Hsp60

Aging and related diseases are associated with alterations in oxidative status and low-grade inflammation, as well as a decreased endoplasmic reticulum (ER) unfolded protein response (UPR). UPR is a functional mechanism by which cells attempt to protect themselves against ER stress. Researchers analyzed these proteins in peripheral blood mononuclear cells of elderly subjects and used computer simulation to predict the key proteins associated with these biomolecules underlying physiological adaptations to exercise. They collected blood samples about five to six days before and after the training period and analyzed various oxidative stress biomarkers in peripheral blood mononuclear cells. The study takes research one step further in helping to elucidate the benefits of exercise in this population. Aging involves a balance between oxidants and antioxidants, low-grade inflammation and a protein response that occurs at the cellular level, which is responsible for many health disorders. Exercise has been shown to regulate the inflammatory response, balance oxidants such as free radicals that build up in the cells and damage DNA; and ameliorate the process by which cells protect themselves against these stressors. Furthermore, resistance training in older adults is recommended to help maintain muscle, flexibility and balance. Aging and related diseases are associated with alterations in oxidative status and low-grade inflammation, as well as a decreased endoplasmic reticulum (ER) unfolded protein response (UPR). UPR is a functional mechanism by which cells attempt to protect themselves against ER stress, resulting from the accumulation of the unfolded/misfolded proteins. One group of proteins associated with the aging process is the mitochondrial heat shock protein 60 (HSP60), which has been demonstrated to play a protective role in the ability for cells to remain active and healthy. Currently, there is limited research investigating the effects of resistance training in older adults on the expression of HSP60 and Klotho, a gene involved in the aging process in mammals. A new study by researchers at Florida Atlantic University, in collaboration with the University of León in Spain, examined whether an eight-week resistance training program would modulate the oxidative status, the UPR activation and key inflammatory pathways as well as their relationships with HSP60 and Klotho proteins. For the study, researchers analyzed these proteins in peripheral blood mononuclear cells of elderly subjects. In addition, they utilized computer simulation to predict the key proteins associated with these biomolecules underlying physiological adaptations to exercise. They collected blood samples approximately five to six days before and after the training period and just before training intervention in young subjects who were included for basal assessments. Researchers also analyzed various oxidative stress biomarkers in peripheral blood mononuclear cells. Results of the study, published in the journal Antioxidants, demonstrated that the levels of the inflammatory proteins (pIRAK1, TLR4, and TRAF6), as well as different markers of the redox balance (catalase, GSH, LP, NRF2, PC, ROS, SOD1, and SOD2) remained unchanged with training. Importantly, untrained elderly subjects showed a significant reduction in pIRE1/IRE1 ratio when compared to trained elderly subjects. Such a finding was further confirmed by a gene ontology analysis, showing that endoplasmic reticulum stress is a key mechanism modulated by IRE1. Additionally, analysis did not show the training effect on the expression of HSP60 and Klotho or their relationships with other outcome variables. Although elderly male and female subjects were included in the training program, researchers did not find any sex effects in the study. These findings might partially support the modulatory effect of resistance training on the endoplasmic reticulum in the elderly. "Regular physical activity is suggested to be an effective intervention in improving age-related diseases such as osteoporosis, sarcopenia or muscle loss and dynapenia or loss of muscle strength, cardiovascular diseases, and type 2 diabetes," said Chun-Jung "Phil" Huang, Ph.D., co-author and a professor in the Department of Exercise Science and Health Promotion within FAU's Charles E. Schmidt College of Science. "Although the beneficial effects of regular physical exercise to alleviate inflammation and oxidative stress are well-established, the processes of these physiological adaptations with regard to protein folding or UPR remains to be explored. That is why we used a systems biology approach for our study." The resistance training protocol for the study consisted of 16 sessions over eight weeks (two sessions per week), with a minimum of 48 hours between sessions. The participants started with a 10-minute warm-up on a cycle ergometer. Subsequently, eight different resistance exercises (leg press, ankle extension, bench press, leg extension, bicep curl, pec deck, high pulley traction, and dumbbell lateral lift) were performed using the exercise device. For each exercise, participants performed three sets of 12-8-12 repetitions. There was a two-to-three-minute rest between each repetition and a three-minute rest between each exercise. "We know how very important physical activity is for older adults and our study takes research one step further in helping to elucidate the benefits of exercise in this population," said Huang. Study co-authors are senior author Brisamar Estébanez, Ph.D.; Marta Rivera-Viloria; and José A. de Paz, M.D., all with the University of León; José E. Vargas, Ph.D., Universidad Federal do Paraná, Curtiba; and Nishant P. Visavadiay, Ph.D.; and Andy V. Kahmoui, Ph.D., both with FAU's Department of Exercise Science and Health Promotion.

