uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Spiegelberg, Diana
Alternative names
Publications (10 of 39) Show all publications
Lundsten, S., Spiegelberg, D., Raval, N. & Nestor, M. (2020). The radiosensitizer Onalespib increases complete remission in Lu-177-DOTATATE-treated mice bearing neuroendocrine tumor xenografts. European Journal of Nuclear Medicine and Molecular Imaging, 47(4), 980-990
Open this publication in new window or tab >>The radiosensitizer Onalespib increases complete remission in Lu-177-DOTATATE-treated mice bearing neuroendocrine tumor xenografts
2020 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 47, no 4, p. 980-990Article in journal (Refereed) Published
Abstract [en]

Purpose: Lu-177-DOTATATE targeting the somatostatin receptor (SSTR) is utilized for treatment of neuroendocrine tumors (NETs). Onalespib, a heat shock protein 90 (HSP90) inhibitor, has demonstrated radiosensitizing properties and may thus enhance the effect of Lu-177-DOTATATE. Consequently, the aim of this study was to assess the potential of Onalespib in combination with Lu-177-DOTATATE in vivo and to examine the toxicity profiles of the treatments.

Methods: Lu-177-DOTATATE selectivity and distribution in NET xenografts were studied using biodistribution and autoradiography. Therapeutic effects of Onalespib in combination with Lu-177-DOTATATE were studied in NET xenografts. Histological analyses were used to assess molecular effects from treatment and to establish toxicity profiles.

Results: Biodistribution and autoradiography confirmed the SSTR-selective tumor uptake of Lu-177-DOTATATE, which was unaffected by Onalespib treatment. Immunohistochemistry verified molecular responses to Onalespib therapy in the tumors. While Onalespib and Lu-177-DOTATATE monotherapies resulted in a 10% and 33% delay in tumor doubling time compared with control, the combination treatment resulted in a 73% delayed tumor doubling time. Moreover, combination treatment increased complete remissions threefold from Lu-177-DOTATATE monotherapy, resulting in 29% complete remissions. In addition, histological analyses demonstrated radiation-induced glomerular injury in the Lu-177-DOTATATE monotherapy group. The damage was decreased tenfold in the combination group, potentially due to Onalespib-induced HSP70 upregulation in the kidneys.

Conclusion: Treatment with Onalespib potentiated Lu-177-DOTATATE therapy of NET xenografts with a favorable toxicity profile. Utilizing Onalespib's radiosensitizing properties with Lu-177-DOTATATE may lead to better therapeutic results in the future and may reduce unwanted side effects in dose-limiting organs.

Place, publisher, year, edition, pages
SPRINGER, 2020
Keywords
Neuroendocrine cancer, Lu-177-DOTATATE, HSP90, Onalespib, Radiosensitization
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-408510 (URN)10.1007/s00259-019-04673-1 (DOI)000519919200025 ()31912256 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2020-04-09 Created: 2020-04-09 Last updated: 2020-04-09Bibliographically approved
Lundsten, S., Spiegelberg, D., Stenerlöw, B. & Nestor, M. (2019). The HSP90 inhibitor onalespib potentiates Lu-177-DOTATATE therapy in neuroendocrine tumor cells. International Journal of Oncology, 55(6), 1287-1295
Open this publication in new window or tab >>The HSP90 inhibitor onalespib potentiates Lu-177-DOTATATE therapy in neuroendocrine tumor cells
2019 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 55, no 6, p. 1287-1295Article in journal (Refereed) Published
Abstract [en]

Lu-177-DOTATATE was recently approved for the treatment of somatostatin receptor (SSTR)-positive neuroen-docrine tumors (NETs). However, despite impressive response rates, complete responses are rare. Heat shock protein 90 (HSP90) inhibitors have been suggested as suitable therapeutic agents for NETs, as well as a potential radiosensitizers. Consequently, the aim of this study was to investigate whether the HSP90-inhibitor onalespib could reduce NET cell growth and act as a radiosensitizer when used in combination with Lu-177-DOTATATE. The NET cell lines BON, NCI-H727 and NCI-H460, were first characterized with regards to Lu-177-DOTATATE uptake and sensitivity to onalespib treatment in monolayer cell assays. The growth inhibitory effects of the monotherapies and combination treatments were then examined in three-dimensional multicellular tumor spheroids. Lastly, the molecular effects of the treatments were assessed. Lu-177-DOTATATE uptake was observed in the BON and NCI-H727 cells, while the NCI-H460 cells exhibited no detectable uptake. Accordingly, Lu-177-DOTATATE reduced the growth of BON and NCI-H727 spheroids, while no effect was observed in the NCI-H460 spheroids. Onalespib reduced cell viability and spheroid growth in all three cell lines. Furthermore, the combination of onalespib and Lu-177-DOTATATE exerted synergistic therapeutic effects on the BON and NCI-H727 spheroids. Western blot analysis of BON spheroids revealed the downregulation of epidermal growth factor receptor (EGFR) and the upregulation of gamma H2A histone family member X (gamma H2AX) following combined treatment with onalespib and Lu-177-DOTATATE. Moreover, flow cytometric analyses revealed a two-fold increase in caspase 3/7 activity in the combination group. In conclusion, the findings of this study demonstrate that onalespib exerts antitumorigenic effects on NET cells and may thus be a feasible treatment option for NETs. Furthermore, onalespib was able to synergistically potentiate Lu-177-DOTATATE treatment in a SSTR-specific manner. The radiosensitizing mechanisms of onalespib involved the downregulation of EGFR expression and the induction of apoptosis. Consequently, the combination of onalespib and Lu-177-DOTATATE may prove to be a promising strategy with which to improve therapeutic responses in patients with NETs. Further studies investigating this strategy in vivo regarding the therapeutic effects and potential toxicities are warranted to expand these promising findings.

