N-terminal tandem GAF domains are present in 5 out of 11 mammalian phosphodiesterase (PDE) families. The ligand for the GAF domains of PDEs 2, 5, and 6 is cGMP, whereas those for PDEs 10 and 11 remained enigmatic for years. Here we used the cyanobacterial cyaB1 adenylyl cyclase, which has an N-terminal tandem GAF domain closely related to those of the mammalian PDEs, as an assay system to identify the ligands for the human PDEs 10 and 11 GAF domains. We report that a chimera between the PDE10 GAF domain and the cyanobacterial cyclase was 9-fold stimulated by cAMP (EC 50 ؍ 19.8 M), whereas cGMP had only low activity. cAMP increased V max in a non-cooperative manner and did not affect the K m for ATP of 27 M. In an analogous chimeric construct with the tandem GAF domain of human PDE11A4, cGMP was identified as an allosteric activator (EC 50 ؍ 72.5 M) that increased V max of the cyclase non-cooperatively 4-fold. GAF-B of PDE10 and GAF-A of PDE11A4 contain an invariant NKFDE motif present in all mammalian PDE GAF ensembles. We mutated the aspartates within this motif in both regions and found that intramolecular signaling was considerably reduced or abolished. This was in line with all data concerning GAF domains with an NKFDE motif as far as they have been tested. The data appeared to define those GAF domains as a distinct subclass within the >3100 annotated GAF domains for which we propose a tentative classification scheme.
The tandem GAF domain of human phosphodiesterase 11A4 (hPDE11A4) requires 72 μm cGMP for half‐maximal effective concentration (EC50) of a cyanobacterial adenylyl cyclase used as a reporter enzyme. Here we examine whether modifications in the N‐terminus of PDE11A4 affect cGMP signalling. The N‐terminus has two phosphorylation sites for cyclic nucleotide monophosphate‐dependent protein kinases (Ser117, Ser168). Phosphorylation of both by cAMP‐dependent protein kinase decreased the EC50 value for cGMP from 72 to 23 μm. Phosphomimetic point mutations (S117D/S167D), which project complete phosphorylation, lowered the EC50 value to 16 μm. Structural and sequence data indicate that 196 amino acids precede the start of the GAF domain in hPDE11A4. Removal of 197 amino acids yielded unregulated cyclase activity, whereas truncation by 196 amino acids resulted in a cGMP‐regulated protein with a cGMP EC50 value of 7.6 μm. Truncation by 176 amino acids was required for cGMP EC50 values to decrease to below 10 μm; a construct truncated by 168 amino acids had an EC50 value of 224 μm. The decrease in EC50 values was accompanied by a sixfold increase in basal activity; the extent of cGMP stimulation remained unaffected, however. We conclude that N‐terminal modifications strongly affect cGMP regulation of hPDE11A4.
The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib is indicated for relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on its observed superior response and survival outcomes compared with salvage chemotherapy (SC). Frontline use of FLT3 tyrosine kinase inhibitors (TKIs) midostaurin and sorafenib may contribute to cross-resistance to single-agent gilteritinib in the R/R AML setting but has not been well characterized. To clarify the potential clinical impact of prior TKI use, we retrospectively compared clinical outcomes in patients with R/R FLT3-mutated AML in the CHRYSALIS and ADMIRAL trials who received prior midostaurin or sorafenib against those without prior FLT3 TKI exposure. Similarly high rates of composite complete remission (CRc) were observed in patients who received a FLT3 TKI before gilteritinib (CHRYSALIS, 42%; ADMIRAL, 52%) and those without prior FLT3 TKI therapy (CHRYSALIS, 43%; ADMIRAL, 55%). Among patients who received a prior FLT3 TKI in ADMIRAL, a higher CRc rate (52%) and trend toward longer median overall survival was observed in the gilteritinib arm versus the SC arm (CRc = 20%; overall survival, 5.1 months; HR = 0.602; 95% CI: 0.299, 1.210). Remission duration was shorter with prior FLT3 TKI exposure. These findings support gilteritinib for FLT3-mutated R/R AML after prior sorafenib or midostaurin.