Taiho Pharmaceutical Co., Ltd. announced today that it has obtained manufacturing and marketing approval from Japan’s Ministry of Health, Labour and Welfare for the oral heat shock protein (HSP) 90 inhibitor Jeselhy® Tablets 40 mg (generic name: pimitespib; development code: TAS-116), for the indication of gastrointestinal stromal tumor (GIST) that has progressed after chemotherapy. Jeselhy®, a compound discovered by Taiho Pharmaceutical, inhibits HSP90, thereby showing an antitumor effect by destabilizing and reducing proteins such as KIT, PDGFRA, HER2, and EGFR which are involved in the growth and survival of cancer. The approval is based on the results of a Phase III trial (CHAPTER-GIST-301 trial) comparing the efficacy and safety of pimitespib versus placebo in patients with previously treated GIST. In the trial, pimitespib prolonged progression-free survival (PFS), the primary endpoint, and demonstrated adverse events were manageable. The results of this study were published in the Annals of Oncology. *1 Taiho Pharmaceutical will promote the proper use of Jeselhy® Tablets for treating GIST, for which there are major unmet medical needs, to ensure that it can contribute to the needs of patients with GIST and healthcare professionals. This was a randomized, double-blind, PhaseIII, clinical trial comparing pimitespib with placebo in patients with GIST judged to be refractory to or intolerant of standard treatments. The primary endpoint in this trial was PFS, and the secondary endpoint measures included overall survival (OS) and safety, as well as quality of life (QOL). Eighty-six GIST patients who were at least 20 years old, and had previously been treated with imatinib, sunitinib, and regorafenib, were enrolled between October 2018 and April 2020 from six Japanese medical institutions specialized in GIST. For more information on the CHAPTER-GIST-301 trial, please visit (JapicCTI-184094) https://www.clinicaltrials.jp/cti-user/trial/Search.jsp CHAPTER-GIST-301 trial: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER TRIAL OF TAS-116 IN PATIENTS WITH ADVANCED GASTROINTESTINAL STROMAL TUMOR, CHAPTER; The molecular CHAperone heat shock protein 90 (HSP90) inhibitor, PimiTEspib GIST develops in the walls of the gastrointestinal tract (frequently in the stomach and small intestine and rarely in the large intestine and esophagus) and is a type of malignant tumor (sarcoma) that causes metastasis and relapses. It has different characteristics than gastric and colorectal cancers that develop from mucous membrane.*2 The incidence in Japan is estimated to be roughly 1,500 to 2,500 patients per year (calculated based on the annual incidence rate reported in different countries),*3 making it a rare cancer. In many cases of GIST, there are mutations in the KIT and PDGFRA genes, which are involved in the growth and survival of cancer. All GIST treatments approved by the three regulatory authorities of Japan’s Ministry of Health, Labour and Welfare, the U.S. Food and Drug Administration (FDA), and the European Medicines Agency (EMA) have as their main mechanism of action the inhibition of receptor tyrosine kinases KIT and PDGFRA. There is an unmet medical need for a therapeutic agent to treat GIST that remains after treatment with the drugs currently approved. Cells are constantly exposed to various stresses within the body. Cancer cells in particular are exposed to a lot of stress in the form of hypoxia, malnutrition, elimination by the immune system, and genetic instability. Expression of HSP90 increases in response to stress, protecting cells from stress and promoting cell survival by maintaining the structural and functional integrity of proteins. HSP90 is overexpressed and exists in a highly active state in cancer cells and tumor tissue, where it is known to be especially important in the survival and maintenance of cancer. Furthermore, it has been reported that the expression of HSP90 in GIST, bladder cancer, acute myelocytic leukemia, breast cancer, non-small cell lung cancer, colorectal cancer, and melanoma correlates with cancer progression and/or a patient’s prognosis. *4 *1: References Kurokawa Y, Honma Y, Sawaki A, Naito Y, Iwagami S, Komatsu Y, et al. Pimitespib in patients with advanced gastrointestinal stromal tumor (CHAPTER-GIST-301): a randomized, double-blind, placebo-controlled phase 3 trial. Ann Oncol. 2022. doi: 10.1016/j.annonc.2022.05.518. *2: See the Cancer Information Service of the National Cancer Center Japan (in Japanese). *3: References 1.Goettsch WG, Bos SD, Breekveldt-Postma N, Casparie M, Herings RM, Hogendoorn PC. Incidence of gastrointestinal stromal tumours is underestimated: Results of a nation-wide study. Eur J Cancer. 