This book highlights recent progress in the development of small-molecule inhibitors of oncogenic transcription factors and is relevant for postgraduates, researchers and practitioners.

Transcription is frequently deregulated in cancer, but targeting of transcriptional processes for cancer therapy has thus far been limited to nuclear receptors. Recent studies, however, have suggested that inhibitors of various general transcriptional regulators can be used in cancer therapy because expression of some oncogenes is disproportionately sensitivity to these inhibitors. Here, I describe the cellular and molecular effects of inhibiting a general transcriptional regulator, CDK7, in T-cell acute lymphoblastic leukemia (T-ALL) cells. Because tumor cells commonly evolve resistance to individual therapies, I have also investigated the potentially synergistic effects of combining two compounds that target transcriptional regulators - the CDK7-inhibitor THZ1 and the BRD4-inhibitor JQ1 - and suggest a model describing the molecular basis of the synergistic effects I observed. My research provides insight into the effects of these inhibitors of general transcriptional regulators on tumor cell behavior and gene expression programs.

This book systematically reviews the most important findings on cancer immune checkpoints, sharing essential insights into this rapidly evolving yet largely unexplored research topic. The past decade has seen major advances in cancer immune checkpoint therapy, which has demonstrated impressive clinical benefits. The family of checkpoints for mediating cancer immune evasion now includes CTLA-4, PD-1/PD-L1, CD27/CD70, FGL-1/LAG-3, Siglec-15, VISTA (PD-1L)/VSIG3, CD47/SIRPA, APOE/LILRB4, TIGIT, and many others. Despite these strides, most patients do not show lasting remission, and some cancers have been completely resistant to the therapy. The potentially lethal adverse effects of checkpoint blockade represent another major challenge, the mechanisms of which remain poorly understood. Compared to the cancer signaling pathways, such as p53 and Ras, mechanistic studies on immune checkpoint pathways are still in their infancy. To improve the responses to checkpoint blockade therapy and limit the adverse effects, it is essential to understand the molecular regulation of checkpoint molecules in both malignant and healthy cells/tissues. This book begins with an introduction to immune checkpoint therapy and its challenges, and subsequently describes the regulation of checkpoints at different levels. In closing, it discusses recent therapeutic developments based on mechanistic findings, and outlines goals for future translational studies. The book offers a valuable resource for researchers in the cancer immunotherapy field, helping to form a roadmap for checkpoint regulation and develop safer and more effective immunotherapies.

Most biological processes including signal transduction via transcription factors are mediated through protein-protein interactions (PPIs). Deregulations of the proteins involved in these interactions have been implicated in contributing to disease progression. It is now well established that cancer can be the result of aberrant PPIs, either through the loss of an essential interaction or, through the overactivation of transcription factors. Thus, targeting transcription factors have become attractive molecular targets. The multi-faceted approach to medicinal chemistry that encompasses synthesis, computational analyses, biophysical and biological evaluations are demonstrated by the invention and production of small molecule inhibitors for two well-known protein targets, the transcription factor STAT5 and the ubiquitin E3 ligase MDM2. A structure based drug design (SBDD) strategy was utilized in the discovery of the first potent and selective inhibitor of the STAT5 protein with optimal metabolic stability. Throughout our efforts in establishing an inhibitor for STAT5, we investigated STAT5 isoforms and their roles in driving several malignancies within the body. A novel STAT5A isoform FP assay was developed and efforts were undertaken to identify an isoform selective inhibitor. A STAT5B selective compound was identified with similar potencies to our first generation lead 13a. With a newly discovered pharmacophore for STAT5, optimizations of the tripodal scaffold were carried out to reduce entropic costs to binding. A new class of benzodiazepines were produced, however, these compounds did not result in a favorable potency/selectivity profile for the STAT5 protein. The class of benzodiazepines was then reevaluated for the MDM2 target with promising preliminary in vitro evaluations. We have identified the first in class and best in class inhibitor for the STAT5 protein reported to date. With a favorable potency/selectivity profile and optimal metabolic stability, two lead compounds have the potential to become candidates for advanced preclinical trials as a STAT5-targeted therapeutic. In addition, these small molecule inhibitors can serve as research tools to investigate the knockdown of STAT5 function at the protein level.

This volume, which includes contributions from leading scientists and clinicians in the field, provides definitive, state-of-the-art information on STAT inhibitors in a biological and clinical context. It gives an overview of the biology of the STAT family of transcription factors and their role in cancer etiology. Additionally, it describes the raft of therapeutic approaches being used to inhibit STATs in the context of various cancers, covering the full spectrum of therapeutic approaches to inhibiting STATs, and presenting emerging data from clinical trials.

