Clinical activity of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, in refractory adult T-Cell leukemia/lymphoma
GSK-3β is a serine/threonine kinase implicated in tumorigenesis and chemotherapy resistance. GSK-3β blockade downregulates the NF-κB pathway, modulates immune cell PD-1 and tumor cell PD-L1 expression, and increases CD8 + T cell and NK cell function. We report a case of adult T-cell leukemia/lymphom...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2022-12-01
|
| Series: | Cancer Biology & Therapy |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15384047.2022.2088984 |
| _version_ | 1797404057410732032 |
|---|---|
| author | Andrew Hsu Kelsey E. Huntington Andre De Souza Lanlan Zhou Adam J. Olszewski Nirav P. Makwana Diana O. Treaba Ludimila Cavalcante Francis J. Giles Howard Safran Wafik S. El-Deiry Benedito A. Carneiro |
| author_facet | Andrew Hsu Kelsey E. Huntington Andre De Souza Lanlan Zhou Adam J. Olszewski Nirav P. Makwana Diana O. Treaba Ludimila Cavalcante Francis J. Giles Howard Safran Wafik S. El-Deiry Benedito A. Carneiro |
| author_sort | Andrew Hsu |
| collection | DOAJ |
| description | GSK-3β is a serine/threonine kinase implicated in tumorigenesis and chemotherapy resistance. GSK-3β blockade downregulates the NF-κB pathway, modulates immune cell PD-1 and tumor cell PD-L1 expression, and increases CD8 + T cell and NK cell function. We report a case of adult T-cell leukemia/lymphoma (ATLL) treated with 9-ING-41, a selective GSK-3β inhibitor in clinical development, who achieved a durable response. A 43-year-old male developed diffuse lymphadenopathy, and biopsy of axillary lymph node showed acute-type ATLL. Peripheral blood flow cytometry revealed a circulating clonal T cell population, and CSF was positive for ATLL involvement. After disease progression on the 3rd line of treatment, he started treatment with 9-ING-41 monotherapy in a clinical trial (NCT03678883). CT imaging after seven months showed a partial response. Sustained reduction of peripheral blood ATLL cells lasted 15 months. Treatment of patient-derived CD8 + T cells with 9-ING-41 increased the secretion of IFN-γ, granzyme B, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In conclusion, treatment of a patient with refractory ATLL with the GSK-3β inhibitor 9-ING-41 resulted in a prolonged response. Ongoing experiments are investigating the hypothesis that 9-ING-41-induced T cell activation and immunomodulation contributes to its clinical activity. Further clinical investigation of 9-ING-41 for treatment of ATLL is warranted. |
| first_indexed | 2024-03-09T02:47:36Z |
| format | Article |
| id | doaj.art-92cb5ee1490243b8bd245afdd67c0799 |
| institution | Directory Open Access Journal |
| issn | 1538-4047 1555-8576 |
| language | English |
| last_indexed | 2024-03-09T02:47:36Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Cancer Biology & Therapy |
| spelling | doaj.art-92cb5ee1490243b8bd245afdd67c07992023-12-05T15:58:13ZengTaylor & Francis GroupCancer Biology & Therapy1538-40471555-85762022-12-0123141742310.1080/15384047.2022.20889842088984Clinical activity of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, in refractory adult T-Cell leukemia/lymphomaAndrew Hsu0Kelsey E. Huntington1Andre De Souza2Lanlan Zhou3Adam J. Olszewski4Nirav P. Makwana5Diana O. Treaba6Ludimila Cavalcante7Francis J. Giles8Howard Safran9Wafik S. El-Deiry10Benedito A. Carneiro11Brown University and the Lifespan Cancer InstituteBrown UniversityBrown University and the Lifespan Cancer InstituteBrown UniversityBrown University and the Lifespan Cancer InstituteBrown UniversityBrown UniversityActuate TherapeuticsActuate TherapeuticsBrown University and the Lifespan Cancer InstituteBrown University and the Lifespan Cancer InstituteBrown University and the Lifespan Cancer InstituteGSK-3β is a serine/threonine kinase implicated in tumorigenesis and chemotherapy resistance. GSK-3β blockade downregulates the NF-κB pathway, modulates immune cell PD-1 and tumor cell PD-L1 expression, and increases CD8 + T cell and NK cell function. We report a case of adult T-cell leukemia/lymphoma (ATLL) treated with 9-ING-41, a selective GSK-3β inhibitor in clinical development, who achieved a durable response. A 43-year-old