by Samuel J. Taylor, Johanna M. Duyvestyn, Samantha A. Dagger, Emma J

Slides:

Advertisements

Similar presentations

An aptamer-based targeted delivery of miR-26a protects mice against chemotherapy toxicity while suppressing tumor growth by Toshihiko Tanno, Peng Zhang,

Advertisements

by Jad I. Belle, David Langlais, Jessica C

Continuous in vivo infusion of interferon-gamma (IFN-γ) enhances engraftment of syngeneic wild-type cells in Fanca–/– and Fancg–/– mice by Yue Si, Samantha.

Francesca Ficara, Mark J. Murphy, Min Lin, Michael L. Cleary

TLR5 signaling in murine bone marrow induces hematopoietic progenitor cell proliferation and aids survival from radiation by Benyue Zhang, Damilola Oyewole-Said,

MP cells are generated from naïve cells in the periphery.

Cited2 Is an Essential Regulator of Adult Hematopoietic Stem Cells

Fig. 1 Increasing UCB cell dose impairs short-term progenitor cell engraftment. Increasing UCB cell dose impairs short-term progenitor cell engraftment.

Pharmacologic Expansion of Donor-Derived, Naturally Occurring CD4+Foxp3+ Regulatory T Cells Reduces Acute Graft-versus-Host Disease Lethality Without.

by Xue Li, Jared Sipple, Qishen Pang, and Wei Du

Fig. 8. In vivo suppression of MM by CMLD

Fig. 4. The effects of AVP or d(Leu4Lys8)VP, a specific AVPR1B agonist, on anemic rodents. The effects of AVP or d(Leu4Lys8)VP, a specific AVPR1B agonist,

The Branching Point in Erythro-Myeloid Differentiation

Cytotoxic CD8+ T Cells Stimulate Hematopoietic Progenitors by Promoting Cytokine Release from Bone Marrow Mesenchymal Stromal Cells Christian M. Schürch,

An aptamer-based targeted delivery of miR-26a protects mice against chemotherapy toxicity while suppressing tumor growth by Toshihiko Tanno, Peng Zhang,

VLPs activate DCs and antigen-specific CD8+ T cells via the STING and cGAS pathway. VLPs activate DCs and antigen-specific CD8+ T cells via the STING and.

Volume 4, Issue 1, Pages (January 2015)

Antitumor effect of local cancer immunotherapy treatment toward distant B16F10 tumors. Antitumor effect of local cancer immunotherapy treatment toward.

Fig. 7 BRD0705 impairs colony formation in AML cell lines and patient cells and shows in vivo efficacy in multiple AML mouse models. BRD0705 impairs colony.

Juana Serrano-Lopez, Kalpana Nattamai, Nicholas A. Pease, Miranda S

Fig. 4. Improved tumor response to docetaxel in TNBC and trastuzumab in HER2-amplified PDX models with the addition of S Improved tumor response.

LV activation of DCs and subsequent CD8+ T cell priming are dependent on STING and cGAS but not on MyD88, TRIF, or MAVS. LV activation of DCs and subsequent.

Volume 18, Issue 4, Pages (October 2010)

Volume 11, Issue 3, Pages (September 2012)

Volume 7, Issue 6, Pages (December 2016)

Volume 4, Issue 2, Pages (February 2009)

Volume 1, Issue 6, Pages (December 2007)

Volume 4, Issue 6, Pages (June 2009)

Volume 1, Issue 6, Pages (December 2007)

Volume 2, Issue 1, Pages (January 2008)

Volume 8, Issue 4, Pages (April 2017)

by Yue Wei, Hong Zheng, Naran Bao, Shan Jiang, Carlos E

Fig. 5 ALRN-6924 shows robust antileukemic activity in primary AML cells and in vivo. ALRN-6924 shows robust antileukemic activity in primary AML cells.

Human cells produce type I and III IFNs upon Af stimulation.

Fig. 6 In utero injection of inflammatory cytokines or adoptive transfer of activated T cells leads to pregnancy loss. In utero injection of inflammatory.