Background: Gilteritinib is a FLT3 inhibitor with demonstrated efficacy and safety in patients with FLT3-mutated relapsed or refractory (R/R) AML. The efficacy of gilteritinib in patients with prior tyrosine kinase inhibitor (TKI) therapy is not clearly defined. The phase 1/2 CHRYSALIS trial demonstrated the safety and antileukemic activity of gilteritinib in a FLT3-mutation-enriched R/R AML population (Perl AE, et al. Lancet Oncol. 2017). The phase 3 ADMIRAL trial demonstrated the superiority of gilteritinib to salvage chemotherapy (SC) in FLT3-mutated patients based on longer median overall survival (OS) with gilteritinib (9.3 vs 5.6 months; hazard ratio [HR]=0.64 [95% CI: 0.49, 0.83]; P<0.001) (Perl AE, et al. N Engl J Med. 2019). We sought to determine whether prior TKI therapy affected response and survival in these two trials. Methods: We retrospectively analyzed clinical outcomes in patients with R/R AML previously treated with TKIs midostaurin or sorafenib, before receiving 120- or 200-mg gilteritinib in the CHRYSALIS trial, or before receiving 120-mg gilteritinib in the ADMIRAL trial. Patients randomized to SC in the ADMIRAL trial were also assessed. Patients in the CHRYSALIS trial had received at least one line of prior AML therapy; patients in the ADMIRAL trial received only one line of prior AML therapy. Results: Of the 145 FLT3-mutation-enriched patients who received 120- or 200-mg gilteritinib in the CHRYSALIS trial, 33 (23%; 120 mg, n=15; 200 mg, n=18) had received a prior TKI (all received sorafenib). Baseline characteristics among patients who received (n=33) or did not receive prior TKIs (n=112) were similar; median age was 56 and 61 years, respectively. Across both dose groups, FLT3 mutation types in prior TKI-treated and non-treated patients were: FLT3-ITD (88% vs 84%, respectively), FLT3-TKD (0 vs 8%, respectively), FLT3-ITD and -TKD (12% vs 6%, respectively), and unknown or missing (0 vs 2%, respectively). Rates of composite complete remission (CRc) were similar in patients who received prior TKIs (42%; n=14/33) and in those who did not (43%; n=48/112). Among patients who received prior TKIs, rates of CRc were 53% (n=8/15) in the 120-mg dose group and 33% (n=6/18) in the 200-mg dose group (Table 1); rates of CRc in patients who did not receive prior TKIs were similar across both the 120- and 200-mg dose groups (44% [n=18/41] and 42% [n=30/71], respectively). Among patients treated with prior TKIs across the 120- or 200-mg dose groups (n=33), most (73%; n=24) had received ≥3 lines of any prior AML therapy. In the phase 3 ADMIRAL trial, 31 of 247 (13%) R/R FLT3-mutated AML patients in the gilteritinib arm and 14 of 124 (11%) patients in the SC arm had received prior TKIs. Demographic and baseline characteristics were well balanced between treatment arms and were also similar between prior TKI-treated (n=45) and non-treated patients (n=326); median age was 57 and 62 years, respectively. Among prior TKI-treated and non-treated patients, FLT3 mutation types in gilteritinib and SC arms were: FLT3-ITD (71% vs 93% and 89% vs 91%, respectively), FLT3-TKD (16% vs 7% and 7% vs 8%, respectively), and FLT3-ITD and -TKD (13% vs 0 and 1% vs 0, respectively). FLT3 mutation type was unconfirmed in 5 of 326 (2%) patients who did not receive prior TKIs (gilteritinib vs SC, 2% vs 1%, respectively). In the gilteritinib arm, CRc rates were comparable in patients who received (48%; n=15/31) and did not receive prior TKIs (55%; n=119/216); lower CRc rates were observed in the SC arm in both TKI-treated and non-treated groups (21% [n=3/14] and 22% [n=24/110], respectively) (Table 2). Median OS in patients treated with prior TKIs, albeit not statistically significant, remained high in patients treated with gilteritinib compared with those treated with SC (6.5 vs 4.7 months, respectively; HR=0.671 [95% CI: 0.328, 1.376]) (Table 2). In patients who did not receive prior TKIs, median OS was 9.6 months in the gilteritinib arm and 6.0 months in the SC arm (HR=0.625 [95% CI: 0.474, 0.824]). Conclusions: Patients with R/R AML who received prior TKIs (midostaurin or sorafenib) were able to achieve remission with gilteritinib. High response rates with gilteritinib were observed in heavily pre-treated FLT3-mutation-enriched patients in the CHRYSALIS trial who received