Lundsten, Sara

##### Alternative names 

### Lundsten Salomonsson, Sara

##### Publications (10 of 16) 

Weber, J., Djurberg, K., Lundsten, S., Kamprath, M., Hoehne, A., Westin, H., . . . Bondza, S. (2023). Modelling ligand depletion for simultaneous affinity and binding site quantification on cells and tissue. Scientific Reports, 13, Article ID 10031. 

Open this publication in new window or tab >>Modelling ligand depletion for simultaneous affinity and binding site quantification on cells and tissue

### Weber, Judith

3B Pharmaceut GmbH, Berlin, Germany..

### Djurberg, Klara

Ridgeview Instruments AB, Uppsala, Sweden..

### Lundsten, Sara

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Ridgeview Instruments AB, Uppsala, Sweden..

### Kamprath, Maria

3B Pharmaceut GmbH, Berlin, Germany..

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2023 (English)In:  Scientific Reports, E-ISSN 2045-2322, Vol. 13, article id 10031Article in journal (Refereed) Published

##### Abstract [en]

The quantification of the number of targets in biological systems is an important parameter to assess the suitability of surface markers as targets for drugs, drug delivery and medical imaging. Likewise, quantifying the interaction with the target in terms of affinity and binding kinetics is essential during drug development. Commonly used approaches to quantify membrane antigens on live cells are based on manual saturation techniques that are labour-intensive, require careful calibration of the generated signal and do not quantify the binding rates. Here, we present how measuring interactions in real-time on live cells and tissue under ligand depletion conditions can be used to simultaneously quantify the kinetic binding parameters as well as the number of available binding sites in a biological system. Suitable assay design was explored with simulated data and feasibility of the method verified with experimental data for exemplary low molecular weight peptide and antibody radiotracers as well as fluorescent antibodies. In addition to revealing the number of accessible target sites and improving the accuracy of binding kinetics and affinities, the presented method does not require knowledge about the absolute signal generated per ligand molecule. This enables a simplified workflow for use with both radioligands and fluorescent binders.

##### Place, publisher, year, edition, pages 

Springer Nature, 2023

##### National Category 

Biochemistry Molecular Biology Biophysics 

##### Identifiers

urn:nbn:se:uu:diva-514064 (URN)10.1038/s41598-023-37015-1 (DOI)001063223800043 ()37340068 (PubMedID)

##### Funder

Uppsala University Available from: 2023-10-16 Created: 2023-10-16 Last updated: 2025-02-20Bibliographically approved

Berglund, H., Lundsten Salomonsson, S., Mohajershojai, T., Ferrer Gago, F. J., Lane, D. P. & Nestor, M. (2023). p53 stabilisation potentiates [177Lu]Lu-DOTATATE treatment in neuroblastoma xenografts. European Journal of Nuclear Medicine and Molecular Imaging

Open this publication in new window or tab >>p53 stabilisation potentiates [177Lu]Lu-DOTATATE treatment in neuroblastoma xenografts

### Berglund, Hanna

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.

### Lundsten Salomonsson, Sara

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Ridgeview Instruments AB, SE-752 38, Uppsala, Sweden.

### Mohajershojai, Tabassom

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.

### Ferrer Gago, Fernando Jose

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2023 (English)In:  European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089Article in journal (Refereed) Epub ahead of print

##### Abstract [en]

Purpose

Molecular radiotherapy is a treatment modality that is highly suitable for targeting micrometastases and [177Lu]Lu-DOTATATE is currently being explored as a potential novel treatment option for high-risk neuroblastoma. p53 is a key player in the proapoptotic signalling in response to radiation-induced DNA damage and is therefore a potential target for radiosensitisation.

Methods

This study investigated the use of the p53 stabilising peptide VIP116 and [177Lu]Lu-DOTATATE, either alone or in combination, for treatment of neuroblastoma tumour xenografts in mice. Initially, the uptake of [177Lu]Lu-DOTATATE in the tumours was confirmed, and the efficacy of VIP116 as a monotherapy was evaluated. Subsequently, mice with neuroblastoma tumour xenografts were treated with placebo, VIP116, [177Lu]Lu-DOTATATE or a combination of both agents.