Place, publisher, year, edition, pages
SPANDIDOS PUBL LTD, 2019
Keywords
neuroendocrine neoplasms, neuroendocrine tumors, peptide receptor radionuclide therapy, Lu-177-DOTATATE, Lutathera, heat shock protein 90, onalespib, AT13387, radiosensitization
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-400409 (URN)10.3892/ijo.2019.4888 (DOI)000500272500009 ()31638190 (PubMedID)
Funder
Swedish Cancer Society, CAN 2018/494Swedish Cancer Society, CAN2016/649Swedish Cancer Society, CAN 2015/1080Swedish Cancer Society, CAN 2015/385Swedish Research Council, 2013-30876-104113-30
Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02Bibliographically approved
Lundgren Mortensen, A., Spiegelberg, D., Brown, C. J., Lane, D. P. & Nestor, M. (2019). The Stapled Peptide PM2 Stabilizes p53 Levels and Radiosensitizes Wild-Type p53 Cancer Cells. Frontiers in Oncology, 9, Article ID 923.
Open this publication in new window or tab >>The Stapled Peptide PM2 Stabilizes p53 Levels and Radiosensitizes Wild-Type p53 Cancer Cells
Show others...
2019 (English)In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 9, article id 923Article in journal (Refereed) Published
Abstract [en]

The tumor suppressor p53 is a key mediator of cellular stress and DNA damage response cascades and is activated after exposure to ionizing radiation. Amplifying wild-type p53 expression by targeting negative regulators such as MDM2 in combination with external beam radiotherapy (EBRT) may result in increased therapeutic effects. The novel stapled peptide PM2 prevents MDM2 from suppressing wild-type p53, and is thus a promising agent for therapeutic combination with EBRT. Effects of PM2 and potential PM2-induced radiosensitivity were assessed in a panel of cancer cell lines using 2D cell viability assays. Western Blot and flow cytometric analyses were used to investigate the mechanisms behind the observed effects in samples treated with PM2 and EBRT. Finally, PM2-treatment combined with EBRT was evaluated in an in vitro 3D spheroid model. PM2-therapy decreased cell viability in wild-type p53, HPV-negative cell lines. Western Blotting and flow cytometry confirmed upregulation of p53, as well as initiation of p53-mediated apoptosis measured by increased cleaved caspase-3 and Noxa activity. Furthermore, 3D in vitro tumor spheroid experiments confirmed the superior effects of the combination, as the only treatment regime resulting in growth inhibition and complete spheroid disintegration. We conclude that PM2 induces antitumorigenic effects in wt p53 HPV-negative cancer cells and potentiates the effects of EBRT, ultimately resulting in tumor eradication in a 3D spheroid model. This strategy shows great potential as a new wt p53 specific tumor-targeting compound, and the combination of PM2 and EBRT could be a promising strategy to increase therapeutic effects and decrease adverse effects from radiotherapy.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2019
Keywords
p53, wild-type p53, radiosensitization, external beam radiation therapy (EBRT), PM2, spheroid apoptosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-395461 (URN)10.3389/fonc.2019.00923 (DOI)000487235800001 ()31616635 (PubMedID)
Funder
Swedish Research Council, 2013-30876-104113-30Swedish Cancer Society, CAN 2018/494Swedish Cancer Society, CAN 2015/1080
Available from: 2019-10-31 Created: 2019-10-31 Last updated: 2019-10-31Bibliographically approved
Spiegelberg, D., Mortensen, A. C., Lundsten, S., Brown, C. J., Lane, D. P. & Nestor, M. (2018). First in vivo study of the MDM2/MDMX-p53 antagonist PM2 as potentiator of external radiotherapy in wt p53 cancer. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY. European Journal of Nuclear Medicine and Molecular Imaging, 45(Supplement: 1), S30-S30
Open this publication in new window or tab >>First in vivo study of the MDM2/MDMX-p53 antagonist PM2 as potentiator of external radiotherapy in wt p53 cancer
Show others...
2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, no Supplement: 1, p. S30-S30Article in journal, Meeting abstract (Other academic) Published
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-373337 (URN)10.1007/s00259-018-4148-3 (DOI)000449266200037 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY
Note

