5 results on '"Abdul K. Hilli"'
Search Results
2. Supplementary Table from Functional Testing to Characterize and Stratify PI3K Inhibitor Responses in Chronic Lymphocytic Leukemia
- Author
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Sigrid S. Skånland, Tero Aittokallio, Geir E. Tjønnfjord, Jennifer R. Brown, Emmanuel Normant, Anthony R. Mato, Francesco Bertoni, Kjetil Taskén, Abdul K. Hilli, Alberto J. Arribas, Stacey M. Fernandes, Ishwarya Murali, Haifeng Xu, Aleksandra Urban, Linda Karlsen, Paschalis Athanasiadis, and Yanping Yin
- Abstract
Supplementary Table from Functional Testing to Characterize and Stratify PI3K Inhibitor Responses in Chronic Lymphocytic Leukemia
- Published
- 2023
3. Data from Functional Testing to Characterize and Stratify PI3K Inhibitor Responses in Chronic Lymphocytic Leukemia
- Author
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Sigrid S. Skånland, Tero Aittokallio, Geir E. Tjønnfjord, Jennifer R. Brown, Emmanuel Normant, Anthony R. Mato, Francesco Bertoni, Kjetil Taskén, Abdul K. Hilli, Alberto J. Arribas, Stacey M. Fernandes, Ishwarya Murali, Haifeng Xu, Aleksandra Urban, Linda Karlsen, Paschalis Athanasiadis, and Yanping Yin
- Abstract
Purpose:PI3K inhibitors (PI3Ki) are approved for relapsed chronic lymphocytic leukemia (CLL). Although patients may show an initial response to these therapies, development of treatment intolerance or resistance remain clinical challenges. To overcome these, prediction of individual treatment responses based on actionable biomarkers is needed. Here, we characterized the activity and cellular effects of 10 PI3Ki and investigated whether functional analyses can identify treatment vulnerabilities in PI3Ki-refractory/intolerant CLL and stratify responders to PI3Ki.Experimental Design:Peripheral blood mononuclear cell samples (n = 51 in total) from treatment-naïve and PI3Ki-treated patients with CLL were studied. Cells were profiled against 10 PI3Ki and the Bcl-2 antagonist venetoclax. Cell signaling and immune phenotypes were analyzed by flow cytometry. Cell viability was monitored by detection of cleaved caspase-3 and the CellTiter-Glo assay.Results:pan-PI3Kis were most effective at inhibiting PI3K signaling and cell viability, and showed activity in CLL cells from both treatment-naïve and idelalisib-refractory/intolerant patients. CLL cells from idelalisib-refractory/intolerant patients showed overall reduced protein phosphorylation levels. The pan-PI3Ki copanlisib, but not the p110δ inhibitor idelalisib, inhibited PI3K signaling in CD4+ and CD8+ T cells in addition to CD19+ B cells, but did not significantly affect T-cell numbers. Combination treatment with a PI3Ki and venetoclax resulted in synergistic induction of apoptosis. Analysis of drug sensitivities to 73 drug combinations and profiling of 31 proteins stratified responders to idelalisib and umbralisib, respectively.Conclusions:Our findings suggest novel treatment vulnerabilities in idelalisib-refractory/intolerant CLL, and indicate that ex vivo functional profiling may stratify PI3Ki responders.
- Published
- 2023
4. Functional testing of PI3K inhibitors stratifies responders to idelalisib and identifies treatment vulnerabilities in idelalisib-refractory/intolerant chronic lymphocytic leukemia
- Author
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Yanping Yin, Paschalis Athanasiadis, Linda Karlsen, Aleksandra Urban, Ishwarya Murali, Stacey M. Fernandes, Alberto J. Arribas, Abdul K. Hilli, Kjetil Taskén, Francesco Bertoni, Anthony R. Mato, Emmanuel Normant, Jennifer R. Brown, Geir E. Tjønnfjord, Tero Aittokallio, and Sigrid S. Skånland
- Abstract
PurposePhosphatidylinositol 3-kinase inhibitors (PI3Ki) are approved for relapsed chronic lymphocytic leukemia (CLL). While patients may show an initial response, development of treatment intolerance or resistance remains a clinically challenging. Prediction of individual treatment responses based on clinically actionable biomarkers is needed to overcome these challenges. Here, we investigated whetherex vivofunctional responses to targeted therapies can stratify responders to idelalisib and guide precision medicine in CLL.Experimental designCLL cells from treatment naïve, idelalisib-responding, and idelalisib-refractory/intolerant patients (n=33 in total) were profiled against ten PI3Ki and the Bcl-2 antagonist venetoclax. Cell signaling and immune phenotypes were analyzed by flow cytometry. Cell viability was monitored by detection of cleaved caspase-3 and the CellTiter-Glo assay.ResultsAmong the ten PI3Ki studied, pan-PI3Ki were most effective at inhibiting PI3K signaling and cell viability, and they showed activity also in CLL cells from idelalisib-refractory/intolerant patients. The pan-PI3Ki copanlisib, but not the p110δ inhibitor idelalisib, inhibited