In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma
Background: Glioblastoma represents the most common primary brain tumor in adults. Despite technological advances, patients with this disease typically die within 1–2 years after diagnosis. In the search for novel therapeutics, drug repurposing has emerged as an alternative to traditional drug devel...
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| Format: | Article |
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MDPI AG
2021-11-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/12/1241 |
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| author | Marc-Eric Halatsch Annika Dwucet Carl Julius Schmidt Julius Mühlnickel Tim Heiland Katharina Zeiler Markus D. Siegelin Richard Eric Kast Georg Karpel-Massler |
| author_facet | Marc-Eric Halatsch Annika Dwucet Carl Julius Schmidt Julius Mühlnickel Tim Heiland Katharina Zeiler Markus D. Siegelin Richard Eric Kast Georg Karpel-Massler |
| author_sort | Marc-Eric Halatsch |
| collection | DOAJ |
| description | Background: Glioblastoma represents the most common primary brain tumor in adults. Despite technological advances, patients with this disease typically die within 1–2 years after diagnosis. In the search for novel therapeutics, drug repurposing has emerged as an alternative to traditional drug development pipelines, potentially facilitating and expediting the transition from drug discovery to clinical application. In a drug repurposing effort, the original CUSP9 and its derivatives CUSP9* and CUSP9v3 were developed as combinations of nine non-oncological drugs combined with metronomic low-dose temozolomide. Methods: In this work, we performed pre-clinical testing of CUSP9v3 in different established, primary cultured and stem-like glioblastoma models. In addition, eight patients with heavily pre-treated recurrent glioblastoma received the CUSP9v3 regime on a compassionate use basis in a last-ditch effort. Results: CUSP9v3 had profound antiproliferative and pro-apoptotic effects across all tested glioblastoma models. Moreover, the cells’ migratory capacity and ability to form tumor spheres was drastically reduced. In vitro, additional treatment with temozolomide did not significantly enhance the antineoplastic activity of CUSP9v3. CUSP9v3 was well-tolerated with the most frequent grade 3 or 4 adverse events being increased hepatic enzyme levels. Conclusions: CUSP9v3 displays a strong anti-proliferative and anti-migratory activity in vitro and seems to be safe to apply to patients. These data have prompted further investigation of CUSP9v3 in a phase Ib/IIa clinical trial (NCT02770378). |
| first_indexed | 2024-03-10T03:21:49Z |
| format | Article |
| id | doaj.art-c4891d57756d4b0b973fc1555f50a04e |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T03:21:49Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-c4891d57756d4b0b973fc1555f50a04e2023-11-23T10:02:55ZengMDPI AGPharmaceuticals1424-82472021-11-011412124110.3390/ph14121241In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in GlioblastomaMarc-Eric Halatsch0Annika Dwucet1Carl Julius Schmidt2Julius Mühlnickel3Tim Heiland4Katharina Zeiler5Markus D. Siegelin6Richard Eric Kast7Georg Karpel-Massler8Department of Neurological Surgery, Ulm University Medical Center, 89081 Ulm, GermanyDepartment of Neurological Surgery, Ulm University Medical Center, 89081 Ulm, GermanyDepartment of Neurological Surgery, Ulm University Medical Center, 89081 Ulm, GermanyDepartment of Neurological Surgery, Ulm University Medical Center, 89081 Ulm, GermanyDepartment of Neurological Surgery, Ulm University Medical Center, 89081 Ulm, GermanyDepartment of Neurological Surgery, Ulm University Medical Center, 89081 Ulm, GermanyDepartment of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USAIIAIGC Study Center, Burlington, VT 05408, USADepartment of Neurological Surgery, Ulm University Medical Center, 89081 Ulm, GermanyBackground: Glioblastoma represents the most common primary brain tumor in adults. Despite technological advances, patients with this disease typically die within 1–2 years after diagnosis. In the search for novel therapeutics, drug repurposing has emerged as an alternative to traditional drug development pipelines, potentially facilitating and expediting the transition from drug discovery to clinical application. In a drug repurposing effort, the original CUSP9 and its derivatives CUSP9* and CUSP9v3 were developed as combinations of nine non-oncological drugs combined with metronomic low-dose temozolomide. Methods: In this work, we performed pre-clinical testing of CUSP9v3 in different established, primary cultured and stem-like glioblastoma models. In addition, eight patients with heavily pre-treated recurrent glioblastoma received the CUSP9v3 regime on a compassionate use basis in a last-ditch effort. Results: CUSP9v3 had profound antiproliferative and pro-apoptotic effects across all tested glioblastoma models. Moreover, the cells’ migratory capacity and ability to form tumor spheres was drastically reduced. In vitro, additional treatment with temozolomide did not significantly enhance the antineoplastic activity of CUSP9v3. CUSP9v3 was well-tolerated with the most frequent grade 3 or 4 adverse events being increased hepatic enzyme levels. Conclusions: CUSP9v3 displays a strong anti-proliferative and anti-migratory activity in vitro and seems to be safe to apply to patients. These data have prompted further investigation of CUSP9v3 in a phase Ib/IIa clinical trial (NCT02770378).https://www.mdpi.com/1424-8247/14/12/1241CUSP9*CUSP9v3glioblastomadrug repurposingcompassionate use |
| spellingShingle | Marc-Eric Halatsch Annika Dwucet Carl Julius Schmidt Julius Mühlnickel Tim Heiland Katharina Zeiler Markus D. Siegelin Richard Eric Kast Georg Karpel-Massler In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma Pharmaceuticals CUSP9* CUSP9v3 glioblastoma drug repurposing compassionate use |
| title | In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma |
| title_full | In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma |
| title_fullStr | In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma |
| title_full_unstemmed | In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma |
| title_short | In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma |
| title_sort | in vitro and clinical compassionate use experiences with the drug repurposing approach cusp9v3 in glioblastoma |
| topic | CUSP9* CUSP9v3 glioblastoma drug repurposing compassionate use |
| url | https://www.mdpi.com/1424-8247/14/12/1241 |
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