Meeting Abstract OP-074

Available from: 2019-01-14 Created: 2019-01-14 Last updated: 2019-01-14Bibliographically approved
Lundsten, S., Spiegelberg, D., Raval, N., Stenerlöw, B. & Nestor, M. (2018). Potentiating Lu-177-DOTATATE Therapy By HSP90 Inhibition - First In Vivo Study. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY. European Journal of Nuclear Medicine and Molecular Imaging, 45, S12-S13
Open this publication in new window or tab >>Potentiating Lu-177-DOTATATE Therapy By HSP90 Inhibition - First In Vivo Study
Show others...
2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S12-S13Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-372968 (URN)000449266200003 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY
Available from: 2019-01-11 Created: 2019-01-11 Last updated: 2019-01-11Bibliographically approved
Mortensen, A., Spiegelberg, D., Haylock, A.-K., Lundqvist, H. & Nestor, M. (2018). Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy. International Journal of Oncology, 52(6), 1875-1885
Open this publication in new window or tab >>Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy
Show others...
2018 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 52, no 6, p. 1875-1885Article in journal (Refereed) Published
Abstract [en]

CD44v6 is overexpressed in a variety of cancers, rendering it a promising target for radio-immunotherapy (RIT). In this study, we have characterized a novel engineered recombinant monoclonal anti-CD44v6 antibody, AbN44v6, and assessed its potential for use in RIT using either Lu-177 or I-131 as therapeutic radionuclides. In vitro affinity and specificity assays characterized the binding of the antibody labeled with Lu-177, I-125 or I-131. The therapeutic effects of Lu-177-AbN44v6 and I-131-AbN44v6 were investigated using two in vitro 3D tumor models with different CD44v6 expression. Finally, the normal tissue biodistribution and dosimetry for Lu-177-AbN44v6 and I-125-AbN44v6/I-131-AbN44v6 were assessed in vivo using a mouse model. All AbN44v6 radioconjugates demonstrated CD44v6-specific binding in vitro. In the in vitro 3D tumor models, dose-dependent therapeutic effects were observed with both Lu-177-AbN44v6 and I-131-AbN44v6, with a greater significant therapeutic effect observed on the cells with a higher CD44v6 expression. Biodistribution experiments demonstrated a greater uptake of Lu-177-AbN44v6 in the liver, spleen and bone, compared to I-125-AbN44v6, whereas I-125-AbN44v6 demonstrated a longer circulation time. In dosimetric calculations, the critical organs for Lu-177-AbN44v6 were the liver and spleen, whereas the kidneys and red marrow were considered the critical organs for I-131-AbN44v6. The effective dose was in the order of 0.1 mSv/MBq for both labels. In conclusion, AbN44v6 bound specifically and with high affinity to CD44v6. Furthermore, in vitro RIT demonstrated growth inhibition in a CD44v6-specific activity-dependent manner for both radioconjugates, demonstrating that both Lu-177-AbN44v6 and I-131-AbN44v6 may be promising RIT candidates. Furthermore, biodistribution and dosimetric analysis supported the applicability of both conjugates for RIT. The CD44v6-specific therapeutic effects observed with radiolabeled AbN44v6 in the 3D tumor models in vitro, combined with the beneficial dosimetry in vivo, render AbN44v6 a potential candidate for RIT.

Place, publisher, year, edition, pages
SPANDIDOS PUBL LTD, 2018
Keywords
radio-immunotherapy, 3D tumor models, dosimetry, biodistribution, Lu-177, I-131
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-356443 (URN)10.3892/ijo.2018.4364 (DOI)000432241200010 ()29658563 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer Society
Available from: 2018-07-31 Created: 2018-07-31 Last updated: 2018-07-31Bibliographically approved
Abramenkovs, A., Spiegelberg, D. & Stenerlöw, B. (2018). Ra223 induced clustered DNA damage reduces cell survival independently of androgen receptor variant 7 expression. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY. European Journal of Nuclear Medicine and Molecular Imaging, 45, S634-S635
Open this publication in new window or tab >>Ra223 induced clustered DNA damage reduces cell survival independently of androgen receptor variant 7 expression
2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S634-S635Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-372955 (URN)000449266206036 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY
Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-01-24Bibliographically approved
Spiegelberg, D., Mortensen, A., Lundsten, S., Brown, C. J., Lane, D. P. & Nestor, M. (2018). The MDM2/MDMX-p53 Antagonist PM2 Radiosensitizes Wild-Type p53 Tumors. Cancer Research, 78(17), 5084-5093
Open this publication in new window or tab >>The MDM2/MDMX-p53 Antagonist PM2 Radiosensitizes Wild-Type p53 Tumors
Show others...
2018 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 17, p. 5084-5093Article in journal (Refereed) Published
Abstract [en]