SLAM Family Markers Resolve Functionally Distinct Subpopulations of Hematopoietic Stem Cells and Multipotent Progenitors Hideyuki Oguro, Lei Ding, Sean J.

TCR signaling is required for exhausted-like TRM cell formation and maintenance. TCR signaling is required for exhausted-like TRM cell formation and maintenance.

Fig. 4. Peanut-specific TH2A cells are specifically targeted during immunotherapy. Peanut-specific TH2A cells are specifically targeted during immunotherapy.

PD-L1 selectively marks circulating NCMs.

Volume 2, Issue 3, Pages (March 2008)

MP cells are generated from naïve cells in the periphery.

Fig. 1. MSCs undergo in vivo apoptosis after infusion without affecting immunosuppression. MSCs undergo in vivo apoptosis after infusion without affecting.

Fig. 5 A competent Fc is required for the antitumor immune response.

Fig. 6. Nontaxane chemotherapies induce TMEM-dependent prometastatic changes in the breast cancer microenvironment. Nontaxane chemotherapies induce TMEM-dependent.

Fig. 4 High P-eIF2α expression in human prostate tumors with loss of PTEN function is associated with increased risk of metastasis or death after surgery.

Fig. 8 Combining M7824 with radiation or chemotherapy enhances antitumor efficacy. Combining M7824 with radiation or chemotherapy enhances antitumor efficacy.

Genetic EGFR ablation in K-RAS–mutated lung AC reduces tumor growth

RAPTOR deficiency impairs the DN-to-DP transition in αβ T cell development. RAPTOR deficiency impairs the DN-to-DP transition in αβ T cell development.

Loss of BAP1 blocks T cell differentiation at the DN3 stage in vitro.

Fig. 4 Administration of BMS to mice inhibits autoimmune-relevant pharmacodynamic endpoints driven by IL-12 and IFNα. Administration of BMS

Fig. 3 BMS blocks functional responses in primary immune cells driven by IL-23 and IL-12. BMS blocks functional responses in primary immune.

Fig. 2 In situ vaccination of CpG in combination with anti-OX40 antibody cures established local and distant tumors. In situ vaccination of CpG in combination.

BMS blocks functional responses in primary immune cells driven by IFNα

Fig. 5 Treatment with BMS (PO BID) protects from wasting and colitis in two SCID mouse models. Treatment with BMS (PO BID) protects from.

Type I and III IFNR expression on hematopoietic cells is required for protection against IA. Type I and III IFNR expression on hematopoietic cells is required.

Granulocyte colony-stimulating factor mobilizes dormant hematopoietic stem cells without proliferation in mice by Jeffrey M. Bernitz, Michael G. Daniel,

Fig. 4 PD-L1 expression is found in the spleen and the BM of mice transplanted with JAK2V617F-transduced bone marrow. PD-L1 expression is found in the.

Fig. 3 Local Maraba treatment of TNBC tumors provides long-term systemic protection. Local Maraba treatment of TNBC tumors provides long-term systemic.

Fig. 1. The HCN channel blocker ivabradine (IVA) is analgesic in a mouse model of type 1 diabetes. The HCN channel blocker ivabradine (IVA) is analgesic.

Fig. 4 Dox-CBD-SA treatment shows reduced toxicity.

by Jianghong Zhong, Tatjana Scholz, Anthony C. Y

Targeting p53-dependent stem cell loss for intestinal chemoprotection

Fig. 2 Neonatal ZIKV infection induces seizures in young mice and increases susceptibility to chemically induced seizures in adult mice. Neonatal ZIKV.

Fig. 4 IP6K1-mediated polyP production by platelets plays a critical role in LPS-induced NPA formation. IP6K1-mediated polyP production by platelets plays.

Fig. 6 Antitumor effect on tumor growth and pulmonary metastasis of CSSD-9 in vivo. Antitumor effect on tumor growth and pulmonary metastasis of CSSD-9.

Response of Tet2−/− Flt3ITD leukemia model to 5-Aza therapy.

AV3 potentiates the effect of gemcitabine in the PDX model in mice

Fig. 6. Combinatorial VCPI and OV M1 treatment is efficacious in vivo and ex vivo. Combinatorial VCPI and OV M1 treatment is efficacious in vivo and ex.