PI3K signaling in CD4+and CD8+T cells in addition to CD19+B cells, while it did not significantly affect T cell numbers. Combination treatment with a PI3Ki and venetoclax resulted in synergistic induction of apoptosis. Based onex vivodrug sensitivity testing, a relapsed CLL patient was treated with idelalisib plus venetoclax, and the patient achieved a partial response. A more systematic analysis revealed that CLL cells from patients with a long-term response to idelalisib showed significantly higher drug sensitivities to 73 drug combinations at baseline compared to short-term responders.ConclusionsOur findings suggest novel treatment vulnerabilities in idelalisib-refractory/intolerant CLL, and demonstrate thatex vivofunctional profiling may guide precision medicine and predict treatment responses of individual CLL patients.TRANSLATIONAL RELEVANCEThe phosphatidylinositol 3-kinase inhibitors (PI3Ki) idelalisib and duvelisib are approved for relapsed chronic lymphocytic leukemia (CLL), but their use has been limited by severe toxicity and acquired resistance. Identification of biomarkers that predict individual treatment responses, as well as alternative treatment vulnerabilities in PI3Ki refractory/intolerant patients, is needed to optimally tailor CLL therapy. We performed functional analyses of CLL cells from treatment naïve, idelalisib-responding and idelalisib-refractory/intolerant patients to identify clinically actionable biomarkers. We show that CLL cells from idelalisib-refractory/intolerant patients remain sensitive to pan-PI3Ki and PI3Ki plus venetoclax combinations.Ex vivodrug sensitivity testing was used to guide treatment of a relapsed CLL patient who obtained a partial response after idelalisib plus venetoclax therapy. A systematic analysis of drug sensitivities to 73 drug combinations stratified responders to idelalisib using baseline samples from short-term and long-term responders to idelalisib. Our study demonstrates the power of functional precision medicine in relapsed CLL.
- Published
- 2022
5. Functional testing to characterize and stratify PI3K inhibitor responses in chronic lymphocytic leukemia
- Author
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Yanping Yin, Paschalis Athanasiadis, Linda Karlsen, Aleksandra Urban, Haifeng Xu, Ishwarya Murali, Stacey M. Fernandes, Alberto J. Arribas, Abdul K. Hilli, Kjetil Taskén, Francesco Bertoni, Anthony R. Mato, Emmanuel Normant, Jennifer R. Brown, Geir E. Tjønnfjord, Tero Aittokallio, and Sigrid S. Skånland
- Subjects
Sulfonamides ,Cancer Research ,Caspase 3 ,Antineoplastic Agents ,Bridged Bicyclo Compounds, Heterocyclic ,Leukemia, Lymphocytic, Chronic, B-Cell ,Article ,Phosphatidylinositol 3-Kinases ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,Leukocytes, Mononuclear ,Humans ,Phosphoinositide-3 Kinase Inhibitors ,Quinazolinones - Abstract
Purpose:PI3K inhibitors (PI3Ki) are approved for relapsed chronic lymphocytic leukemia (CLL). Although patients may show an initial response to these therapies, development of treatment intolerance or resistance remain clinical challenges. To overcome these, prediction of individual treatment responses based on actionable biomarkers is needed. Here, we characterized the activity and cellular effects of 10 PI3Ki and investigated whether functional analyses can identify treatment vulnerabilities in PI3Ki-refractory/intolerant CLL and stratify responders to PI3Ki.Experimental Design:Peripheral blood mononuclear cell samples (n = 51 in total) from treatment-naïve and PI3Ki-treated patients with CLL were studied. Cells were profiled against 10 PI3Ki and the Bcl-2 antagonist venetoclax. Cell signaling and immune phenotypes were analyzed by flow cytometry. Cell viability was monitored by detection of cleaved caspase-3 and the CellTiter-Glo assay.Results:pan-PI3Kis were most effective at inhibiting PI3K signaling and cell viability, and showed activity in CLL cells from both treatment-naïve and idelalisib-refractory/intolerant patients. CLL cells from idelalisib-refractory/intolerant patients showed overall reduced protein phosphorylation levels. The pan-PI3Ki copanlisib, but not the p110δ inhibitor idelalisib, inhibited PI3K signaling in CD4+ and CD8+ T cells in addition to CD19+ B cells, but did not significantly affect T-cell numbers. Combination treatment with a PI3Ki and venetoclax resulted in synergistic induction of apoptosis. Analysis of drug sensitivities to 73 drug combinations and profiling of 31 proteins stratified responders to idelalisib and umbralisib, respectively.Conclusions:Our findings suggest novel treatment vulnerabilities in idelalisib-refractory/intolerant CLL, and indicate that ex vivo functional profiling may stratify PI3Ki responders.
- Published
- 2022
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