male developed diffuse lymphadenopathy, and biopsy of axillary lymph node showed acute-type ATLL. Peripheral blood flow cytometry revealed a circulating clonal T cell population, and CSF was positive for ATLL involvement. After disease progression on the 3rd line of treatment, he started treatment with 9-ING-41 monotherapy in a clinical trial (NCT03678883). CT imaging after seven months showed a partial response. Sustained reduction of peripheral blood ATLL cells lasted 15 months. Treatment of patient-derived CD8 + T cells with 9-ING-41 increased the secretion of IFN-γ, granzyme B, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In conclusion, treatment of a patient with refractory ATLL with the GSK-3β inhibitor 9-ING-41 resulted in a prolonged response. Ongoing experiments are investigating the hypothesis that 9-ING-41-induced T cell activation and immunomodulation contributes to its clinical activity. Further clinical investigation of 9-ING-41 for treatment of ATLL is warranted.http://dx.doi.org/10.1080/15384047.2022.2088984atllgsk-3gsk-3b9-ing-41glycogen synthase kinase 3 |
| spellingShingle | Andrew Hsu Kelsey E. Huntington Andre De Souza Lanlan Zhou Adam J. Olszewski Nirav P. Makwana Diana O. Treaba Ludimila Cavalcante Francis J. Giles Howard Safran Wafik S. El-Deiry Benedito A. Carneiro Clinical activity of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, in refractory adult T-Cell leukemia/lymphoma Cancer Biology & Therapy atll gsk-3 gsk-3b 9-ing-41 glycogen synthase kinase 3 |
| title | Clinical activity of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, in refractory adult T-Cell leukemia/lymphoma |
| title_full | Clinical activity of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, in refractory adult T-Cell leukemia/lymphoma |
| title_fullStr | Clinical activity of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, in refractory adult T-Cell leukemia/lymphoma |
| title_full_unstemmed | Clinical activity of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, in refractory adult T-Cell leukemia/lymphoma |
| title_short | Clinical activity of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, in refractory adult T-Cell leukemia/lymphoma |
| title_sort | clinical activity of 9 ing 41 a small molecule selective glycogen synthase kinase 3 beta gsk 3β inhibitor in refractory adult t cell leukemia lymphoma |
| topic | atll gsk-3 gsk-3b 9-ing-41 glycogen synthase kinase 3 |
| url | http://dx.doi.org/10.1080/15384047.2022.2088984 |
| work_keys_str_mv | AT andrewhsu clinicalactivityof9ing41asmallmoleculeselectiveglycogensynthasekinase3betagsk3binhibitorinrefractoryadulttcellleukemialymphoma AT kelseyehuntington clinicalactivityof9ing41asmallmoleculeselectiveglycogensynthasekinase3betagsk3binhibitorinrefractoryadulttcellleukemialymphoma AT andredesouza clinicalactivityof9ing41asmallmoleculeselectiveglycogensynthasekinase3betagsk3binhibitorinrefractoryadulttcellleukemialymphoma AT lanlanzhou clinicalactivityof9ing41asmallmoleculeselectiveglycogensynthasekinase3betagsk3binhibitorinrefractoryadulttcellleukemialymphoma AT adamjolszewski clinicalactivityof9ing41asmallmoleculeselectiveglycogensynthasekinase3betagsk3binhibitorinrefractoryadulttcellleukemialymphoma AT niravpmakwana clinicalactivityof9ing41asmallmoleculeselectiveglycogensynthasekinase3betagsk3binhibitorinrefractoryadulttcellleukemialymphoma AT dianaotreaba clinicalactivityof9ing41asmallmoleculeselectiveglycogensynthasekinase3betagsk3binhibitorinrefractoryadulttcellleukemialymphoma AT ludimilacavalcante clinicalactivityof9ing41asmallmoleculeselectiveglycogensynthasekinase3betagsk3binhibitorinrefractoryadulttcellleukemialymphoma AT francisjgiles clinicalactivityof9ing41asmallmoleculeselectiveglycogensynthasekinase3betagsk3binhibitorinrefractoryadulttcellleukemialymphoma AT howardsafran clinicalactivityof9ing41asmallmoleculeselectiveglycogensynthasekinase3betagsk3binhibitorinrefractoryadulttcellleukemialymphoma AT wafikseldeiry clinicalactivityof9ing41asmallmoleculeselectiveglycogensynthasekinase3betagsk3binhibitorinrefractoryadulttcellleukemialymphoma AT beneditoacarneiro clinicalactivityof9ing41asmallmoleculeselectiveglycogensynthasekinase3betagsk3binhibitorinrefractoryadulttcellleukemialymphoma |