Results

The results demonstrated that monotherapy with either VIP116 or [177Lu]Lu-DOTATATE significantly prolonged median survival compared to the placebo group (90 and 96.5 days vs. 50.5 days, respectively). Notably, the combination treatment further improved median survival to over 120 days. Furthermore, the combination group exhibited the highest percentage of complete remission, corresponding to a twofold increase compared to the placebo group. Importantly, none of the treatments induced significant nephrotoxicity. Additionally, the therapies affected various molecular targets involved in critical processes such as apoptosis, hypoxia and angiogenesis.

Conclusion

In conclusion, the combination of VIP116 and [177Lu]Lu-DOTATATE presents a promising novel treatment approach for neuroblastoma. These findings hold potential to advance research efforts towards a potential cure for this vulnerable patient population.

##### Place, publisher, year, edition, pages 

Springer, 2023

##### Keywords

Neuroblastoma, Molecular radiotherapy, p53, [177Lu]Lu-DOTATATE, Radiosensitisation 

##### National Category 

Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology 

##### Identifiers

urn:nbn:se:uu:diva-517191 (URN)10.1007/s00259-023-06462-3 (DOI)001085247400001 ()37823909 (PubMedID)

##### Funder

Swedish Childhood Cancer Foundation, PR2020-0023Swedish Research Council, 2020-01377Swedish Cancer Society, CAN 20 0191Swedish Cancer Society, 2018/494Uppsala UniversitySwedish Childhood Cancer Foundation, TJ2021-0072Ulf Lundahls minnesfond 

##### Note

De två första författarna delar förstaförfattarskapet

Available from: 2023-12-05 Created: 2023-12-05 Last updated: 2024-12-06Bibliographically approved

Fernandes, S. R. .., Mohajershojai, T., Lundsten, S., Sarmento, B., Tomé, J. P. .., Nestor, M. & Jha, P. (2023). Photoactive immunoconjugates for targeted photodynamic therapy of cancer. Journal of Photochemistry and Photobiology. B: Biology, 243, Article ID 112716. 

Open this publication in new window or tab >>Photoactive immunoconjugates for targeted photodynamic therapy of cancer

### Fernandes, Sara R.G.

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Centro de Química Estrutural, Institute of Molecular Sciences & Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal:INEB – Instituto Nacional de Engenharia Biomédica, University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.

### Mohajershojai, Tabassom

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.

### Lundsten, Sara

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine. Ridgeview Instruments AB, Uppsala University, Uppsala 752 37, Sweden.

### Sarmento, Bruno

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2023 (English)In:  Journal of Photochemistry and Photobiology. B: Biology, ISSN 1011-1344, E-ISSN 1873-2682, Vol. 243, article id 112716Article in journal (Refereed) Published

##### Abstract [en]

Photodynamic therapy (PDT) has been used as an alternative or as a complement of conventional approaches for cancer treatment. In PDT, the reactive oxygen species (ROS) produced from the interaction between the photosensitizer (PS), visible light and molecular oxygen, kill malignant cells by triggering a cascade of cytotoxic reactions. In this process, the PS plays an extremely important role in the effectiveness of the therapy. In the present work, a new photoimmunoconjugate (PIC), based on cetuximab and the known third generation PS-glycophthalocyanine ZnPcGal4, was synthesized via reductive amination. The rationale behind this was the simultaneous cancer-associated specific targeting of PIC and photosensitization of targeted receptor positive cells. Varied reaction parameters and photodynamic conditions, such as PS concentrations and both type and intensities of light, were optimized. ZnPcGal4 showed significant photoactivity against EGFR expressing A431, EGFR-transfected HCT116 and HT29 cells when irradiated with white light of stronger intensity (38 mW/cm2). Similarly, the synthesized PICs-T1 and T2 also demonstrated photoactivity with high intensity white light. The best optimized PIC: sample 28 showed no precipitation and aggregation when inspected visually and analyzed through SE-HPLC. Fluorescence excitation of sample 28 and 125I-sample 28 radioconjugate (125I-PIC, 125I-radiolabeling yield ≥95%, determined with ITLC) at 660 nm showed presence of appended ZnPcGal4. In addition, simultaneous fluorescence and radioactivity detection of the 125I-PIC in serum and PBS (pH 7.4) for the longest incubated time point of 72 h, respectively, and superimposed signals thereof demonstrated ≥99% of loading and/or labeling yield, assuring overall stability of the PIC and corresponding PIC-radioconjugate w.r.t. both the appended ZnPcGal4 and bound-125I. Moreover, real-time binding analyses on EGFR-transfected HCT116 cells showed specific binding of 125I-PIC**,** suggesting no alternation in the binding kinetics of the mAb after appending it with ZnPcGal4. These results suggest dual potential applications of synthesized PICs both for PDT and radio-immunotherapy of cancer.