prior TKIs. Higher response rates with gilteritinib than with SC were observed in prior TKI-treated patients with FLT3 mutations in the ADMIRAL trial. Disclosures Perl: Takeda: Honoraria, Other: Travel costs for meeting; Syndax: Consultancy, Honoraria; Leukemia & Lymphoma Society, Beat AML: Consultancy; Agios: Consultancy, Honoraria, Other; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Novartis: Honoraria, Other, Research Funding; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; New Link Genetics: Honoraria, Other; Bayer HealthCare Pharmaceuticals: Research Funding; FORMA Therapeutics: Consultancy, Honoraria, Other; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; Jazz: Honoraria, Other; Biomed Valley Discoveries: Research Funding. Altman:Cancer Expert Now: Consultancy; ASH: Consultancy; PeerView: Consultancy; Bristol-Myers Squibb: Consultancy; Fujifilm: Research Funding; AbbVie: Other: advisory board, Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; Theradex: Other: Advisory Board; Immune Pharmaceuticals: Consultancy; Syros: Consultancy; Janssen: Consultancy; Kartos: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; ImmunoGen: Research Funding; Amgen: Research Funding; Aprea: Research Funding; Amphivena: Research Funding; Genentech: Research Funding; Novartis: Consultancy; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Agios: Other: advisory board, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; PrIME Oncology: Consultancy; France Foundation: Consultancy. Montesinos:Celgene, Pfizer, Abbvie: Consultancy; Pfizer, Abbvie, Daiichi Sankyo: Research Funding; Astellas, Novartis, Janssen: Speakers Bureau. Podoltsev:Blueprint Medicines: Consultancy, Honoraria; Astellas Pharma: Research Funding; AI Therapeutics: Research Funding; Samus Therapeutics: Research Funding; Novartis: Consultancy, Honoraria; Bristol-Myers Squib: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria; Daiichi Sankyo: Research Funding; Genentech: Research Funding; CTI biopharma: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Sunesis Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Incyte: Consultancy, Honoraria; Kartos Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding. Martinelli:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; AbbVie: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; Pfizer: Consultancy, Research Funding, Speakers Bureau; Daichii Sankyo: Consultancy, Research Funding; Incyte: Consultancy; Jazz: Consultancy. Smith:FujiFilm: Other: Research support, Research Funding; Abbvie: Other: Research Support, Research Funding; Revolution Medicines: Other: Research Support, Research Funding; Daiichi Sanyko: Consultancy, Honoraria; Sanofi: Honoraria; Astellas Pharma: Honoraria, Other: Research Support, Research Funding. Levis:Amgen: Honoraria; Menarini: Honoraria; FujiFilm: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria. Röllig:Abbvie, Novartis, Pfizer: Consultancy, Research Funding; Amgen, Astellas, BMS, Daiichi Sankyo, Janssen, Roche: Consultancy. Groß-Langenhoff:Astellas: Current Employment. Hasabou:Astellas Pharma: Current Employment. Lu:Astellas: Current Employment. Tiu:Astellas Pharma Global Development: Current Employment; Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months.
Introduction: We evaluated the efficacy and tolerability of 3- and 6-month leuprorelin acetate (LA) depot formulations (Eligard®, Astellas Pharma GmbH) in patients with advanced prostate cancer treated in routine clinical practice in Germany. Materials and Methods: Data was pooled from 2 prospective, open-label, non-interventional studies in which 1,906 patients were treated for 12 months with either the 3-month (n = 633) or 6-month (n = 1,273) LA formulation. Results: Median prostate-specific antigen levels in the pooled patient population declined from 12.0 ng/mL at baseline to 0.5 ng/mL after 12 months. Prostate-specific antigen reduction was achieved in treatment-naïve and pre-treated patients. Adverse events were documented in 8.8% of patients. Conclusions: These pooled data from routine clinical practice in Germany indicate that LA 3- and 6-month depot injections can effectively reduce prostate-specific antigen levels in a broad patient population with advanced prostate cancer.
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