Lindwoods2605

This personal perspective focuses on small-molecule inhibitors of proteostasis networks in cancer-specifically the discovery and development of chemical probes and drugs acting on the molecular chaperones HSP90 and HSP70, and on the HSF1 stress pathway. Emphasis is on progress made and lessons learned and a future outlook is provided. Highly potent, selective HSP90 inhibitors have proved invaluable in exploring the role of this molecular chaperone family in biology and disease pathology. Clinical activity was observed, especially in non small cell lung cancer and HER2 positive breast cancer. Optimal use of HSP90 inhibitors in oncology will likely require development of creative combination strategies. HSP70 family members have proved technically harder to drug. However, recent progress has been made towards useful chemical tool compounds and these may signpost future clinical drug candidates. The HSF1 stress pathway is strongly validated as a target for cancer therapy. HSF1 itself is a ligandless transcription factor that is extremely challenging to drug directly. HSF1 pathway inhibitors have been identified mostly by phenotypic screening, including a series of bisamides from which a clinical candidate has been identified for treatment of ovarian cancer, multiple myeloma and potentially other cancers.Targeting aberrant protein homeostasis (proteostasis) in cancer is an attractive therapeutic strategy. However, this approach has thus far proven difficult to bring to clinical practice, with one major exception proteasome inhibition. These small molecules have dramatically transformed outcomes for patients with the blood cancer multiple myeloma. However, these agents have failed to make an impact in more common solid tumors. Major questions remain about whether this therapeutic strategy can be extended to benefit even more patients. Here we discuss the role of the proteasome in normal and tumor cells, the basic, preclinical, and clinical development of proteasome inhibitors, and mechanisms proposed to govern both intrinsic and acquired resistance to these drugs. Years of study of both the mechanism of action and modes of resistance to proteasome inhibitors reveal these processes to be surprisingly complex. Here, we attempt to draw lessons from experience with proteasome inhibitors that may be relevant for other compounds targeting proteostasis in cancer, as well as extending the reach of proteasome inhibitors beyond blood cancers.Molecular chaperones are responsible for maintaining intracellular protein quality control by facilitating the conformational maturation of new proteins as well as the refolding of denatured proteins. While there are several classes of molecular chaperones in the cell, this chapter will focus solely on the small molecule modulation of Hsp90, the 90 kDa heat shock protein. Hsp90 is not only responsible for folding nascent proteins, but it also regulates the triage of numerous client proteins through partnering with the ubiquitin-proteasome pathway. Consequently, Hsp90 plays critical role in maintaining the protein homeostasis (proteostasis) network within the cell and is required for the activation/maturation of more than 300 client protein substrates. selleck inhibitor Many of the clients that depend upon Hsp90 are overexpressed or mutated during malignant transformation. This often renders the clients thermodynamically unstable and dependent on Hsp90 for stability. This phenomenon results in an oncogenic 'addiction' to the Hsp90 protein folding machinery as Hsp90 maintains onco-client proteins. Furthermore, Hsp90-dependent substrates are associated with all ten hallmarks of cancer, making Hsp90 an attractive target for the development of cancer chemotherapeutics. In fact, 17 small molecule inhibitors of Hsp90 have been developed and clinically evaluated for the treatment of cancer. Unfortunately, most of these molecules have failed for various reasons, necessitating a new approach to modulate the Hsp90 protein folding machine.Cellular stress induced by the accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates an elaborate signalling network termed the unfolded protein response (UPR). This adaptive response is mediated by the transmembrane signal transducers IRE1, PERK, and ATF6 to decide cell fate of recovery or death. In malignant cells, UPR signalling may be required to maintain ER homeostasis and survival in the tumor microenvironment characterized by oxidative stress, hypoxia, lactic acidosis and compromised protein folding. Here we provide an overview of the ER response to cellular stress and how the sustained activation of this network enables malignant cells to develop tumorigenic, metastatic and drug-resistant capacities to thrive under adverse conditions. Understanding the complexity of ER stress responses and how to target the UPR in disease will have significant potential for novel future therapeutics.Tumors are stressful environments. As tumors evolve from single mutated cancer cells into invasive malignancies they must overcome various constraints and barriers imposed by a hostile microenvironment. To achieve this, cancer cells recruit and rewire cells in their microenvironment to become pro-tumorigenic. We propose that chaperones are vital players in this process, and that activation of stress responses helps tumors adapt and evolve into aggressive malignancies, by enabling phenotypic plasticity in the tumor microenvironment (TME). In this chapter we will review evidence supporting non-cancer-cell-autonomous activity of chaperones in human patients and mouse models of cancer, discuss the mechanisms by which this non-cell-autonomous activity is mediated and provide an evolutionary perspective on the basis of this phenomenon.The chaperome is a large family of proteins composed of chaperones, co-chaperones and a multitude of other factors. Elegant studies in yeast and other organisms have paved the road to how we currently understand the complex organization of this large family into protein networks. The goal of this chapter is to provide an overview of chaperome networks in cancer cells, with a focus on two cellular states defined by chaperome network organization. One state characterized by chaperome networks working in isolation and with little overlap, contains global chaperome networks resembling those of normal, non-transformed, cells. We propose that in this state, redundancy in chaperome networks results in a tumor type unamenable for single-agent chaperome therapy. The second state comprises chaperome networks interconnected in response to cellular stress, such as MYC hyperactivation. This is a state where no redundant pathways can be deployed, and is a state of vulnerability, amenable for chaperome therapy. We conclude by proposing a change in how we discover and implement chaperome inhibitor strategies, and suggest an approach to chaperome therapy where the properties of chaperome networks, rather than genetics or client proteins, are used in chaperome inhibitor implementation.