##### Place, publisher, year, edition, pages 

Elsevier, 2023

##### National Category 

Medicinal Chemistry 

##### Identifiers

urn:nbn:se:uu:diva-508250 (URN)10.1016/j.jphotobiol.2023.112716 (DOI)001042154000001 ()37126865 (PubMedID)

##### Funder

Swedish Cancer Society, CAN 21/1534Swedish Cancer Society, CAN 20 0191Swedish Research Council, 2020-01377Swedish Childhood Cancer Foundation, PR2020-0023Swedish Childhood Cancer Foundation, TJ2021-0072Ulf Lundahls minnesfond Available from: 2023-07-24 Created: 2023-07-24 Last updated: 2023-08-17Bibliographically approved

Lundsten, S. (2022). Searching for Synergy: Radiosensitization of 177Lu-DOTATATE. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis

Open this publication in new window or tab >>Searching for Synergy: Radiosensitization of 177Lu-DOTATATE

### Lundsten, Sara

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.

2022 (English)Doctoral thesis, comprehensive summary (Other academic)

##### Abstract [en]

Cancers presents a major health challenge, and there is a pressing need to develop new therapeutic strategies. Surgery, chemotherapy and radiation are the most commonly used treatments for cancer today. Radiation can be given as targeted radionuclide therapy (TRT), i.e., systemic administration of a radiolabeled cancer-targeting molecule. This is especially suitable for inoperable and disseminated tumors.

177Lu-DOTATATE, a TRT directed against the somatostatin receptors (SSTRs), was recently approved for therapy of a subset of neuroendocrine tumors (NETs). Although it has prolonged the life of NET patients, complete remission is seldom achieved. Consequently, to increase the efficacy of the treatment, this thesis aimed to assess potential radiosensitizing strategies for 177Lu-DOTATATE. The two radiosensitization targets in focus were HSP90, a chaperone protein with numerous oncogenic client proteins, and p53, a central regulator of DNA damage.

In **papers I and II** , we investigated the HSP90-inhibitor Onalespib, as a treatment for NETs, and as a potential radiosensitizer. The drugs were assessed _in vitro_ and _in vivo_. We concluded that Onalespib reduced NET cell growth and acted synergistically with 177Lu-DOTATATE. Inhibition of EGFR, a HSP90 client protein, was suggested as a mediator of the observed synergy. Furthermore, the combination had a favorable toxicity profile. 

In **paper III** , we assessed the novel stapled peptide VIP116, which inhibits the p53 repressors MDM2 and MDM4, as a potentiator of 177Lu-DOTATATE in wildtype p53 neuroblastoma cells. Combination therapy exhibited growth-inhibitory effects, with resulting additive or synergistic effects. The treatment-mediated effects on p53 signaling were characterized, revealing a possible involvement of V-myc myelocytomatosis viral oncogene homolog, neuroblastoma derived (MYCN), a prognostic marker for poor survival in neuroblastoma.