2005;41:2868-2872. 2.Tryggvason G, Gíslason HG, Magnússon MK, Jónasson JG. Gastrointestinal stromal tumors in Iceland, 1990-2003: the icelandic GIST study, a population-based incidence and pathologic risk stratification study. Int J Cancer. 2005;117:289-293. 3.Nilsson B, Bümming P, Meis-Kindblom JM, Odén A, Dortok A, Gustavsson B, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in western Sweden. Cancer. 2005;103:821-829. 4.Chan KH, Chan CW, Chow WH, Kwan WK, Kong CK, Mak KF, et al. Gastrointestinal stromal tumors in a cohort of Chinese patients in Hong Kong. World J Gastroenterol. 2006;12:2223-2228. *4: References 1.Li CF, Huang WW, Wu JM, Yu SC, Hu TH, Uen YH, et al. Heat shock protein 90 overexpression independently predicts inferior disease-free survival with differential expression of the alpha and beta isoforms in gastrointestinal stromal tumors. Clin Cancer Res. 2008;14:7822-7831. 2.Lebret T, Watson RW, Molinié V, O'Neill A, Gabriel C, Fitzpatrick JM, et al. Heat shock proteinsHSP27, HSP60, HSP70, and HSP90: expression in bladder carcinoma. Cancer. 2003;98:970-977 3.Thomas X, Campos L, Mounier C, Cornillon J, Flandrin P, Le QH, et al. Expression of heat-shock proteins is associated with major adverse prognostic factors in acute myeloid leukemia. Leuk Res.2005;29:1049-1058. 4.Pick E, Kluger Y, Giltnane JM, Moeder C, Camp RL, Rimm DL, et al. High HSP90 expression is associated with decreased survival in breast cancer. Cancer Res. 2007;67:2932-2937. 5.Gallegos Ruiz MI, Floor K, Roepman P, Rodriguez JA, Meijer GA, Mooi WJ, et al. Integration of gene dosage and gene expression in non-small cell lung cancer, identification of HSP90 as potential target. PLoS One. 2008;3:e0001722. 6． Milicevic Z, Bogojevic D, Mihailovic M, Petrovic M, Krivokapic Z. Molecular characterization ofhsp90 isoforms in colorectal cancer cells and its association with tumour progression. Int J Oncol.2008; 32:1169-1178. 7.McCarthy MM, Pick E, Kluger Y, Gould-Rothberg B, Lazova R, Camp RL, et al. HSP90 as a marker of progression in melanoma. Ann Oncol. 2008;19:590-594. Product name Jeselhy® Tablets 40mg Generic name Pimitespib Indications GIST that has progressed after chemotherapy Dosage and administration The usual dosage of 160 mg (as the pimitespib dose) for adults, once a day in the fasting conditions. The oral administration is once a day for 5 consecutive days, followed by a 2-day rest, repeating this cycle subsequently. Dosage should be reduced based on the patient's condition.

Taiho Pharmaceutical Co., Ltd. announced today that it has submitted to the Japanese Ministry of Health, Labour and Welfare a new drug application for TAS-116 (Oral Heat Shock Protein [HSP] 90 inhibitor; generic name: Pimitespib) for gastrointestinal stromal tumor (GIST) that has progressed after chemotherapy. The new drug application is based on the results of a Phase III trial (CHAPTER-GIST-301 trial) comparing the efficacy and safety of Pimitespib versus placebo in patients with previously treated GIST. In the trial, Pimitespib prolonged progression-free survival (PFS), the primary endpoint, and demonstrated a safety profile consistent with that observed in earlier clinical trials. The results of the trial were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in June 2021.*1 Taiho Pharmaceutical will continue to work towards obtaining approval, aiming to deliver this new therapeutic agent to patients. This was a randomized, double-blind, Phase III clinical trial comparing TAS-116 to placebo in patients with GIST refractory to standard treatments. The primary endpoint in this trial was PFS, and the secondary endpoint measures included overall survival (OS) and safety, as well as quality of life (QOL). The trial was conducted in Japan with the participation of 81 patients with GIST aged 20 or older who had been treated with imatinib, sunitinib, and regorafenib. For more information on the CHAPTER-GIST-301 trial, please see Japic CTI-184094. https://www.clinicaltrials.jp/cti-user/trial/Search.jsp CHAPTER-GIST-301 trial: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER TRIAL OF TAS-116 IN PATIENTS WITH ADVANCED GASTROINTESTINAL STROMAL TUMOR, CHAPTER; The molecular CHAperone heat shock protein 90 (HSP90) inhibitor, PimiTEspib GIST develops in the walls of the gastrointestinal tract (frequently in the stomach and small intestine and rarely in the large intestine and esophagus) and is a type of malignant tumor (sarcoma) that causes metastasis and relapses. It has different characteristics than gastric and colorectal cancers that develop from mucous membrane.