isolated from Streptomyces bacteria, was demonstrated to potently inhibit a related oncogenic fusion, EWS-FLI1. This fusion is found in a childhood cancer called Ewing sarcoma, and MTM has now entered a clinical trial as a Ewing sarcoma therapeutic. MTM targets EWS-FLI1 specifically, most likely through interfering with the DNA binding function of FLI1, as MTM itself binds DNA. The DNA binding regions of FLI1 and ERG are nearly identical and constitute a major critical component of their respective fusions. Indeed, we showed that MTM and its analogues potently and kill TMPRSS2-ERG cancer cells. Therefore, ERG emerges as an attractive potential target for inhibition by MTM analogues in prostate cancers that are refractory to conventional treatment. Because MTM is toxic and only modestly selective against TMPRSS2-ERG cells, analogues of MTM that are more selectively toxic to prostate cancer cells expressing TMPRSS2-ERG are needed. Some of our new MTM analogues display higher selectivity against TMPRSS2-ERG prostate cancer cells and lower toxicity against other cells than MTM does. Our preliminary data explain this selectivity and suggest a unique mechanism of action of these MTM analogues. We propose to (1) investigate the mechanism of MTM/analogues against ERG in TMPRSS2-ERG prostate cancers and (2) develop highly selective and less toxic MTM analogues against such cancers that can then be used as prostate cancer drugs. This approach is highly innovative, as transcription factors like ERG have so far been viewed as "undruggable" targets. Our approach has, thus, the potential of filling a highly significant medical need. Our highly synergistic preliminary studies showed that MTM analogues break the "undruggable" target dogma by acting against ERG (and FLI1) through a novel mechanism. Our studies show that novel modifications (3-side chain modifications) on the MTM, like an antenna, interact directly with ERG bound to DNA (rather than displacing ERG from DNA, as do toxic anticancer agents). Selective and potent stabilization of ERG-TMPRSS2 along with decreased non-specific toxicity in the proposed next generation of MTM analogues could yield novel drugs that can be dosed safely due to a wide dosing range between efficacy and toxicity. The outcomes of this research will be (1) detailed elucidation of mechanism of MTM/analogues as TMPRSS2-ERG inhibitors in prostate cancer cells (an interim outcome) and (2) development of a highly selective MTM analogue against prostate cancers that express TMPRSS2-ERG that can ultimately be used against prostate cancers that are not treatable conventionally. Development can be that of the existing novel MTM analogues as well as the development of additional novel molecules that we propose to design. This approach is novel both at a fundamental level, as it explores and exploits an unprecedented mode of action of MTM analogues against a transcription factor and at a translational level, as it focuses on an innovative, cancer-specific target.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610479
Entities
People
- Jürgen Rohr
Organizations
- United States Army
- University of Kentucky