Fig. 7 Differences in the tumor microenvironment between transplant and transgenic BRAFV600E-driven melanoma models may underlie refractoriness of iBIP2.

Fig. 5. Paclitaxel promotes breast cancer cell dissemination and metastasis in a MENA-dependent manner. Paclitaxel promotes breast cancer cell dissemination.

Presentation transcript:

Preventing chemotherapy-induced myelosuppression by repurposing the FLT3 inhibitor quizartinib by Samuel J. Taylor, Johanna M. Duyvestyn, Samantha A. Dagger, Emma J. Dishington, Catherine A. Rinaldi, Oliver M. Dovey, George S. Vassiliou, Carolyn S. Grove, and Wallace Y. Langdon Sci Transl Med Volume 9(402):eaam8060 August 9, 2017 Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 1. Quizartinib induces a rapid and transient quiescence in MPPs. Quizartinib induces a rapid and transient quiescence in MPPs. (A) B6 mice were dosed once daily over a 16-day time course with either vehicle (VEH) or quizartinib (QUIZ; 10 mg/kg) and analyzed 24 hours after the final dose. FLT3+ LSK cells (MPPs) were analyzed by flow cytometry for the expression of Ki-67 and cell size [forward light scatter (FSC)], and the percentages of cells within each quadrant are shown. Cells in the top right quadrant are large Ki-67+ cells (highly proliferative cells), and the cells in the lower left quadrant are small Ki-67− cells (G0 quiescent cells). (B) Percentages of Ki-67+ MPPs and (C) large Ki-67+ MPPs at each time point. (D) Cell cycle analysis showing the proportion of MPPs in the S + G2-M phases after 1 or 2 days of vehicle or quizartinib dosing. (E) Amount of FLT3 ligand in the serum over the 16-day time course. Data are from three to four mice at each time point for each group, and the graphs are expressed as mean ± SEM. All statistics were calculated using Student’s t tests; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Samuel J. Taylor et al., Sci Transl Med 2017;9:eaam8060 Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 2. A single priming dose of quizartinib protects hematopoietic progenitors from 5-FU–induced death. A single priming dose of quizartinib protects hematopoietic progenitors from 5-FU–induced death. (A) Numbers of MPPs from B6 mice dosed twice as indicated, with either vehicle or quizartinib (10 mg/kg) 24 hours apart, and an intraperitoneal injection of 5-FU (150 mg/kg) that was given at the time of the second dose. Bone marrow cells were analyzed by flow cytometry 2 days later to identify MPP numbers. (B) Experimental scheme of a 24-hour dosing time course before the mice were injected with 5-FU. Quizartinib or vehicle was administered to B6 mice at 0, 2, 6, 12, 18, or 24 hours before receiving an intraperitoneal (ip) injection of 5-FU. Bone marrow was examined 2 days later by flow cytometry. Fold change in the numbers of MPPs (C), ST-HSCs (D), LT-HSCs (E), and LK cells (F) from quizartinib-primed mice over a 24-hour time course compared to vehicle + 5-FU–treated mice, as represented by dashed line. (G) Experimental scheme for B6 mice dosed with vehicle or quizartinib 6 hours before an intraperitoneal injection of 5-FU. The bone marrow was examined at 2, 4, 6, 8, or 10 days after 5-FU treatment. (H) Representative flow cytometry profiles showing the lineage-negative bone marrow cells from either vehicle- or quizartinib-primed mice at the indicated time points. Gates shown identify the LK (left) and LSK (right) populations. Numbers of (I) LK cells, (J) LSK cells, (K) MPPs, (L) ST-HSCs, (M) LT-HSCs, and (N) total nucleated bone marrow (BM) cells over the time course. The blue shading shows the normal range of cell numbers from two femurs and two tibias from untreated age-matched B6 mice. Data are from three to six mice at each time point for each group, and the graphs are expressed as mean ± SEM. All statistics were calculated using Student’s t tests; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Samuel J. Taylor et al., Sci