Heat shock protein antagonists in early stage clinical trials for NSCLC

Hendriks, Lizza; Dingemans, Anne‐Marie C.

doi:10.1080/13543784.2017.1302428

Cited by 52 publications

(46 citation statements)

References 63 publications

(66 reference statements)

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“…We noted that the AEs with TAS-116 were similar to those reported with previous clinical studies of HSP90 inhibitors: gastrointestinal disorders, hepatic enzyme increased, and eye disorders such as night blindness and blurred vison (12,13,17,18).…”

Section: Discussionsupporting

confidence: 83%

“…HSP90 has been regarded as one of targets for cancer treatment, as HSP90 inhibition may block multiple signaling pathways in tumor cells, resulting in potent, selective anticancer activity (1,3,5). Although many HSP90 inhibitors including ansamycine-, purine-, and resorcinol derivatives have been developed, none of them have been approved for any cancer indication due to their limited single-agent clinical activity and off-target and/or HSPrelated toxicities, such as eye disorders (10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

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First-in-Human Phase I Study of an Oral HSP90 Inhibitor, TAS-116, in Patients with Advanced Solid Tumors

Shimomura

Yamamoto

Kondo

et al. 2019

Molecular Cancer Therapeutics

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HSP90 is involved in stability and function of cancer-related proteins. This study was conducted to define the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of TAS-116, a novel class, orally available, highly selective inhibitor of HSP90. Patients with advanced solid tumors received TAS-116 orally once daily (QD, step 1) or every other day (QOD, step 2) in 21-day cycles. Each step comprised a dose escalation phase to determine MTD and an expansion phase at the MTD. In the dose escalation phase, an accelerated dose-titration design and a "3þ3" design were used. Sixty-one patients were enrolled in Japan and the United Kingdom. MTD was determined to be 107.5 mg/m 2 /day for QD, and 210.7 mg/m 2 /day for QOD. In the expansion phase of step 1, TAS-116 was administered 5 days on/2 days off per week (QD Â 5). The most common treatment-related adverse events included gastrointestinal disorders, creatinine increases, AST increases, ALT increases, and eye disorders. Eye disorders have been reported with HSP90 inhibitors; however, those observed with TAS-116 in the expansion phases were limited to grade 1. The systemic exposure of TAS-116 increased dose-proportionally with QD and QOD regimens. Two patients with non-small cell lung cancer and one patient with gastrointestinal stromal tumor (GIST) achieved a confirmed partial response. TAS-116 had an acceptable safety profile with some antitumor activity, supporting further development of this HSP90 inhibitor. This is a result from a first-inhuman study, in which the HSP90 inhibitor TAS-116 demonstrated preliminary antitumor efficacy in patients with advanced solid tumors, including those with heavily pretreated GIST.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

First-in-Human Phase I Study of an Oral HSP90 Inhibitor, TAS-116, in Patients with Advanced Solid Tumors

Shimomura

Yamamoto

Kondo

et al. 2019

Molecular Cancer Therapeutics

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“…In fact inhibitors of several HSPs are under clinical trials (see e.g. [108]). We found that one FDA approved drug Gilotrif, which is a client of HSP90, together with a HSP90 inhibitor showed much better anti-cancer effects than using Gilotrif alone in in vivo animal study (see Table 1).…”

Section: Targeting Hsp90 Alonementioning

confidence: 99%

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

Fung¹,

Kong²

2017

JCT

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Heat shock proteins (HSPs) serve to correct proteins' conformation, send the damaged proteins for degradation (quality control function). Heat shock factors (HSFs) are their transcription factors. The protein complexes mTOR1 and 2 (with the same core mTOR), the phosphoinositide-dependent protein kinase-1 (PDK1), the seine/threonine-specific protein kinase (Akt), HSF1, plus their associated proteins form a network participating in protein synthesis, bio-energy generation, signaling for apoptosis with the help of HSPs. A cancer cell synthesizes proteins at fast rate and needs more HSPs to work on quality control. Shutting down this network would lead to cell death. Thus inhibitors of mTOR (mTORI) and inhibitors of HSPs (HSPI) could drive cancer cell to apoptosis-a "passive approach". On the other hand, HSPs form complexes with polypeptides characteristic of the cancer cells; on excretion from the cell, they becomes antigens for the immunity cells, eventually leading to maturation of the cytotoxic T cells, forming the basic principle of preparing cancer-specific, person-specific vaccine. Recent finding shows that HSP70 can penetrate cancer cell and expel its analog to extracellular region, giving the hope to prepare a non-person-specific vaccine covering a variety of cancers. Activation of anti-cancer immunity is the "active approach". On the other hand, mild hyperthermia, with increase of intracellular HSPs, has been found to activate the immunity response, and demonstrate anti-cancer effects. There are certain "mysteries" behind the mechanisms of the active and passive approaches. We analyze the mechanisms involved and provide explanations to some mysteries. We also suggest future research to improve our understanding of these two approaches, in which HSPs play many roles.

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“…2c ), indicating the effectiveness of NCT-50 in suppressing the tumorigenicity of NSCLC cells, regardless of their drug resistance status. NCT-50 displayed weak but comparable cytotoxic effects in NSCLC cells compared with known Hsp90 inhibitors that have been evaluated in clinical trials such as ganetespib and PU-H71 31 , 32 (Fig. 2d ).…”

Section: Resultsmentioning

confidence: 92%

Development of a novel Hsp90 inhibitor NCT-50 as a potential anticancer agent for the treatment of non-small cell lung cancer

Hyun

Nguyen

et al. 2018

Sci Rep

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Despite the development of advanced therapeutic regimens such as molecular targeted therapy and immunotherapy, the 5-year survival of patients with lung cancer is still less than 20%, suggesting the need to develop additional treatment strategies. The molecular chaperone heat shock protein 90 (Hsp90) plays important roles in the maturation of oncogenic proteins and thus has been considered as an anticancer therapeutic target. Here we show the efficacy and biological mechanism of a Hsp90 inhibitor NCT-50, a novobiocin-deguelin analog hybridizing the pharmacophores of these known Hsp90 inhibitors. NCT-50 exhibited significant inhibitory effects on the viability and colony formation of non-small cell lung cancer (NSCLC) cells and those carrying resistance to chemotherapy. In contrast, NCT-50 showed minimal effects on the viability of normal cells. NCT-50 induced apoptosis in NSCLC cells, inhibited the expression and activity of several Hsp90 clients including hypoxia-inducible factor (HIF)-1α, and suppressed pro-angiogenic effects of NSCLC cells. Further biochemical and in silico studies revealed that NCT-50 downregulated Hsp90 function by interacting with the C-terminal ATP-binding pocket of Hsp90, leading to decrease in the interaction with Hsp90 client proteins. These results suggest the potential of NCT-50 as an anticancer Hsp90 inhibitor.

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Heat shock protein antagonists in early stage clinical trials for NSCLC

Cited by 52 publications

References 63 publications

First-in-Human Phase I Study of an Oral HSP90 Inhibitor, TAS-116, in Patients with Advanced Solid Tumors

First-in-Human Phase I Study of an Oral HSP90 Inhibitor, TAS-116, in Patients with Advanced Solid Tumors

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

Development of a novel Hsp90 inhibitor NCT-50 as a potential anticancer agent for the treatment of non-small cell lung cancer

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