Panobinostat mediated cell death: a novel therapeutic approach for osteosarcoma

Wirries, André; Jabari, Samir; Jansen, Esther P.; Roth, Silvia; Figueroa‐Juárez, Elizabeth; Wissniowski, TT; Neureiter, Daniel; Klieser, E.; Lechler, Philipp; Ruchholtz, Steffen; Bartsch, Detlef K.; Boese, Christoph Kolja; Fazio, Pietro Di

doi:10.18632/oncotarget.26038

Cited by 22 publications

(17 citation statements)

References 46 publications

(58 reference statements)

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“…We consistently observed that the HDAC inhibitor panobinostat compromised the survival of all osteosarcoma cell lines at low concentrations. These observations are consistent with studies examining the in vitro effects of panobinostat and other broad‐spectrum HDAC inhibitors such as vorinostat on osteosarcoma cell lines 12,21 . Independent studies conducting an in vitro screen of drug efficacy on three osteosarcoma PDXs also identified HDAC inhibitors and specifically panobinostat as effective at inducing osteosarcoma cell death 20 .…”

Section: Discussionsupporting

confidence: 78%

Histone deacetylase inhibition prevents the growth of primary and metastatic osteosarcoma

McGuire

Nerlakanti

et al. 2020

Intl Journal of Cancer

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Overall survival rates for patients with advanced osteosarcoma have remained static for over three decades. An in vitro analysis of osteosarcoma cell lines for sensitivity to an array of approved cancer therapies revealed that panobinostat, a broad spectrum histone deacetalyase (HDAC) inhibitor, is highly effective at triggering osteosarcoma cell death. Using in vivo models of orthotopic and metastatic osteosarcoma, here we report that panobinostat impairs the growth of primary osteosarcoma in bone and spontaneous metastasis to the lung, the most common site of metastasis for this disease. Further, pretreatment of mice with panobinostat prior to tail vein inoculation of osteosarcoma prevents the seeding and growth of lung metastases. Additionally, panobinostat impaired the growth of established lung metastases and improved overall survival, and these effects were also manifest in the lung metastatic SAOS2-LM7 model. Mechanistically, the efficacy of panobinostat was linked to high expression of HDAC1 and HDAC2 in osteosarcoma, and silencing of HDAC1 and 2 greatly reduced osteosarcoma growth in vitro. In accordance with these findings, treatment with the HDAC1/2 selective inhibitor romidepsin compromised the growth of osteosarcoma in vitro and in vivo. Analysis of patient-derived xenograft osteosarcoma cell lines further demonstrated the sensitivity of the disease to panobinostat or romidepsin. Collectively, these studies provide rationale for clinical trials in osteosarcoma patients using the approved therapies panobinostat or romidepsin.

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Section: Discussionsupporting

confidence: 78%

Histone deacetylase inhibition prevents the growth of primary and metastatic osteosarcoma

McGuire

Nerlakanti

et al. 2020

Intl Journal of Cancer

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“…For these drugs we also found in vitro data for effect in osteosarcoma cell lines, separate and independent of the experiments already included in PharmacoDB. These drugs include dinaciclib 31 , panobinostat 32 , trametinib 33 , TAE684 34 (ceritinib), pictilisib 35 , and tozasertib 36 . Interestingly, TAE684 (ceritinib) was previously found to reverse cisplatin resistance in vitro in osteosarcoma by our own sarcoma research group 34 .…”

Section: Gene Sets Regulated By the Mirna Profiles Are Strongly Prognmentioning

confidence: 99%

MicroRNA-mRNA networks define translatable molecular outcome phenotypes in osteosarcoma

Lietz

Garbutt

Barry

et al. 2020

Sci Rep

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there is a lack of well validated prognostic biomarkers in osteosarcoma, a rare, recalcitrant disease for which treatment standards have not changed in over 20 years. We performed microRNA sequencing in 74 frozen osteosarcoma biopsy samples, constituting the largest single center translationally analyzed osteosarcoma cohort to date, and we separately analyzed a multi-omic dataset from a large nci supported national cooperative group cohort. We validated the prognostic value of candidate microRnA signatures and contextualized them in relevant transcriptomic and epigenomic networks. our results reveal the existence of molecularly defined phenotypes associated with outcome independent of clinicopathologic features. through machine learning based integrative pharmacogenomic analysis, the microRNA biomarkers identify novel therapeutics for stratified application in osteosarcoma. The previously unrecognized osteosarcoma subtypes with distinct clinical courses and response to therapy could be translatable for discerning patients appropriate for more intensified, less intensified, or alternate therapeutic regimens.

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“…Autophagy is a metabolic and circulatory process in which cells decompose damaged organelles and proteins and release decomposition products [7]. It has been reported that autophagy regulates many pathological and physiological processes, such as cell differentiation and death, immune stress, inflammatory reaction, and antiaging [7][8][9][10][11]. Nevertheless, autophagy had dual effects in the process of tumorigenesis and tumor progression.…”

Section: Introductionmentioning

confidence: 99%

Systematic profiling of diagnostic and prognostic value of autophagy-related genes for sarcoma patients

Wang

Shao

et al. 2021

BMC Cancer

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Background Autophagy-related genes (ARGs) have been confirmed to have an important role in tumorigenesis and tumor microenvironment formation. Nevertheless, a systematic analysis of ARGs and their clinical significance in sarcoma patients is lacking. Methods Gene expression files from The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression (GTEx) were used to select differentially expressed genes (DEGs). Differentially expressed ARGs (DEARGs) were determined by matching the DEG and HADb gene sets, which were evaluated by functional enrichment analysis. Unsupervised clustering of the identified DEARGs was conducted, and associations with tumor microenvironment (TME), immune checkpoints, and immune cells were analyzed simultaneously. Two prognostic signatures, one for overall survival (OS) and one for disease-free survival (DFS), were established and validated in an independent set. Results In total, 84 DEARGs and two clusters were identified. TME scores, five immune checkpoints, and several types of immune cells were found to be significantly different between two clusters. Two prognostic signatures incorporating DEARGs showed favorable discrimination and were successfully validated. Two nomograms combining signature and clinical variables were generated. The C-indexes were 0.818 and 0.747 for the OS and DFS nomograms, respectively. Conclusion This comprehensive analyses of the ARG landscape in sarcoma showed novel ARGs related to carcinogenesis and the immune microenvironment. These findings have implications for prognosis and therapeutic responses, which reveal novel potential prognostic biomarkers, promote precision medicine, and provide potential novel targets for immunotherapy.

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Panobinostat mediated cell death: a novel therapeutic approach for osteosarcoma

Cited by 22 publications

References 46 publications

Histone deacetylase inhibition prevents the growth of primary and metastatic osteosarcoma

Histone deacetylase inhibition prevents the growth of primary and metastatic osteosarcoma

MicroRNA-mRNA networks define translatable molecular outcome phenotypes in osteosarcoma

Systematic profiling of diagnostic and prognostic value of autophagy-related genes for sarcoma patients

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