ORCID Profile
0000-0003-1672-2262
Current Organisation
Universidad Autonoma de Madrid Centro de Biología Molecular Severo Ochoa
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Publisher: American Association for Cancer Research (AACR)
Date: 16-05-2023
DOI: 10.1158/1078-0432.22841378.V1
Abstract: These are all the Supplementary Figures: S1, S2, S3, S4, S5, S6, and S7
Publisher: American Association for Cancer Research (AACR)
Date: 05-04-2014
DOI: 10.1158/1078-0432.C.6649142
Abstract: AbstractPurpose: This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs). Patients and Methods: Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. Results: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6–43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2–8) cycles. Conclusions: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose r -up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation. /
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23626900.V1
Abstract: These are all the Supplementary Figures: S1, S2, S3, S4, S5, S6, and S7
Publisher: EMBO
Date: 25-08-2020
Publisher: Rockefeller University Press
Date: 15-11-2010
Abstract: Tethering factors are organelle-specific multisubunit protein complexes that identify, along with Rab guanosine triphosphatases, transport vesicles and trigger their SNARE-mediated fusion of specific transport vesicles with the target membranes. Little is known about how tethering factors discriminate between different trafficking pathways, which may converge at the same organelle. In this paper, we describe a phosphorylation-based switch mechanism, which allows the homotypic vacuole fusion protein sorting effector subunit Vps41 to operate in two distinct fusion events, namely endosome–vacuole and AP-3 vesicle–vacuole fusion. Vps41 contains an hipathic lipid-packing sensor (ALPS) motif, which recognizes highly curved membranes. At endosomes, this motif is inserted into the lipid bilayer and masks the binding motif for the δ subunit of the AP-3 complex, Apl5, without affecting the Vps41 function in endosome–vacuole fusion. At the much less curved vacuole, the ALPS motif becomes available for phosphorylation by the resident casein kinase Yck3. As a result, the Apl5-binding site is exposed and allows AP-3 vesicles to bind to Vps41, followed by specific fusion with the vacuolar membrane. This multifunctional tethering factor thus discriminates between trafficking routes by switching from a curvature-sensing to a coat recognition mode upon phosphorylation.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23626900
Abstract: These are all the Supplementary Figures: S1, S2, S3, S4, S5, S6, and S7
Publisher: American Association for Cancer Research (AACR)
Date: 16-05-2023
DOI: 10.1158/1078-0432.22841378
Abstract: These are all the Supplementary Figures: S1, S2, S3, S4, S5, S6, and S7
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23626897
Abstract: Representativeness of study participants.
Publisher: American Society for Cell Biology (ASCB)
Date: 04-2009
Abstract: Membrane fusion depends on multisubunit tethering factors such as the vacuolar HOPS complex. We previously showed that the vacuolar casein kinase Yck3 regulates vacuole biogenesis via phosphorylation of the HOPS subunit Vps41. Here, we link the identified Vps41 phosphorylation site to HOPS function at the endosome–vacuole fusion site. The nonphosphorylated Vps41 mutant (Vps41 S-A) accumulates together with other HOPS subunits on punctate structures proximal to the vacuole that expand in a class E mutant background and that correspond to in vivo fusion sites. Ultrastructural analysis of this mutant confirmed the presence of tubular endosomal structures close to the vacuole. In contrast, Vps41 with a phosphomimetic mutation (Vps41 S-D) is mislocalized and leads to multilobed vacuoles, indicative of a fusion defect. These two phenotypes can be rescued by overproduction of the vacuolar Rab Ypt7, revealing that both Ypt7 and Yck3-mediated phosphorylation modulate the Vps41 localization to the endosome–vacuole junction. Our data suggest that Vps41 phosphorylation fine-tunes the organization of vacuole fusion sites and provide evidence for a fusion “hot spot” on the vacuole limiting membrane.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23626894.V1
Abstract: Summary of BH3 profiling for PBMC s les collected at baseline.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.C.6649142.V2
Abstract: AbstractPurpose: This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs). Patients and Methods: Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. Results: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6–43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2–8) cycles. Conclusions: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose r -up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation. /
Publisher: American Association for Cancer Research (AACR)
Date: 16-05-2023
DOI: 10.1158/1078-0432.22841375.V1
Abstract: Representativeness of study participants.
Publisher: American Association for Cancer Research (AACR)
Date: 16-05-2023
DOI: 10.1158/1078-0432.C.6649142.V1
Abstract: AbstractPurpose: This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs). Patients and Methods: Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. Results: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6–43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2–8) cycles. Conclusions: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose r -up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation. /
Publisher: American Association for Cancer Research (AACR)
Date: 19-04-2023
DOI: 10.1158/1078-0432.CCR-22-3321
Abstract: This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs). Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6–43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2–8) cycles. Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose r -up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.
Publisher: American Association for Cancer Research (AACR)
Date: 16-05-2023
DOI: 10.1158/1078-0432.22841372
Abstract: Summary of BH3 profiling for PBMC s les collected at baseline.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23626897.V1
Abstract: Representativeness of study participants.
Publisher: American Association for Cancer Research (AACR)
Date: 05-07-2023
DOI: 10.1158/1078-0432.23626894
Abstract: Summary of BH3 profiling for PBMC s les collected at baseline.
Publisher: American Association for Cancer Research (AACR)
Date: 16-05-2023
DOI: 10.1158/1078-0432.22841372.V1
Abstract: Summary of BH3 profiling for PBMC s les collected at baseline.
Publisher: American Association for Cancer Research (AACR)
Date: 16-05-2023
DOI: 10.1158/1078-0432.22841375
Abstract: Representativeness of study participants.
Location: Spain
Location: Netherlands
No related grants have been discovered for Yifan Zhai.