HIJACKING CANCER DRIVERS TO ACTIVATE PROAPOPTOTIC GENES IN DLBCL

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Project Summary The past two decades of cancer research have identified one or more drivers for most human malignancies. In addition, multiple cell death genes and pathways have been identified that normally protect the organism against developmental mutations or defects in genomic maintenance. These observations suggest that one might be able to rewire the transcriptional circuitry to cause the cancer cell to kill itself with its own driver. We have invented a new class of molecules that use Chemically Induced Proximity (CIP) to rewire the cancer cell such that the cancer driver activates proapoptotic pathways. We call these molecules Transcriptional Chemical Inducers of Proximity or TCIPs because they induce proximity or recruit a cancer driver to the promoters of proapopotic genes. For development of these two-sided, “bifunctional” molecules, we will focus on Diffuse Large Cell B Cell Lymphoma (DLBCL), using the master inhibitor of cell death, BCL6, as an anchoring transcription factor on the promoters of proapoptotic genes. For an activator we use any of several aberrantly-expressed transcription or epigenetic activators, to simultaneously derepress and activate proapoptotic genes. We have synthesized bifunctional small molecules that recruit transcriptional activators over-expressed in DLBCL to the promoters of proapoptotic genes normally bound and repressed by BCL6. In our preliminary studies, these molecules lead to rapid and robust killing of DLBCL that is superior to the best-in-class inhibitors and also specific for cells that over-express the targets of the bifunctional molecule. Using a strategy similar to genetic dominant gain-of-function mutations, TCIP can engage cancers with multiple drivers, thereby going beyond conventional inhibitors and degraders. Because bifunctional molecules rely on two separately overexpressed proteins, TCIP takes advantage of the natural, fundamental basis of transcriptional specificity to provide precise, predictable and selective killing of cancer cells. To further develop this approach, we will first optimize these molecules for stability, solubility and specificity of killing of DLBCL. Secondly, we will define the mechanism by which they produce robust and rapid killing. Finally, we will test them in established PDX models. Our studies will involve a multidisciplinary approach drawing on expertise in chemistry, clinical lymphoma treatment, cancer biology and genomic biology. If successful, we will lay the foundation for a new concept in the treatment of lymphoma, and more broadly, cancer chemotherapy, that is more specific than many existing approaches. The use of a novel dominant gain-of-function strategy by TCIPs addresses the issue of treatment of cancers, such as DLBCL, that have multiple, concurrent drivers.