The Eμ-TCL1 mouse is a B cell leukemia model commonly used to test the efficacy of experimental therapeutics and interrogate the functions of oncogenes and tumor suppressors. The CLL-like disease in this mouse shares similar pathology and molecular etiology with the human variant. We therefore hypothesized that overexpression of the human isoform of Par-4 in the B cells of this mouse would impede disease progression through either an anti-proliferative or pro-apoptotic mechanism. Consistent with this hypothesis, results indicated that B cell-specific overexpression of human Par-4 reduced the rate of T Cell Leukemia/Lymphoma 1 (TCL1)-induced leukemogenesis. In addition, B cell-specific knockout of endogenous Par-4 increased the rate of TCL1-induced leukemogenesis. Par-4 activity is regulated through a variety of mechanisms, which seem to give it a pleiotropic property. It is generally thought to act as either an anti-proliferative or pro-apoptotic tumor suppressor. In our study, TCL1 mice overexpressing human Par-4 were found to harbor malignant B cell clones that proliferated at reduced rates when compared to their Par-4 wild-type (WT) littermates. This indicated that Par-4 was reducing the expansion of overexpressing cells; which we found interesting, because Par-4 overexpressing mice null for the TCL1 oncogene exhibited no phenotype when examined in various immune response assays.

Par-4 is a naturally occurring tumor suppressor. Studies have indicated that overexpression of Par-4 selectively induces apoptosis in cancer cells while leaving normal, health, cells unaffected. Mechanisms contributing to this cancer-selective action of Par-4 have been associated with PKA activation of intracellular Par-4 in cancer cells or GRP78 expression primarily on the surface of cancer cells. On the other hand, endogenous Par-4 sensitizes cells to the action of a broad range of apoptotic inducers acting via the extrinsic and intrinsic pathways. A number of binding partners of Par-4 have been identified and shown to regulate Par-4 function in cancer and other diseases, such as Alzheimer’s and major depression. Recent studies have recognized a number of natural products, dietary supplements, synthetic molecules and FDA-approved drugs that induce the secretion of Par-4 protein to cause apoptosis in primary or metastatic tumors, one of which is in clinical trials. More than 50 different laboratories worldwide are involved in Par-4 based research of this unique protein that has progressed from the bench to clinical trials. This second, companion volume will provide a comprehensive overview of Par-4’s role in cancer and other diseases. Chapters are written by leading researchers, and will be useful for a broad audience across the scientific community, particularly students and trainees, who are the next generation of scientists and clinicians to participate in new studies and discoveries on Par-4.

Par-4 is a naturally occurring tumor suppressor. Studies have indicated that overexpression of Par-4 selectively induces apoptosis in cancer cells while leaving normal, health, cells unaffected. Mechanisms contributing to this cancer-selective action of Par-4 have been associated with PKA activation of intracellular Par-4 in cancer cells or GRP78 expression primarily on the surface of cancer cells. On the other hand, endogenous Par-4 sensitizes cells to the action of a broad range of apoptotic inducers acting via the extrinsic and intrinsic pathways. A number of binding partners of Par-4 have been identified and shown to regulate Par-4 function in cancer and other diseases, such as Alzheimer’s and major depression. Recent studies have recognized a number of natural products, dietary supplements, synthetic molecules and FDA-approved drugs that induce the secretion of Par-4 protein to cause apoptosis in primary or metastatic tumors, one of which is in clinical trials. More than 50 different laboratories worldwide are involved in Par-4 based research of this unique protein that has progressed from the bench to clinical trials. This second, companion volume will provide a comprehensive overview of Par-4’s role in cancer and other diseases. Chapters are written by leading researchers, and will be useful for a broad audience across the scientific community, particularly students and trainees, who are the next generation of scientists and clinicians to participate in new studies and discoveries on Par-4.

Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies A thorough compilation of the many scientific breakthroughs in the ongoing development of precision cancer therapies related to lymphoma Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies: From Concept to Practice focuses on lymphoma, an area which has seen a remarkable number of breakthroughs in the ongoing development of precision cancer therapies. Each section on a specific biology or class of drugs has an introductory chapter written by an authority in the field, exclusively focused on the science and its relevance to cancer biology. This approach addresses the need for scientists, physicians, and the private sector to understand the broader context of the extraordinary advances that have produced such astonishing advances in the disease. The work primarily focuses on how to understand and translate fundamental principles of basic science into information that can be directly applied to patients – hence the subtitle, From Concept to Practice. To aid in readers’ comprehension, the first page of each chapter contains a box entitled ‘Take Home Points’. This short text will highlight the major unique points about the information contained within the chapter. Some of the key topics addressed in the work are as follows: Biological basis of the lymphoid malignancies: fundamental principles of lymphomagenesis and molecular classification of lymphoid malignancies Targeting programmed cell death: principles for understanding the many types of cell death and promising combinations of drugs targeting apoptosis Targeting the PI3K pathway: understanding the intricacies of this complex biology and precisely how targeted drugs can be leveraged therapeutically Targeting the cancer epigenome: pharmacologic features of drugs targeting the epigenome and future prospects for targeting various aspects of epigenetic control Targeting the tumour proteome: understanding the mechanisms of protein degradation in cancer including both older drugs like proteasome inhibitors, and newer PROTAC based approaches Written primarily for scientists and physicians in both the public and private sectors, Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies: From Concept to Practice is a comprehensive reference work for those interested in the growing area of Precision Cancer Therapies. Seamlessly integrating the basic and applied science, this volume will be an indispensable reference for those interested in translating the most important advances in science to innovative novel treatments for patients.

Par-4 is a tumor suppressor protein first discovered and identified in 1993 by Dr. Vivek Rangnekar's laboratory in prostate cancer cells undergoing apoptosis. Par-4 (later also known as PAWR) is a naturally occurring tumor suppressor. Studies have indicated that Par-4 selectively induces apoptosis in cancer cells while leaving normal, healthy, cells unaffected. Mechanisms contributing to the cancer-selective action of Par-4 have been associated with protein kinase A activation of intracellular Par-4 in cancer cells or GRP78 expression primarily on the surface of cancer cells. Par-4 is downregulated, inactivated or mutated in diverse cancers. This first of two volumes will be the first on the market on the topic of Par-4, and will provide the opportunity for researchers to discuss the future direction of studies, broaden the scope of research, and contribute a more complete understanding of the molecule's structural features, key functional domains, regulation and relevant basic and clinical/translational facets.