Transl Med 2017;9:eaam8060 Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 3. Quizartinib priming before multiple 5-FU treatments enhances survival and blood recovery and prevents weight loss. Quizartinib priming before multiple 5-FU treatments enhances survival and blood recovery and prevents weight loss. (A) Experimental scheme. B6 mice were primed with vehicle or quizartinib (10 mg/kg) 6 or 12 hours before an intraperitoneal injection of 5-FU (150 mg/kg). This process was repeated every 7 or 10 days, with mouse survival, blood counts, and weights monitored. (B and C) Kaplan-Meier survival plots of B6 mice primed with vehicle or quizartinib 12 hours before a 5-FU injection. The treatment cycles were repeated every 7 days (B) or 10 days (C), and the arrows indicate each treatment. Another cohort of B6 mice was treated with three 10-day cycles of 5-FU and primed with vehicle or quizartinib 6 hours before 5-FU treatment. The mice were bled every 5 days after the last injection to track numbers of (D) WBCs, (E) lymphocytes, (F) neutrophils, (G) RBCs, and (H) platelets. (I) The weights of mice over the time course were also recorded. One vehicle-primed mouse succumbed 8 days after the third 5-FU injection. Data are from five mice in each treatment group, with blood counts expressed as mean ± SEM. All statistics were calculated using Student’s t tests; *P < 0.05 and **P < 0.01. Samuel J. Taylor et al., Sci Transl Med 2017;9:eaam8060 Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 4. Quizartinib priming protects hematopoietic progenitors and stem cells from gemcitabine-induced death. Quizartinib priming protects hematopoietic progenitors and stem cells from gemcitabine-induced death. (A) Experimental scheme. B6 mice were primed with vehicle or quizartinib at 0, 6, and 12 hours, and intraperitoneal injections of gemcitabine were administered at 6, 12, and 24 hours. Bone marrow was analyzed 1 and 3 days after the final gemcitabine injection. (B) Total nucleated bone marrow cell numbers and (C) lineage-negative bone marrow cell numbers at 1 and 3 days. Numbers of (D) LK cells and (E) LSK cells from mice at 1 and 3 days after the final gemcitabine injection. (F) Representative flow cytometry profiles from vehicle or quizartinib plus gemcitabine-treated mice at 1 or 3 days after treatment, displaying the expression of c-Kit and Sca-1 on lineage-negative bone marrow cells. Displayed are the gates that identify LK and LSK populations. Numbers of (G) MPPs, (H) ST-HSCs, and (I) LT-HSCs from mice at 1 and 3 days after the final gemcitabine injection. Data are from four mice at each time point for each group, and the graphs are expressed as mean ± SEM. All statistics were calculated using Student’s t tests; *P < 0 .05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Samuel J. Taylor et al., Sci Transl Med 2017;9:eaam8060 Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 5. Hematopoietic progenitors from FLT3-ITD(F692L) mutant mice dosed with quizartinib are not induced into quiescence or protected from 5-FU cytotoxicity. Hematopoietic progenitors from FLT3-ITD(F692L) mutant mice dosed with quizartinib are not induced into quiescence or protected from 5-FU cytotoxicity. (A) Percentage of Ki-67+ MPPs from FLT3-ITD(F692L)–transplanted mice dosed daily for 1 or 2 days with vehicle or quizartinib (10 mg/kg). n = 5 per group. (B) Numbers of surviving MPP cells from FLT3-ITD(F692L)–transplanted mice primed with quizartinib (10 mg/kg) at 0, 2, 6, 12, or 18 hours before an injection of 5-FU normalized to vehicle-primed mice at each time point, as shown by the dashed line. n = 5 per time point. (C) Representative flow cytometry profiles of CD11b+ cells from the blood of WT:FLT3-ITD(F692L) chimeric mice, showing the percentages of CD45.1 (WT) versus CD45.2 [FLT3-ITD(F692L)] cells. The mice were bled at the indicated times after the first treatment, and the arrows represent the