In **paper IV** , we aimed to improve targeted delivery of VIP116, with the use of lipid bilayer disks (lipodisks). VIP116 was successfully loaded onto epidermal growth factor receptor (EGFR)-targeting lipodisks, leading to specific delivery and reduction of viability of EGFR expressing tumor cells. The study provided a proof-of-concept for utilizing lipodisks as a drug delivery system for p53-stabilizing peptides.

In conclusion, we have investigated, and found, suitable candidates for potentiating 177Lu-DOTATATE therapy. We have addressed the feasibility of the treatments, toxicity and targeted delivery. Moreover, the work has explored the biology of TRT. This is an area in need of more attention, as more and more radionuclide-based therapies are entering clinicals trials and reaching approval.

##### Place, publisher, year, edition, pages 

Uppsala: Acta Universitatis Upsaliensis, 2022. p. 58

##### Series 

Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1797

##### Keywords

Cancer, targeted radionuclide therapy, radiosensitization, p53, MDM2/MDM4 inhibition, HSP90, drug synergy, drug delivery, lipid nanoparticles, lipodisks 

##### National Category 

Cell and Molecular Biology Cancer and Oncology 

##### Research subject 

Biomedical Radiation Science

##### Identifiers

urn:nbn:se:uu:diva-459961 (URN)978-91-513-1358-0 (ISBN)

##### Public defence 

2022-02-04, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English) 

##### Opponent 

### Nonnekens, Julie

Erasmus University Medical Center, Molecular Genetics and Radiology & Nuclear Medicine.

##### Supervisors 

### Nestor, Marika

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.

### Björkelund, Hanna

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Ridgeview Instruments.

### Edwards, Katarina

Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Physical Chemistry I. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Physical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.

##### Funder

Swedish Cancer Society, 2018/494Swedish Cancer Society, 2016/649Swedish Cancer Society, 2015/1080Swedish Cancer Society, 2015/385Swedish Research Council, 2013-30876-104113-30Swedish Childhood Cancer Foundation, PR3018-0067Clas Groschinski Memorial FoundationSwedish Childhood Cancer Foundation, PR2020-0023Swedish Childhood Cancer Foundation, TJ2021-0072Swedish Research Council, 2020-01377Swedish Cancer Society, CAN 20 0191Swedish Cancer Society, CAN 2017/422 Available from: 2022-01-10 Created: 2021-12-01 Last updated: 2022-01-18

Lundsten, S., Berglund, H., Jha, P., Krona, C., Hariri, M., Nelander, S., . . . Nestor, M. (2021). p53-Mediated Radiosensitization of 177Lu-DOTATATE in Neuroblastoma Tumor Spheroids. Biomolecules, 11(11), Article ID 1695. 

Open this publication in new window or tab >>p53-Mediated Radiosensitization of 177Lu-DOTATATE in Neuroblastoma Tumor Spheroids

### Lundsten, Sara

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.

### Berglund, Hanna

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.

### Jha, Preeti

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.

### Krona, Cecilia

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.

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2021 (English)In:  Biomolecules, E-ISSN 2218-273X, Vol. 11, no 11, article id 1695Article in journal (Refereed) Published

##### Abstract [en]

p53 is involved in DNA damage response and is an exciting target for radiosensitization in cancer. Targeted radionuclide therapy against somatostatin receptors with 177Lu-DOTATATE is currently being explored as a treatment for neuroblastoma. The aim of this study was to investigate the novel p53-stabilizing peptide VIP116 in neuroblastoma, both as monotherapy and together with 177Lu-DOTATATE. Five neuroblastoma cell lines, including two patient-derived xenograft (PDX) lines, were characterized in monolayer cultures. Four out of five were positive for 177Lu-DOTATATE uptake. IC50 values after VIP116 treatments correlated with p53 status, ranging between 2.8&ndash;238.2 &mu;M. IMR-32 and PDX lines LU-NB-1 and LU-NB-2 were then cultured as multicellular tumor spheroids and treated with 177Lu-DOTATATE and/or VIP116. Spheroid growth was inhibited in all spheroid models for all treatment modalities. The most pronounced effects were observed for combination treatments, mediating synergistic effects in the IMR-32 model. VIP116 and combination treatment increased p53 levels with subsequent induction of p21, Bax and cleaved caspase 3. Combination treatment resulted in a 14-fold and 1.6-fold induction of MDM2 in LU-NB-2 and IMR-32 spheroids, respectively. This, together with differential MYCN signaling, may explain the varying degree of synergy. In conclusion, VIP116 inhibited neuroblastoma cell growth, potentiated 177Lu-DOTATATE treatment and could, therefore, be a feasible treatment option for neuroblastoma.

