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- Lundgren Mortensen, Anja Charlotte, et al.
(författare)
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Combination therapy of tyrosine kinase inhibitor sorafenib with the HSP90 inhibitor onalespib as a novel treatment regimen for thyroid cancer
- 2023
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Thyroid cancer is the most common endocrine malignancy, affecting nearly 600,000 new patients worldwide. Treatment with the BRAF inhibitor sorafenib partially prolongs progression-free survival in thyroid cancer patients, but fails to improve overall survival. This study examines enhancing sorafenib efficacy by combination therapy with the novel HSP90 inhibitor onalespib. In vitro efficacy of sorafenib and onalespib monotherapy as well as in combination was assessed in papillary (PTC) and anaplastic (ATC) thyroid cancer cells using cell viability and colony formation assays. Migration potential was studied in wound healing assays. The in vivo efficacy of sorafenib and onalespib therapy was evaluated in mice bearing BHT-101 xenografts. Sorafenib in combination with onalespib significantly inhibited PTC and ATC cell proliferation, decreased metabolic activity and cancer cell migration. In addition, the drug combination approach significantly inhibited tumor growth in the xenograft model and prolonged the median survival. Our results suggest that combination therapy with sorafenib and onalespib could be used as a new therapeutic approach in the treatment of thyroid cancer, significantly improving the results obtained with sorafenib as monotherapy. This approach has the potential to reduce treatment adaptation while at the same time providing therapeutic anti-cancer benefits such as reducing tumor growth and metastatic potential.
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| 2. |
- Spiegelberg, Diana, 1982-, et al.
(författare)
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The Novel Anti-cMet Antibody seeMet 12 Potentiates Sorafenib Therapy and Radiotherapy in a Colorectal Cancer Model
- 2020
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Rational: cMet is abnormally regulated in gastrointestinal cancer, and is associated with increased invasiveness of the disease and poor overall survival. There are indications that targeted therapy against cMet, alone or in combination with additional cancer therapies, can help improve treatment outcome. Thus, in the present study we investigated the therapeutic efficacy of a novel cMet-targeting antibody therapy in gastrointestinal cancer models, and assessed potential augmenting effects in combination with tyrosine kinase inhibitor (TKI) targeted therapy or radiotherapy.Methods: Three different cMet-targeting antibodies were first characterized with respect to antigen binding and effects on cell viability in vitro. The best performing candidate seeMet 12 was then further assessed for effects on colorectal cancer cell growth, proliferation and migration. Combinations with the TKI-inhibitor sorafenib or external beam radiotherapy were then evaluated for potential additive or synergistic effects in vitro using monolayer- and multicellular tumor spheroid assays. Finally, the combination of seeMet 12 and radiotherapy was evaluated in vivo in a proof-of-concept colorectal cancer xenograft study.Results: Dose-dependent therapeutic effects were demonstrated for all three cMet-targeting antibodies. Monotherapy using seeMet 12 resulted in impaired cellular migration/proliferation and reduced tumor spheroid growth. Moreover, seeMet 12 was able to potentiate therapeutic effects in vitro for both sorafenib and radiotherapy treatments. Finally, the in vivo therapy study demonstrated promising results, where a combination of seeMet 12 and fractionated radiotherapy increased median survival by 79% compared to radiotherapy alone, and tripled maximum survival.Conclusion: The novel anti-cMet antibody seeMet 12 demonstrated therapeutic effects in cMet positive gastrointestinal cancer cells in vitro. Moreover, the addition of seeMet 12 augmented the effects of sorafenib and radiotherapy. An in vivo proof-of-concept study of seeMet 12 and radiotherapy further validated the results. Thus, cMet-targeted therapy should be further explored as a promising approach to increase therapeutic effects, circumvent treatment resistance, and reduce side effects.
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