*2 The incidence in Japan is estimated to be roughly 1,500 to 2,500 patients per year (calculated based on the annual incidence rate reported in different countries),*3 making it a rare cancer. In many cases of GIST, there are mutations in the KIT and PDGFRA genes, which are involved in the growth and survival of cancer. All GIST treatments approved by the three regulatory authorities of Japan’s Ministry of Health, Labour and Welfare, the U.S. Food and Drug Administration (FDA), and the European Medicines Agency (EMA) have as their main mechanism of action the inhibition of receptor tyrosine kinases KIT and PDGFRA. There is still a substantial medical need for a therapeutic agent to treat GIST that remains after treatment with the drugs currently approved. Cells are constantly exposed to various stresses within the body. Cancer cells in particular are exposed to a lot of stress in the form of hypoxia, malnutrition, elimination by the immune system, and genetic instability. Expression of HSP90 increases in response to stress, protecting cells from stress and promoting cell survival by maintaining the structural and functional integrity of proteins. HSP90 is overexpressed and exists in a highly active state in cancer cells and tumor tissue, where it is known to be especially important in the survival and maintenance of cancer. Furthermore, it has been reported that the expression of HSP90 in GIST, bladder cancer, acute myelocytic leukemia, breast cancer, non-small cell lung cancer, colorectal cancer, and melanoma correlates with cancer progression and a patient’s prognosis.*4 *1: References: 1. Honma Y, Kurokawa Y, Sawaki A, Naito Y, Iwagami S, Baba H, et al. Randomized, double-blind, placebo (PL)-controlled, phase III trial of pimitespib (TAS-116), an oral inhibitor of heat shock protein 90 (HSP90), in patients (pts) with advanced gastrointestinal stromal tumor (GIST) refractory to imatinib (IM), sunitinib (SU) and regorafenib (REG). J Clin Oncol (2021) 39(15):11524. doi: 10.1200/JCO.2021.39.15_suppl.11524 *2: See the Cancer Information Service of the National Cancer Center Japan. *3: References: 1.Goettsch WG, Bos SD, Breekveldt-Postma N, Casparie M, Herings RM, Hogendoorn PC. Incidence of gastrointestinal stromal tumours is underestimated: Results of a nation-wide study. Eur J Cancer. 2005;41:2868-2872. 2.Tryggvason G, Gíslason HG, Magnússon MK, Jónasson JG. Gastrointestinal stromal tumors in Iceland, 1990-2003: the icelandic GIST study, a population-based incidence and pathologic risk stratification study. Int J Cancer. 2005;117:289-293. 3.Nilsson B, Bümming P, Meis-Kindblom JM, Odén A, Dortok A, Gustavsson B, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in western Sweden. Cancer. 2005;103:821-829. 4.Chan KH, Chan CW, Chow WH, Kwan WK, Kong CK, Mak KF, et al. Gastrointestinal stromal tumors in a cohort of Chinese patients in Hong Kong. World J Gastroenterol. 2006;12:2223-2228. *4: References: 1.Li CF, Huang WW, Wu JM, Yu SC, Hu TH, Uen YH, et al. Heat shock protein 90 over expression independently predicts inferior disease-free survival with differential expression of the alpha and beta isoforms in gastrointestinal stromal tumors. Clin Cancer Res. 2008;14:7822-7831. 2.Lebret T, Watson RW, Molinié V, O'Neill A, Gabriel C, Fitzpatrick JM, et al. Heat shock proteinsHSP27, HSP60, HSP70, and HSP90: expression in bladder carcinoma. Cancer. 2003;98:970-977 3.Thomas X, Campos L, Mounier C, Cornillon J, Flandrin P, Le QH, et al. Expression of heat-shock proteins is associated with major adverse prognostic factors in acute myeloid leukemia. Leuk Res.2005;29:1049-1058. 4.Pick E, Kluger Y, Giltnane JM, Moeder C, Camp RL, Rimm DL, et al. High HSP90 expression isassociated with decreased survival in breast cancer. Cancer Res. 2007;67:2932-2937. 5.Gallegos Ruiz MI, Floor K, Roepman P, Rodriguez JA, Meijer GA, Mooi WJ, et al. Integration of gene dosage and gene expression in non-small cell lung cancer, identification of HSP90 as potential target. PLoS One. 2008;3:e0001722. 6. Milicevic Z, Bogojevic D, Mihailovic M, Petrovic M, Krivokapic Z. Molecular characterization ofhsp90 isoforms in colorectal cancer cells and its association with tumour progression. Int J Oncol.2008;32:1169-1178. 7. McCarthy MM, Pick E, Kluger Y, Gould-Rothberg B, Lazova R, Camp RL, et al. HSP90 as a marker of progression in melanoma. Ann Oncol. 2008;19:590-594.