Radiotherapy amplifies p53 expression in cancer cells with wild-type (wt) p53. Blocking the negative regulators MDM2 and MDMX stabilizes p53 and may therefore potentiate radiotherapy outcomes. In this study, we investigate the efficacy of the novel anti-MDM2/X stapled peptide PM2 alone and in combination with externalgamma radiation in vitro and in vivo. PM2 therapy combined with radiotherapy elicited synergistic therapeutic effects compared with monotherapy in cells with wt p53 in both in vitro and in vivo assays, whereas these effects did not manifest in p53(-/-) cells. Biodistribution and autoradiography of 125I-PM2 revealed high and retained uptake homogenously distributed throughout the tumor. In mice carrying wt p53 tumors, PM2 combined with radiother-apy significantly prolonged the median survival by 50%, whereas effects of PM2 therapy on mutant and p53(-/-) tumors were negligible. PM2-dependent stabilization of p53 was confirmed with ex vivo immunohistochemistry. These data demonstrate the potential of the stapled peptide PM2 as a radiotherapy potentiator in vivo and suggest that clinical application of PM2 with radiotherapy in wt p53 cancers might improve tumor control.

Significance: These findings contribute advances to cancer radiotherapy by using novel p53-reactivating stapled peptides as radiosensitizers in wild-type p53 cancers.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-365821 (URN)10.1158/0008-5472.CAN-18-0440 (DOI)000443753700024 ()30026328 (PubMedID)
Funder
Swedish Research Council, 2013-30876-104113-30Swedish Research Council, 2013-8807Swedish Cancer Society, CAN 2015/1080Swedish Cancer Society, CAN 2015/385
Available from: 2018-11-26 Created: 2018-11-26 Last updated: 2018-11-26Bibliographically approved
Spiegelberg, D. & Nilvebrant, J. (2017). CD44v6-Targeted Imaging of Head and Neck Squamous Cell Carcinoma: Antibody-Based Approaches. Contrast Media & Molecular Imaging, 2017, Article ID 2709547.
Open this publication in new window or tab >>CD44v6-Targeted Imaging of Head and Neck Squamous Cell Carcinoma: Antibody-Based Approaches
2017 (English)In: Contrast Media & Molecular Imaging, ISSN 1555-4309, E-ISSN 1555-4317, Vol. 2017, article id 2709547Article, review/survey (Refereed) Published
Abstract [en]

Head and neck squamous cell carcinoma (HNSCC) is a common and severe cancer with low survival rate in advanced stages. Noninvasive imaging of prognostic and therapeutic biomarkers could provide valuable information for planning and monitoring of the different therapy options. Thus, there is amajor interest in development of new tracers towards cancer-specific molecular targets to improve diagnostic imaging and treatment. CD44v6, an oncogenic variant of the cell surface molecule CD44, is a promising molecular target since it exhibits a unique expression pattern in HNSCC and is associated with drug-and radio-resistance.

In this review we summarize results from preclinical and clinical investigations of radiolabeled anti-CD44v6 antibody-based tracers: full-length antibodies, Fab, F(ab')(2) fragments, and scFvs with particular focus on the engineering of various antibody formats and choice of radiolabel for the use as molecular imaging agents in HNSCC. We conclude that the current evidence points to CD44v6 imaging being a promising approach for providing more specific and sensitive diagnostic tools, leading to customized treatment decisions and functional diagnosis. Improved imaging tools hold promise to enable more effective treatment for head and neck cancer patients.

National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-335835 (URN)10.1155/2017/2709547 (DOI)000404941200001 ()29097914 (PubMedID)
Available from: 2017-12-15 Created: 2017-12-15 Last updated: 2017-12-15Bibliographically approved
Spiegelberg, D. (2017). HSP90 inhibition in angiosarcoma. British Journal of Dermatology, 177(2), 343-344
Open this publication in new window or tab >>HSP90 inhibition in angiosarcoma
2017 (English)In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 177, no 2, p. 343-344Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
WILEY, 2017
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:uu:diva-345889 (URN)10.1111/bjd.15609 (DOI)000407994100015 ()28833016 (PubMedID)
Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-03-13Bibliographically approved
Organisations

Search in DiVA

Show all publications