Synergistic therapeutic benefit by combining the antibody drug conjugate, depatux-m with temozolomide in pre-clinical models of glioblastoma with overexpression of EGFR
| Autor: | Hugh D. Falls, Michael J. Mitten, Edward B. Reilly, Adelyn L Zelaya-Lazo, Erwin R. Boghaert, Anatol Oleksijew, Kedar S. Vaidya, Joann P. Palma, Sasmita Mishra, Cory Alvey, Peter Ansell, Mark Anderson, Andrew C. Phillips |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Antibody-drug conjugate Temozolomide biology Combination therapy business.industry 03 medical and health sciences 0302 clinical medicine Neurology Oncology Antigen In vivo Apoptosis 030220 oncology & carcinogenesis Cancer cell Cancer research biology.protein Medicine Neurology (clinical) Epidermal growth factor receptor business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Journal of Neuro-Oncology. 152:233-243 |
| ISSN: | 1573-7373 0167-594X |
| Popis: | Purpose: Depatux-m is an antibody drug conjugate (ADC) that targets and inhibits growth of cancer cells overexpressing the epidermal growth factor receptor (EGFR) or the 2–7 deletion mutant (EGFRvIII) in tumor models in vitro and in vivo. Treatment of patients suffering from relapsed/refractory glioblastoma (GBM) with a combination of depatux-m and temozolomide (TMZ) tended to increase overall survival. As a first step to understand the nature of the interaction between the two drugs, we investigated whether the interaction was synergistic, additive or antagonistic. Methods: The efficacy of ADCs, antibodies, TMZ and radiation was tested in xenograft models of GBM, U-87MG and U-87MG EGFRvIII. Both models express EGFR. U-87MG EGFRvIII was transduced to express EGFRvIII. Changes in tumor volume, biomarkers of cell death and apoptosis after treatment were used to measure efficacy of the various treatments. Synergism of depatux-m and TMZ was verified in three-dimensional cultures of U-87MG and U-87MG EGFRvIII by the method of Chou and Talalay. Results: Combined with TMZ and radiotherapy (RT), depatux-m inhibited xenograft growth of U-87MG and U-87MG EGFRvIII more than either treatment with depatux-m or TMZ + RT. Durability of the response to depatux-m + TMZ + RT or depatux-m + TMZ was more pronounced in U-87MG EGFRvIII than in U-87MG. Efficacy of depatux-m + TMZ was synergistic in U-87MG EGFRvIII and additive in U-87MG. Conclusion: Adding depatux-m enhances the efficacy of standard of care therapy in preclinical models of GBM. Durability of response to depatux-m + TMZ in vivo and synergy of the drug-drug interaction correlates with the amount of antigen expressed by the tumor cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink