Ari M. Melnick   Professor of Medicine

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Therapeutic Targeting of Oncogenic Transcription Factors

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 However, we propose that this concept is outdated and that a rigorous study of the biochemical mechanism of action of these proteins can provide sufficient information for the rational design of therapeutic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.

Transcriptional Programming in Normal and Malignant B-cells

B-cells undergo dramatic phenotypic shifts during their normal maturation process and in response to antigen stimulation. T-cell dependent antigen responses induce B-cell activation and cause a subset of B-cells to form germinal centers within which they undergo clonal expansion, somatic hypermutation and class switch recombination. A majority of B-cell neoplasms arise from germinal center B-cells or from cells that have undergone the germinal center reaction. Because of this we are particularly interested in the biochemical and biological mechanism of action of transcription factors that impose the germinal center phenotype, since many of these are also expressed in lymphoma cells and may contribute to lymphomagenesis. A major focus for the lab in recent years is the BCL6 transcriptional repressor, however several other factors are under investigation. The overall goal is to determine how these different transcription factors function from the biochemical standpoint and how they interact to form a network of interactions throughout the genome that results in the phenotypic features of the different compartments of B-cells.

Integrative Epigenomics in Hematologic Malignancies

Aberrant transcriptional programming is a hallmark of cancer, and is dependent on the deregulated action of transcription factors and chromatin modifying proteins. The phenotype of a given tumor is dependent on the collective information contained within the DNA sequence and epigenetic settings associated with the genome. We hypothesize that integrative analysis of epigenetic and genetic settings in cancer cells can provide a rational basis for more accurately modeling the critical biological pathways involved in mediating the malignant phenotype of tumors in individual patients. We also predict that epigenomic integrative analysis can be used to determine the identity of chromatin and transcription factors that contribute mechanistically to aberrant transcriptional programming in given tumors, and that this information can be used for designing therapeutic strategies.


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