##### Place, publisher, year, edition, pages 

MDPI, 2021

##### Keywords

neuroblastoma, radionuclide therapy, p53, 177Lu-DOTATATE, radiosensitization, stapled peptides 

##### National Category 

Cell and Molecular Biology 

##### Identifiers

urn:nbn:se:uu:diva-459959 (URN)10.3390/biom11111695 (DOI)000724965100001 ()34827693 (PubMedID)

##### Funder

Swedish Research Council, 2020-01377Swedish Cancer Society, CAN 2018/494Swedish Cancer Society, CAN 20 0191Swedish Childhood Cancer Foundation, PR2020-0023Swedish Childhood Cancer Foundation, TJ2021-0072 

##### Note

Title in Web of Science: p53-Mediated Radiosensitization of Lu-177-DOTATATE in Neuroblastoma Tumor Spheroids

Available from: 2021-11-30 Created: 2021-11-30 Last updated: 2024-12-06Bibliographically approved

Johansson, P., Krona, C., Kundu, S., Doroszko, M., Baskaran, S., Schmidt, L., . . . Nelander, S. (2020). A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma. Cell Reports, 32(2), Article ID 107897. 

Open this publication in new window or tab >>A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma

### Johansson, Patrik

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.

### Krona, Cecilia

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.

### Kundu, Soumi

Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.

### Doroszko, Milena

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.

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2020 (English)In:  Cell Reports, E-ISSN 2211-1247, Vol. 32, no 2, article id 107897Article in journal (Refereed) Published

##### Abstract [en]

Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells, We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.

##### National Category 

Cell and Molecular Biology Cell Biology 

##### Identifiers

urn:nbn:se:uu:diva-419794 (URN)10.1016/j.celrep.2020.107897 (DOI)000548535600002 ()32668248 (PubMedID)

##### Funder

Swedish Research CouncilSwedish Cancer SocietySwedish Childhood Cancer Foundation 

##### Note

Patrik Johansson, Cecilia Krona and Soumi Kundu share first authorship

Available from: 2020-09-16 Created: 2020-09-16 Last updated: 2024-01-17Bibliographically approved

Spiegelberg, D., Abramenkovs, A., Mortensen, A., Lundsten, S., Nestor, M. & Stenerlöw, B. (2020). The HSP90 inhibitor Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy: an in vitro and in vivo approach. Scientific Reports, 10(1), Article ID 5923. 

Open this publication in new window or tab >>The HSP90 inhibitor Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy: an in vitro and in vivo approach

### Spiegelberg, Diana

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.

### Abramenkovs, Andris

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.

### Mortensen, Anja

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.

### Lundsten, Sara

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.

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2020 (English)In:  Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 5923Article in journal (Refereed) Published

