Retaspimycin hydrochloride (IPI-504): a novel heat shock protein inhibitor as an anticancer agent

Hanson, Britt; Vesole, David H.

doi:10.1517/13543780903158934

Cited by 49 publications

(31 citation statements)

References 18 publications

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“…[41][42][43][44][45][46][47] A few examples of UPR-targeted cancer drugs in development and their mechanisms include Bortezomib (proteasome inhibitor), Tanespimycin (HSP90 inhibitor), Retaspimycin (HSP90 inhibitor), Versipelostatin (GRP78 inhibitor), and Irestatins (IRE1a inhibitor). [48][49][50] The purpose of these studies was to evaluate an immunotherapeutic approach for targeting the XBP1, an important transcription activator of UPR, in a variety of solid tumor. Previously, we identified highly immunogenic heteroclitic XBP1 US [184][185][186][187][188][189][190][191][192] (YISPWILAV) and XBP1 SP 367-375 (YLFPQLISV) peptides with higher HLA-A2 binding affinities and stabilities than their native counterparts.…”

Section: Discussionmentioning

confidence: 99%

Heteroclitic XBP1 peptides evoke tumor-specific memory cytotoxic T lymphocytes against breast cancer, colon cancer, and pancreatic cancer cells

et al. 2014

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Keywords: breast / colon / pancreatic cancer, cancer vaccine, heteroclitic peptides, XBP1XBP1 is a critical transcriptional activator of the unfolded protein response (UPR), which increases tumor cell survival under prolonged endoplasmic reticulum (ER) stress and hypoxic conditions.This study was designed to evaluate the immunogenicity of heteroclitic XBP1 unspliced (US) [184][185][186][187][188][189][190][191][192] (YISPWILAV) and heteroclictic XBP1 spliced (SP) [367][368][369][370][371][372][373][374][375] (YLFPQLISV) HLA-A2 peptides, and to characterize the specific activities of XBP1 peptides-specific cytotoxic T lymphocytes (XBP1-CTL) against breast cancer, colon cancer, and pancreatic cancer cells.The XBP1-CTL had upregulated expression of critical T cell markers and displayed HLA-A2-restricted and antigen-specific activities against breast cancer, colon cancer and pancreatic cancer cells. XBP1-CTL were enriched withCD45RO C memory CTL, which showed high expression of critical T cell markers (CD28, ICOS, CD69, CD40L), cell proliferation and antitumor activities as compared to CD45RO ¡ non-memory CTL. The effector memory (EM: CD45RO C CCR7 ¡ ) subset had the highest level of cell proliferation while the central memory (CM: CD45ROC CCR7 C ) subset demonstrated enhanced functional activities (CD107a degranulation, IFNg/IL-2 production) upon recognition of the respective tumor cells. Furthermore, both the EM and CM XBP1-CTL subsets expressed high levels of Th1 transcription regulators Tbet and Eomes. The highest frequencies of IFNg or granzyme B producing cells were detected within CM XBP1-CTL subset that were either Tbet C or Eomes C in responding to the tumor cells.These results demonstrate the immunotherapeutic potential of a cocktail of immunogenic HLA-A2 specific heteroclitic XBP1 US [184][185][186][187][188][189][190][191][192] and heteroclictic XBP1 SP 367-375 peptides to induce CD3 C CD8C CTL enriched for CM and EM cells with specific antitumor activities against a variety of solid tumors.

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Section: Discussionmentioning

confidence: 99%

Heteroclitic XBP1 peptides evoke tumor-specific memory cytotoxic T lymphocytes against breast cancer, colon cancer, and pancreatic cancer cells

et al. 2014

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“…The prototype molecule geldanamycin and its 2 analogues 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) showed unacceptable toxicities or unsatisfactory pharmaceutical properties (9)(10)(11). The hydroquinone hydrochloride salt of 17-AAG (IPI-504, retaspimycin hydrochloride), has a more favorable pharmacologic profile (15)(16). More recently, a related compound, the orally bioavailable IPI-493 [17-amino-17-demethoxygeldanamycin (17-AG)] has shown promising results in preclinical models (17).…”

Section: Introductionmentioning

confidence: 99%

The Novel HSP90 Inhibitor, IPI-493, Is Highly Effective in Human Gastrostrointestinal Stromal Tumor Xenografts Carrying Heterogeneous KIT Mutations

