Therapeutic targeting of oncogenic transcription factors


Rationale:

Transcription factors can induce profound and sustained phenotypic effects in cells by binding and altering the expression of thousands of genes. It is therefore not surprising that many of these factors have been shown to play critical roles in tumorigenesis, especially in the hematological malignancies. From the mechanistic standpoint transcription factors function by binding to a specific DNA consensus sequence, or by forming a complex with other transcription factors, and recruiting chromatin modifying complexes to their various genetic target loci. Because transcription factors mediate their action largely through protein-protein interactions rather than enzymatic activities they have been traditionally been regarded as "undruggable targets". However, we propose that this concept is outdated and that a rigorous study of the biochemical mechanism of action of these proteins can provide sufficient information for the rational design of therapeutic inhibitors. We hypothesize that it is possible to design potent, specific and clinically viable transcription factor inhibitors. Such transcription therapy drugs would be predicted to therapeutically reprogram tumor cells so that they would either die or cease to display the malignant phenotype. We further hypothesize that the downstream pathways of these transcription factors can be harnessed for the development of more potent combinatorial treatments that by offering powerful anti-tumor efficacy could reduce the need for cytotoxic drugs in the clinical setting. Finally, we predict that transcription therapy drugs could offer superior activity against chemo-resistant and semi-quiescent tumor repopulating cells, allowing for complete eradication of disease.

Goals:

To design specific inhibitors against oncogenic transcription factors.
To test the mechanism of action, specificity, pharmacodynamics, pharmacokinetics, toxicities and of transcription therapy drugs.
To use information derived from transcriptional programming studies to identify pathways that can be combinatorially targeted and induce synergistic anti-tumor effects in lymphomas and leukemias.
To develop clinical trials and perform correlative studies on transcription factor targeted therapy trials.


Projects:

Development of peptidomimetic inhibitors of the BCL6 oncogene.
Development of small molecule inhibitors of BCL6.
Rational design of combinatorial therapy for B-cell lymphomas.
Identification of transcription factor targets in lymphomas and leukemias.

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