##### Abstract [en]

Oncogenic client-proteins of the chaperone Heat shock protein 90 (HSP90) insure unlimited tumor growth and are involved in resistance to chemo- and radiotherapy. The HSP90 inhibitor Onalespib initiates the degradation of oncoproteins, and might also act as a radiosensitizer. The aim of this study was therefore to evaluate the efficacy of Onalespib in combination with external beam radiotherapy in an in vitro and in vivo approach. Onalespib downregulated client proteins, lead to increased apoptosis and caused DNA-double-strands. Monotherapy and combination with radiotherapy reduced colony formation, proliferation and migration assessed in radiosensitive HCT116 and radioresistant A431 cells. In vivo, a minimal treatment regimen for 3 consecutive days of Onalespib (3 x 10 mg/kg) doubled survival, whereas Onalespib with radiotherapy (3 x 2 Gy) caused a substantial delay in tumor growth and prolonged the survival by a factor of 3 compared to the HCT116 xenografted control group. Our results demonstrate that Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy, most prominent in the radiosensitive cell models. We speculate that the depletion and downregulation of client proteins involved in signalling, migration and DNA repair mechanisms is the cause. Thus, individually, or in combination with radiotherapy Onalespib inhibits tumor growth and has the potential to improve radiotherapy outcomes, prolonging the overall survival of cancer patients.

##### Place, publisher, year, edition, pages 

NATURE PUBLISHING GROUP, 2020

##### National Category 

Cancer and Oncology 

##### Identifiers

urn:nbn:se:uu:diva-422436 (URN)10.1038/s41598-020-62293-4 (DOI)000563493600006 ()32246062 (PubMedID)

##### Funder

Swedish Cancer Society, CAN 2018/494Swedish Cancer Society, CAN2016/649Swedish Cancer Society, CAN 2015/1080 Available from: 2020-10-28 Created: 2020-10-28 Last updated: 2022-09-15Bibliographically approved

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

### Lundsten, Sara

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.

### Spiegelberg, Diana

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.

### Raval, Nakul

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.

### Nestor, Marika

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.

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: 2021-12-01Bibliographically approved

Lundsten, S., Hernandez, V. A., Gedda, L., Sarén, T., Brown, C. J., Lane, D. P., . . . Nestor, M. (2020). Tumor-Targeted Delivery of the p53-Activating Peptide VIP116 with PEG-Stabilized Lipodisks. Nanomaterials, 10(4), Article ID 783. 

Open this publication in new window or tab >>Tumor-Targeted Delivery of the p53-Activating Peptide VIP116 with PEG-Stabilized Lipodisks

### Lundsten, Sara

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.

### Hernandez, Victor Agmo

Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.

### Gedda, Lars

Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.

### Sarén, Tina

Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.

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2020 (English)In:  Nanomaterials, E-ISSN 2079-4991, Vol. 10, no 4, article id 783Article in journal (Refereed) Published

##### Abstract [en]

Stapled peptides targeting the interaction between p53 and its negative regulators MDM2 and MDM4 have exhibited great potential as anti-cancer drugs, albeit with room for improvement in formulation and tumor specificity. Lipid bilayer disks (lipodisks) have emerged as promising drug nanocarriers and can by attachment of targeting moieties be directed selectively towards tumor cells. Tumor-targeted delivery of stapled peptides by use of lipodisks may therefore increase the uptake in the tumors and limit toxicity in healthy tissue. Here, we utilized epidermal growth factor receptor (EGFR)-targeted lipodisks to deliver p53-activating stapled peptide VIP116 to EGFR-expressing tumor cells. We demonstrate that VIP116 can be stably formulated in lipodisks (maximum peptide/lipid molar ratio 0.11). In vitro cell studies verify specific binding of EGF-decorated lipodisks to tumor cells and confirm that targeted delivery of VIP116 significantly decreases tumor cell viability.

##### Keywords

targeted tumor therapy, targeted drug delivery, Lipid bilayer disks, lipodisks, nanocarriers, p53, stapled peptides 

##### National Category 

Medical and Health Sciences Physical Chemistry 

##### Identifiers

urn:nbn:se:uu:diva-417730 (URN)10.3390/nano10040783 (DOI)000539577200186 ()32325827 (PubMedID)

##### Funder

Swedish Cancer Society, CAN 2018/494Swedish Cancer Society, CAN 2017/422Swedish Research Council, 2013-30876-104113-30 Available from: 2020-08-24 Created: 2020-08-24 Last updated: 2021-12-01Bibliographically 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

##### Organisations 

### Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC

### Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science (Closed down 2022-08-31)

### Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine

##### Identifiers

ORCID iD: orcid.org/0000-0002-0063-3233