The ETS family of transcription factors share a conserved DNA binding domain that recognizes a purine rich consensus sequence with GGAA/T motif. ETS genes have been implicated in a wide array of malignancies including acute myeloid leukemia, Ewing sarcoma and prostate cancer. These genes are suppressed in most adult tissues, while in cancer; their expression is upregulated as a result of chromosomal rearrangements that leave the factors under a control of ubiquitously active promoters. In Ewing sarcoma (ES) patients, tumor specific chromosomal translocation involving FLI1 creates EWS-FLI1 protein. In previous studies, we identified a small molecule inhibitor, YK-4-279, that directly binds to EWS-FLI1 and inhibit its activities. Due to lack of an ES transgenic mouse model, we tested the in vivo therapeutic efficacy of YK-4-279 in the only available transgenic mouse model with EWS-FLI1 induced neoplasm. We showed that short-term YK-4-279 treatment led to correction of abnormal hematopoiesis and improved overall survival of EWS-FLI1+ leukemic mice. Thus far, a genetically engineered mouse model for EWS-FLI1 driven Ewing sarcoma has not been successfully generated. Here, we present data where we tried various approaches to conditionally express EWS-FLI1 using cre recombinase in order to generate a Ewing sarcoma transgenic mouse model. We used the Osx promoter to target Cre recombinase expression to the osteoblast lineage. Alternatively, we injected Cre expressing adenovirus to induce EWS-FLI1 expression locally. Most attempts resulted in embryonic lethality or developmental defects. Chromosomal translocations that involve members of the ETS transcription factor family are also present in a majority of prostate cancer patients. In order to understand how ETS transcription factors drive tumorigenicity in prostate cancer, we investigated their interacting protein partners. We identified and validated ezrin, RHA, and PARP as ERG interacting partners and show that YK-4-279 can inhibit these interactions. Overall, in this study, we demonstrate that direct targeting of ETS transcription factors with small molecules could be of significant therapeutic value in oncology.

Acute Leukemias IX provides an extended and thorough overview of recent developments in cell biology and experimental therapy for acute leukemias. Following the tradition of the Acute Leukemias series since 1987, this book bridges the gap between basic research and clinical studies and emphasizes that both aspects are equally necessary to achieve improvements, not only in understanding the disease but also in providing better therapy. As a forum for world-wide activities in the field of acute leukemias the volume contains invaluable contributions that provide the reader with new, previously unpublished information.

This volume provides the reader with an overview of the diverse functions of the RUNX family of genes. As highlighted in the introduction and several of the 29 chapters, humans and other mammals have three RUNX genes that are known to play specific roles in blood, bone and neuronal development. However, their evolutionary history has recently been traced back to unicellular organisms and their involvement in many well-known signaling pathways (Wnt, TGFb, Notch, Hippo) is indicative of a more general function in cell biology. Their documented roles in cell fate decisions include control of proliferation, differentiation, survival, senescence and autophagy. The pleiotropic effects of RUNX in development are mirrored in cancer, where RUNX genes can function as oncogenes that collaborate strongly with Myc family oncogenes or as tumour suppressor genes. In the latter role, they display hallmarks of both ‘gatekeepers’ that modulate p53 responses and ‘caretakers’ that protect the genome from DNA damage. Several chapters focus on the importance of these genes in leukemia research, where RUNX1 and CBFB are frequently affected by chromosomal translocations that generate fusion oncoproteins, while recent studies suggest wider roles for RUNX modulation in solid cancers. Moreover, RUNX genes are intimately involved in the development and regulation of the immune system, while emerging evidence suggests a role in innate immunity to infectious agents, including HIV. At the biochemical level, the RUNX family can serve as activators or repressors of transcription and as stable mediators of epigenetic memory through mitosis. Not surprisingly, RUNX activity is controlled at multiple levels, this includes miRNAs and a plethora of post-translational modifications. Several chapters highlight the interplay between the three mammalian RUNX genes, where cross-talk and partial functional redundancies are evident. Finally, structural analysis of the RUNX/CBFB interaction has led to the development of small molecule inhibitors that provide exciting new tools to decipher the roles of RUNX in development and as targets for therapy. This volume provides a compendium and reference source that will be of broad interest to cancer researchers, developmental biologists and immunologists.