Floris

Sciot

Woźniak

et al. 2011

Clinical Cancer Research

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Purpose: KIT activity is crucial for gastrointestinal stromal tumors (GIST). Imatinib (IMA) and sunitinib (SUN) are very effective KIT-inhibitors in patients with advanced GIST but have no curative potential. We evaluated the efficacy of the novel HSP90 inhibitor IPI-493 alone, or in combination with IMA or SUN in GIST xenografts with KIT mutations.Experimental Design: Nude mice (n ¼ 98) were grafted bilaterally with human GIST carrying KIT exon 11 (GIST-PSW), KIT exon 9 (GIST-BOE), or double, KIT imatinib-sensitive exon 11 and imatinib-resistant exon 17 mutations (GIST-48). Mice were divided into six treatment groups and dosed orally for 15 days as follows: (i) control group, sterile water; (ii) IMA alone; (iii) SUN alone; (iv) IPI-493 alone; (v) IPI-493þIMA; and (vi) IPI-493þSUN.Results: Treatment with IPI-493 resulted in tumor growth stabilization, variable proliferation arrest, induction of apoptosis and necrosis, and downregulation of KIT and its signaling cascade, especially in the GIST-BOE model. Significant reduction of vessel density was observed with IPI-493 treatment, and was equal to SUN treatment in GIST-PSW and GIST-BOE xenografts. IPI-493 treatment effects were enhanced in combination with TKIs, especially with IPI-493þSUN. In our hands, IPI-493 showed dose-dependent liver damages.Conclusions: When administered as a single agent in a xenograft model, the HSP90 inhibitor IPI-493 has consistent antitumor activity and induces KIT downregulation in GISTs with heterogeneous KIT mutations. IPI-493 synergizes with TKIs that are commonly used for the treatment of advanced or IMAresistant GIST. The antitumor response of IPI-493 is particularly enhanced in combination with SUN.

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“…Retaspimycin hydrochloride (IPI-504; Infinity Pharmaceuticals), the hydroquinone hydrochloride salt of 17-AAG, is rapidly converted in vivo to 17-AAG and is 4,000-fold more soluble. It can be given intravenously and has a favorable pharmacologic profile, as shown in a number of clinical trials (21,22).…”

Section: Introductionmentioning

confidence: 99%

The Heat Shock Protein 90 Inhibitor IPI-504 Induces KIT Degradation, Tumor Shrinkage, and Cell Proliferation Arrest in Xenograft Models of Gastrointestinal Stromal Tumors

Floris

Dębiec‐Rychter²,

Woźniak³

et al. 2011

Molecular Cancer Therapeutics

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The activity of the receptor tyrosine kinase KIT is crucial for gastrointestinal stromal tumor (GIST) growth and survival. Imatinib and sunitinib are very effective in advanced GIST, but have no curative potential. The observation that heat shock protein 90 (HSP90) inhibition results in KIT degradation prompted us to assess the efficacy of the HSP90 inhibitor retaspimycin hydrochloride (IPI-504) alone or in combination with imatinib or sunitinib in two GIST xenografts with distinctive KIT mutations. Nude mice were grafted with human GIST carrying KIT exon 13 (GIST-882; n ¼ 59) or exon 11 (GIST-PSW; n ¼ 44) mutations and dosed with imatinib (50 mg/kg twice daily), sunitinib (40 mg/kg once daily), IPI-504 (100 mg/kg 3 times per week), IPI-504 þ imatinib, or IPI-504 þ sunitinib. We evaluated tumor volume, proliferation and apoptosis, KIT expression and activation, as well as adverse events during treatment. Treatment with IPI-504 alone resulted in tumor regression, proliferation arrest, and induction of tumor necrosis. We documented downregulation of KIT and its signaling cascade in IPI-504-treated animals. Treatment effects were enhanced by combining IPI-504 with imatinib or sunitinib. On histologic examination, liver damage was frequently observed in animals exposed to combination treatments. In conclusion, IPI-504 shows consistent antitumor activity and induces KIT downregulation in GIST, as a single agent, and is more potent in combination with imatinib or sunitinib.

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Retaspimycin hydrochloride (IPI-504): a novel heat shock protein inhibitor as an anticancer agent

Cited by 49 publications

References 18 publications

Heteroclitic XBP1 peptides evoke tumor-specific memory cytotoxic T lymphocytes against breast cancer, colon cancer, and pancreatic cancer cells

Heteroclitic XBP1 peptides evoke tumor-specific memory cytotoxic T lymphocytes against breast cancer, colon cancer, and pancreatic cancer cells

The Novel HSP90 Inhibitor, IPI-493, Is Highly Effective in Human Gastrostrointestinal Stromal Tumor Xenografts Carrying Heterogeneous KIT Mutations

The Heat Shock Protein 90 Inhibitor IPI-504 Induces KIT Degradation, Tumor Shrinkage, and Cell Proliferation Arrest in Xenograft Models of Gastrointestinal Stromal Tumors

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