administration of quizartinib (10 mg/kg; 12-hour priming) + 5-FU (150 mg/kg) at days 0 and 10. (D) Proportions of WT CD11b+ blood cells over the time course (n = 5), where the arrows represent the two treatment cycles. PreB, prebleed. (E) Kaplan-Meier survival curves of WT:FLT3-ITD(F692L) chimeric mice primed with vehicle or quizartinib before 5-FU administration (n = 10 and 5, respectively). Samuel J. Taylor et al., Sci Transl Med 2017;9:eaam8060 Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 6. Quizartinib priming in combination with 5-FU provides an effective treatment for FLT3-ITD(F692L)/NPM1c–driven AML. Quizartinib priming in combination with 5-FU provides an effective treatment for FLT3-ITD(F692L)/NPM1c–driven AML. (A) Percentage of Ki-67+ MPPs from naturally bred double-mutant FLT3-ITD(F692L)/NPM1c mice dosed for 2 days with vehicle or quizartinib (30 mg/kg). Bone marrow was analyzed 24 hours after the second dose. n = 3 for each group. (B) Kaplan-Meier survival curves of B6 mice transplanted with FLT3-ITD(F692L)/NPM1c AML cells and dosed daily with either vehicle or quizartinib (10 mg/kg). (C) A second cohort of FLT3-ITD(F692L)/NPM1c–transplanted mice was established to investigate the effectiveness of the quizartinib priming plus 5-FU protocol versus induction chemotherapy of Ara-C and Dox. Displayed are pretreatment percentages of CD45.2+ CD11b+ blood cells and total WBC counts for each test group (n = 5). (D) Kaplan-Meier survival curves of FLT3-ITD(F692L)/NPM1c–transplanted mice from the three test groups. (E) WBC counts and (F) spleen weights from untreated and Ara-C + Dox groups at the time of death. (G) Percentages of CD45.2+ CD11b+ WBCs and (H) total WBC counts from individual mice (M1 to M5) treated with quizartinib + 5-FU over the 176-day time course. (I) Flow cytometry profiles displaying CD45.1+ (WT) versus CD45.2+ [FLT3-ITD(F692L)/NPM1c] LSK cells from the bone marrow of the four surviving quizartinib + 5-FU–treated mice culled at day 176. Samuel J. Taylor et al., Sci Transl Med 2017;9:eaam8060 Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 7. Quizartinib priming in combination with 5-FU provides an effective treatment for NPM1c/NrasG12D-driven AML. Quizartinib priming in combination with 5-FU provides an effective treatment for NPM1c/NrasG12D-driven AML. (A) Percentages of Ki-67+ cells within the CD45.2+ (AML) and CD45.1+ (WT) LSK populations from NPM1c/NrasG12D-transplanted mice dosed for 2 days with vehicle or quizartinib (30 mg/kg). n = 5 for each group. ***P < 0.001. (B) A cohort of NPM1c/NrasG12D-transplanted mice was established to investigate the effectiveness of the quizartinib priming plus 5-FU protocol versus standard induction chemotherapy of Ara-C + Dox. Displayed are pretreatment percentages of CD45.2+ CD11b+ blood cells and WBC counts for each test group (n = 5). (C) Kaplan-Meier survival curves of NPM1c/NrasG12D-transplanted mice from the three test groups. (D) WBC counts and (E) spleen weights from untreated and Ara-C + Dox groups at the time of death. (F) Percentages of CD45.2+ CD11b+ WBCs and (G) WBC counts from individual mice (M1 to M5) treated with quizartinib + 5-FU over the time course. (H) A second cohort of NPM1c/NrasG12D-transplanted B6.CD45.1 mice was established to repeat the examination of quizartinib priming plus 5-FU versus induction chemotherapy. Displayed are pretreatment percentages of CD45.2+ CD11b+ blood cells and total WBC counts for each test group (n = 5). (I) Kaplan-Meier survival curves of NPM1c/NrasG12D-transplanted mice from the three test groups. (J) WBC counts and (K) spleen weights from untreated and Ara-C + Dox groups at the time of death. (L) Percentages of CD45.2+ CD11b+ WBCs and (M) WBC counts from individual mice (M1 to M5) treated with quizartinib and 5-FU over the time course. Samuel J. Taylor et al., Sci Transl Med 2017;9:eaam8060 Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works