Biochemical and immunological roles of heat shock proteins in human cancer

Found in every cell of every organism, heat shock proteins (hsps) participate in a wide range of cellular processes and primarily function as molecular chaperones that mediate the activity of other cellular proteins. Hsps are required for a range of fundamental mechanisms used by cancer cells and they have consequently been identified as valid targets in the treatment of cancer. It was the aim of this thesis to further investigate these roles in breast cancer and melanoma using novel approaches from a biochemical and immunological perspective. In a preliminary study, breast cancer tissues (n = 30) were demonstrated by Western immunoblotting to widely express hsps 90 and 70. Two-dimensional gel electrophoresis indicated that a number of proteins were differentially expressed in tumour and healthy breast tissue from the same patient. These results suggest that a number of possibly unidentified proteins may play important roles in breast cancer and thus have use as therapeutic targets or biomarkers. The role of hsp90 and associated client proteins in breast cancer was further investigated by non-denaturing immunoprecipitation followed by elution with geldanamycin, a specific inhibitor of hsp90. Geldanamycin-sensitive hsp90 client proteins were observed in seven of 11 protein extracts from breast cancer patients and one healthy individual. Immunoprecipitation, Western immunoblotting and LC-MS identified hsps 40, 56/FKBP52, 60, 70, 105 and lumican as potential hsp90 client proteins. These proteins may thus assist breast cancer progression alongside hsp90. In one patient sample, a cancer-specific group of proteins was identified, while in all experiments geldanamycin resistance was observed. The results of this study may have relevance for the future of breast cancer research and clinical treatment

Incidence of Severe Hepatotoxicity Related to Antiretroviral Therapy in HIV/HCV Coinfected Patients

Introduction. Hepatotoxicity is a concern in HIV/hepatitis C virus (HCV) coinfected patients due to their underlying liver disease. This study assessed the incidence of hepatotoxicity in HIV/HCV co-infected patients in two outpatient infectious diseases clinics. Methods. HIV/HCV co-infected adults were included in this retrospective study if they were PI or NNRTI naïve at their first clinic visit and were initiated on an NNRTI- and/or PI-based antiretroviral regimen. Patients were excluded if they had active or chronic hepatitis B virus (HBV). The primary objective was to determine the overall incidence of severe hepatotoxicity. Results. Fifty-six of the 544 patients identified met inclusion criteria. The incidence of severe hepatotoxicity was 10.7% (6/56 patients). Severe hepatotoxicity occurred with efavirenz (N = 2), nevirapine (N = 1), indinavir (N = 1), nelfinavir (N = 1), and saquinavir/ritonavir (N = 1). Conclusion. The incidence of severe hepatotoxicity appears to be low in this retrospective analysis of HIV/HCV co-infected patients receiving a PI-and/or NNRTI-based regimen

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of hematologic malignancies: multiple myeloma, lymphoma, and acute leukemia

Increasing knowledge concerning the biology of hematologic malignancies as well as the role of the immune system in the control of these diseases has led to the development and approval of immunotherapies that are resulting in impressive clinical responses. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a hematologic malignancy Cancer Immunotherapy Guidelines panel consisting of physicians, nurses, patient advocates, and patients to develop consensus recommendations for the clinical application of immunotherapy for patients with multiple myeloma, lymphoma, and acute leukemia. These recommendations were developed following the previously established process based on the Institute of Medicine’s clinical practice guidelines. In doing so, a systematic literature search was performed for high-impact studies from 2004 to 2014 and was supplemented with further literature as identified by the panel. The consensus panel met in December of 2014 with the goal to generate consensus recommendations for the clinical use of immunotherapy in patients with hematologic malignancies. During this meeting, consensus panel voting along with discussion were used to rate and review the strength of the supporting evidence from the literature search. These consensus recommendations focus on issues related to patient selection, toxicity management, clinical endpoints, and the sequencing or combination of therapies. Overall, immunotherapy is rapidly emerging as an effective therapeutic strategy for the management of hematologic malignances. Evidence-based consensus recommendations for its clinical application are provided and will be updated as the field evolves

Associations of HSP90 Client Proteins in Human Breast Cancer

Background: HSP90 has been studied intensively as a therapeutic target, however little is known regarding specific interactions of the large number of HSP90 client proteins. Therefore, this study investigated HSP90 client proteins sensitive to the HSP90 inhibitor geldanamycin in tumour and healthy breast tissue. Materials and Methods: Co-immunoprecipitation and SDS-PAGE were used to investigate protein interactions. Western blotting and LC-MS were used to infer protein identities. Results: HSP90 client proteins were observed in 7 out of 11 breast cancer patients. Further experiments inferred HSP40, -56/FKBP52, -60, -70, -105 and lumican to associate with HSP90 and to belong to this group of geldanamycin-sensitive proteins. In one patient, a cancer-specific group of proteins was identified. In all experiments geldanamycin resistance was observed. Conclusion: HSP90 differentially associated with client proteins and this was patient dependent. Geldanamycin resistance and lack of HSP90 client protein expression may limit clinical applications of HSP90 inhibitors

Hsps 70 and 105 associate with a group of hsp90 client proteins that are selectively found in human breast cancer

This study investigated the interaction of heat shock proteins (hsps) and their client proteins in tumour and normal human breast tissue. The objective of the study was to discover hsp interactions specific to cancer cells. Hsps have been observed to be over-expressed in a range of human cancers. Of which hsps 70, 90 and others have been noted to be up-regulated in breast cancer. Up-regulation of these hsps has been shown to predict patient prognosis and response to therapies [1, 2]. The majority of hsp90's client proteins are signal transduction proteins. In addition, hsp90 is essential for cellular survival and has been proposed to participate in all 6 "hallmarks of cancer" [3]. Hsp90 inhibitors are under intense investigation and are currently in phase III clinical trials for the treatment of cancer. Hsp90 is known to associate with other hsps in the assembly and function of chaperone complexes. These experiments examined the hsp chaperone complexes and the effect of geldanamycin (an hsp90 inhibitor) on these complexes in human breast cancer

Stress Proteins in Human Breast Cancer

In this study we investigated stress protein (hsp70 and 90) expression in tumour tissue taken from various breast cancer patients and compared this with expression in a cultured breast cancer cell line as well as in normal peripheral lymphocytes with and without heat shock treatment. Given the importance of hsp90 in the steroid receptor complex we compared the effect of the anticancer drug geldanamycin on the assembly of the hsp90 complex in breast tumour tissue, breast cancer cells and normal lymphocytes in short term culture before and after heat shock

doi:10.1155/2010/856542 Research Article Incidence of Severe Hepatotoxicity Related to Antiretroviral Therapy in HIV/HCV Coinfected Patients

Copyright © 2010 Emily L. Heil et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. Hepatotoxicity is a concern in HIV/hepatitis C virus (HCV) coinfected patients due to their underlying liver disease. This study assessed the incidence of hepatotoxicity in HIV/HCV co-infected patients in two outpatient infectious diseases clinics. Methods. HIV/HCV co-infected adults were included in this retrospective study if they were PI or NNRTI naïve at their first clinic visit and were initiated on an NNRTI- and/or PI-based antiretroviral regimen. Patients were excluded if they had active or chronic hepatitis B virus (HBV). The primary objective was to determine the overall incidence of severe hepatotoxicity. Results