Targeting Pi3k Mtor Signaling In Cancer

The phosphatidylinositol 3-kinase (PI3K)/mTOR pathway integrates signals from growth factors with nutrient signals and other conditions and controls multiple cell responses, including proliferation, survival and metabolism. Deregulation of the PI3K pathway has been extensively investigated in connection to cancer. Somatic or inherited mutations frequently occur in tumor suppressor genes (PTEN, TSC1/2, LKB1) and oncogenes (PIK3CA, PIK3R1, AKT) in the PI3K/mTOR pathway. The fact that the PI3K/mTOR pathway is deregulated in a large number of human malignancies, and its importance for different cellular responses, makes it an attractive drug target. Pharmacological PI3K inhibitors have played a very important role in studying cellular responses involving these enzymes. Currently, a wide range of selective PI3K inhibitors have been tested in preclinical studies and some have entered clinical trials in oncology. Rapamycin and its analogs targeting mTOR are effective in many preclinical cancer models. Although rapalogs are approved for the treatment of some cancers, their efficacy in clinical trials remains the subject of debate. Due to the complexity of the PI3K/mTOR signaling pathway, developing an effective anti-cancer therapy remains a challenge. The biggest challenge in curing cancer patients with various signaling pathway abnormalities is to target multiple components of different signal transduction pathways with mechanism-based combinatorial treatments.

In the post human-genome project era, cancer specific genomic maps are redesigning tumor taxonomy by evolving from histopathology to molecular pathology. The success of a cancer drug today is fundamentally based on the success in identifying target genes that control beneficial pathways. The overwhelming power of genomics and proteomics has enlightened researchers about the fact that the PI3K-mTOR pathway is the most commonly up-regulated signal transduction pathway in various cancers, either by virtue of its activation downstream of many cell surface growth factor receptors or by virtue of its collateral and compensatory circuitry with RAS-MAPK pathway. Oncogenic signaling in the majority of solid tumors is sustained via the PI3K-AKT-mTOR pathway. Because of its prominent role in many cancer types, the PI3K-mTOR pathway has become a major therapeutic target. The volume includes two complementary parts which address the problem of etiology and disease progression and is intended to portray the very basic mechanisms of the PI3K-AKT-mTOR signaling pathway’s involvement in various facets of the cancer, including stem cell renewal, cell metabolism, angiogenesis, genetic instability, and drug resistance. Significant progress has been made in recent years elucidating the molecular mechanism of cancer cell proliferation, angiogenesis, and drug-resistance in relation to the PI3K-mTOR pathway and this volume provides an in-depth overview of recent developments made in this area.​

This book describes the challenges involved in developing mTOR inhibitors for cancer treatment, starting with an in-depth examination of their molecular mechanism of action, with emphasis on the class side-effects, efficacy and mechanisms of resistance, as well as on promising novel directions for their development, including novel compounds and rational combinations with other anti-neoplastic drugs. Over the last 10 years, inhibitors of mTOR have emerged as a major class of anticancer drugs. Two rapamycin analogs are currently approved for the treatment of renal cell carcinoma, and it is estimated that a variety of other tumor types could benefit from mTOR inhibition, with numerous clinical trials (including pivotal registration trials) already underway. Second-generation small-molecule inhibitors of the pathway have also shown promise in terms of their superior tolerability and efficacy and are undergoing extensive clinical evaluation, with an estimated 30+ compounds currently under evaluation.

The mechanistic/mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a central regulator for human physiological activity. Deregulated mTOR signaling is implicated in a variety of disorders, such as cancer, obesity, diabetes, and neurodegenerative diseases. The papers published in this Special Issue summarize the current understanding of the mTOR pathway and its role in the regulation of tissue regeneration, regulatory T cell differentiation and function, and different types of cancer including hematologic malignancies, skin, prostate, breast, and head and neck cancer. The findings highlight that targeting mTOR pathway is a promising strategy to fight against certain human diseases.

The main objective of this book is to provide an up-to-date survey of the rapidly advancing eld of cancer therapy. Moreover, since our knowledge in this area rapidly evolves, some data have got obsolete during the process of book editing. Our understanding of the mechanisms involved in cancer genesis and progression underwent unprecedented expansion during the last decade, opening a new era of cancer treatment – targeted therapy. The surge in this area results in no small part from studies conducted jointly by basic health scientists and clinical investigators. It is our hope that this book will help foster even further collaboration between investigators in these two disciplines. The target of rapamycin (TOR) was rst identi ed in Saccharomyces cerevisiae and subsequently in mammals (mTOR) as a conserved atypical serine/threonine kinase. In mammalian cells, mTOR exists in at least two multi-protein complexes that have critical roles in regulating cellular homeostasis and survival. As with many other areas of science, discovery of TOR signaling was fortuitous. Rapamycin was isolated as a product of the soil bacteria Streptomyces hygroscopicus, identi ed in a soil sample taken from the island of Rapa Nui (Easter Island). Rapamycin was rst discovered to be a potent antifungal agent and next as an immune suppressive drug. It was only later that it was found to be active as an antitumor agent in non-clinical models; although it was not developed for this indication. The history of rapamycin presents one of the rst examples of chemical genetics.

The PI3Ks control many key functions in immune cells. PI3Ks phosphorylate PtdIns(4,5)P2 to yield PtdIns(3,4,5)P3. Initially, PI3K inhibitors such as Wortmannin, LY294002 and Rapamycin were used to establish a central role for Pi3K pathway in immune cells. Considerable progress in understanding the role of this pathway in cells of the immune system has been made in recent years, starting with analysis of various PI3K and Pten knockout mice and subsequently mTOR and Foxo knockout mice. Together, these experiments have revealed how PI3Ks control B cell and T cell development, T helper cell differentiation, regulatory T cell development and function, B cell and T cell trafficking, immunoglobulin class switching and much, much more. The PI3Kd inhibitor idelalisib has recently been approved for the treatment of B cell lymphoma. Clinical trials of other PI3K inhibitors in autoimmune and inflammatory diseases are also in progress. This is an opportune time to consider a Research Topic considering when what we have learned about the PI3K signalling module in lymphocyte biology and how this is making an impact on clinical immunology and haematology.

This volume details standard techniques for the characterization of urothelial carcinoma as well as methods to investigate mechanisms of carcinogenesis. Chapters guide readers on cellular and animal models for urothelial carcinoma and related diseases, molecular analyses from body fluids, and new approaches to therapy. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, Urothelial Carcinoma: Methods and Protocols hopes that the techniques described in this volume will contribute to the current upturn in research on urothelial carcinoma and to the application of its results in clinical practice.

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is an important signaling route that regulates several cell functions. PI3K/AKT/mTOR pathway is a crossroad of cell death and survival, playing a pivotal role in multiple interconnected cell signaling mechanisms implicated in cell metabolism, growth and proliferation, apoptosis, and angiogenesis. Disruptions in the Akt‑regulated pathways and alterations in PTEN expression are associated to Reactive oxygen species (ROS) homeostasis and different types of cancer. Genomic studies have shown that activating mutations in oncogenes as well as inactivating mutations in tumor suppressor genes are present across a variety of malignancies, including constitutive activation of the PI3K/AKT/mTOR pathway. The regulation of the Akt signaling pathway renders multiple challenges and valuable therapeutic targets. The discovery process of Akt, PDK1 and mTOR synthetic and natural products as inhibitors or immune checkpoint inhibitors using various strategies, could led to the identification of small molecule inhibitors with great selectivity, low side‑effects and also low toxicity regarding drug development.