In vivo synergism between PARP-inhibitor olaparib and HSP90-inhibitor AT13387 in high grade serous ovarian cancer patient derived xenografts.

Konstantinopoulos, Panagiotis A.; Palakurthi, Sangeetha; Zeng, Qing; Zhou, Shan; Liu, Joyce F.; Ivanova, Elena; Paweletz, Cloud P.; Kommajosyula, Naveen; D’Andrea, Alan D.; Shapiro, Geoffrey I.; Matulonis, Ursula A.

doi:10.1200/jco.2016.34.15_suppl.e17045

Cited by 6 publications

(3 citation statements)

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“…10,11 These findings are also in line with abstract describing synergy effects in HGSOC patient-derived xenograft models treated with the HSP90i AT13387 and olaparib. 48 Taken together, the findings herein support the hypothesis that via HSP90 blockade, synthetic lethality can be achieved in HGSOC cells that would otherwise not respond well to PARP inhibition. Moreover, our findings may suggest a potential method for overcoming PARP inhibitor resistance, an important emerging clinical issue as the indications for PARP inhibitor therapy continue to expand in both the treatment and maintenance therapy settings.…”

Section: Discussionsupporting

confidence: 77%

Targeted blockade of HSP90 impairs DNA-damage response proteins and increases the sensitivity of ovarian carcinoma cells to PARP inhibition

Gabbasov

Benrubi

O'Brien

et al. 2019

Cancer Biology & Therapy

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Pharmacological inhibition of PARP is a promising approach in treating high grade serous ovarian carcinoma (HGSOC). PARP inhibitors (PARPi) are most active in patients with defects in DNA damage repair (DDR) mechanisms, such as alterations in expression/function of DNA repair and homologous recombination (HR) genes/proteins, including BRCA1 and BRCA2. Benefit of PARPi could be extended towards HR-proficient patients by combining PARPi with agents that functionally abrogate HR. An attractive molecular target for this purpose is heat shock protein 90 (HSP90), which mediates the maturation and stability of several key proteins required for DDR. Here, we tested the hypothesis that targeted inhibition of HSP90 with a small-molecule inhibitor ganetespib would sensitize non-BRCA mutant ovarian carcinoma (OC) cells to PARP inhibition by talazoparib. We used commercially available cell lines, along with several novel HGSOC OC cell lines established in our laboratory. Ganetespib treatment destabilized HSP90 client proteins involved in DNA damage response and cell cycle checkpoint, and disrupted γ-irradiation-induced DNA repair. The effects of the combination of ganetespib and talazoparib on OC cell viability and survival were also analyzed, and among the non-BRCA mutant cell lines analyzed, the combination was synergistic in several cell lines (OVCAR-3, OC-1, OC-16). Together, our data suggest that ganetespib-mediated inhibition of HSP90 effectively disrupts critical DDR pathway proteins and may sensitize OC cells without 'BRCAness' to PARPi. From a clinical perspective, this suggests that HSP90 inhibition has the potential to sensitize some HGSOC patients without HR pathway alterations to PARPi, and potentially other DNA-damage inducing agents.

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Section: Discussionsupporting

confidence: 77%

Targeted blockade of HSP90 impairs DNA-damage response proteins and increases the sensitivity of ovarian carcinoma cells to PARP inhibition

Gabbasov

Benrubi

O'Brien

et al. 2019

Cancer Biology & Therapy

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“…In a single-arm phase II clinical study, Olaparib had a 50% observed objective response rate and a 60% disease control rate in advanced cancer patients with germline BRCA1/2 mutation [ 47 ]. And Konstantinopoulos P et al reported that there was in vivo synergism between the heat shock protein (HSP) 90 inhibitor AT13387 Onalespib and the PARP inhibitor Olaparib [ 48 ]. These are encouraging outcomes.…”

Section: Discussionmentioning

confidence: 99%

Novel cuproptosis-related long non-coding RNA signature to predict prognosis in prostate carcinoma

et al. 2023

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Background Cuproptosis, an emerging form of programmed cell death, has recently been identified. However, the association between cuproptosis-related long non-coding RNA (lncRNA) signature and the prognosis in prostate carcinoma remains elusive. This study aims to develop the novel cuproptosis-related lncRNA signature in prostate cancer and explore its latent molecular function. Methods RNA-seq data and clinical information were downloaded from the TCGA datasets. Then, cuproptosis-related gene was identified from the previous literature and further applied to screen the cuproptosis-related differentially expressed lncRNAs. Patients were randomly assigned to the training cohort or the validation cohort with a 1:1 ratio. Subsequently, the machine learning algorithms (Lasso and stepwise Cox (direction = both)) were used to construct a novel prognostic signature in the training cohorts, which was validated by the validation and the entire TCGA cohorts. The nomogram base on the lncRNA signature and several clinicopathological traits were constructed to predict the prognosis. Functional enrichment and immune analysis were performed to evaluate its potential mechanism. Furthermore, differences in the landscape of gene mutation, tumour mutational burden (TMB), microsatellite instability (MSI), drug sensitivity between both risk groups were also assessed to explicit their relationships. Results The cuproptosis-related lncRNA signature was constructed based on the differentially expressed cuproptosis-related lncRNAs, including AC005790.1, AC011472.4, AC099791.2, AC144450.1, LIPE-AS1, and STPG3-AS1. Kaplan–Meier survival and ROC curves demonstrate that the prognosis signature as an independent risk indicator had excellent potential to predict the prognosis in prostate cancer. The signature was closely associated with age, T stage, N stage, and the Gleason score. Immune analysis shows that the high-risk group was in an immunosuppressive microenvironment. Additionally, the significant difference in landscape of gene mutation, tumour mutational burden, microsatellite instability, and drug sensitivity between both risk groups was observed. Conclusions A novel cuproptosis-related lncRNA signature was constructed using machine learning algorithms to predict the prognosis of prostate cancer. It was closely with associated with several common clinical traits, immune cell infiltration, immune-related functions, immune checkpoints, gene mutation, TMB, MSI, and the drug sensitivity, which may be useful to improve the clinical outcome.

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“…Heat shock protein 90 ( Hsp90 ) is a crucial molecular chaperone that functions to correctly fold client proteins, and consequently prevents them from degradation by the ubiquitin-proteasome system. In vivo synergism between an HSP90 -inhibitor (AT13387) and olaparib in PARP inhibitor resistant ovarian cancer has been described [126]. Alternatively, the evidence that acquired epigenetic changes, such as hypermethylation promoter of BRCA1 , may restore normal BRCA1 protein expression levels [121].…”

Section: Resistancementioning

confidence: 99%

PARP Inhibitors in Ovarian Cancer: The Route to “Ithaca”

et al. 2019

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Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.

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In vivo synergism between PARP-inhibitor olaparib and HSP90-inhibitor AT13387 in high grade serous ovarian cancer patient derived xenografts.

Cited by 6 publications

References 0 publications

Targeted blockade of HSP90 impairs DNA-damage response proteins and increases the sensitivity of ovarian carcinoma cells to PARP inhibition

Targeted blockade of HSP90 impairs DNA-damage response proteins and increases the sensitivity of ovarian carcinoma cells to PARP inhibition

Novel cuproptosis-related long non-coding RNA signature to predict prognosis in prostate carcinoma

PARP Inhibitors in Ovarian Cancer: The Route to “Ithaca”

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