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1.
Pediatr Blood Cancer ; 67(11): e28360, 2020 11.
Article in English | MEDLINE | ID: mdl-32909665

ABSTRACT

BACKGROUND: Inadequate myelosuppression during maintenance therapy for acute lymphoblastic leukemia (ALL) is associated with an increased risk of relapse. One mechanism is skewed metabolism of 6-mercaptopurine (6MP), a major component of maintenance therapy, which results in preferential formation of the hepatotoxic metabolite (6-methyl mercaptopurine [6MMP]) with low levels of the antileukemic metabolite, 6-thioguanine nucleotides (6TGN). Allopurinol can modify 6MP metabolism to favor 6TGN production and reduce 6MMP. METHODS: Patients in maintenance were considered for allopurinol treatment who had the following features: (a) Grade ≥3 hepatotoxicity; (b) Grade ≥2 nonhepatic gastrointestinal (GI) toxicity; or (c) persistently elevated absolute neutrophil count (ANC) despite >150% protocol dosing of oral chemotherapy. RESULTS: From 2013 to 2017, 13 ALL patients received allopurinol: nine for hepatotoxicity, five for inadequate myelosuppression, and three for nonhepatic GI toxicity (four met multiple criteria). Allopurinol was well tolerated, without significant adverse events. Allopurinol resulted in a significant decrease in the average 6MMP/6TGN ratio (mean reduction 89.1, P = .0001), with a significant increase in 6TGN (mean 550.4, P = .0008) and a significant decrease in 6MMP (mean 13 755, P = .0013). Patients with hepatotoxicity had a significant decrease in transaminase elevation after starting allopurinol (alanine transaminase [ALT] mean decrease 22.1%, P = .02), and all with nonhepatic GI toxicity had improved symptoms. Those with inadequate myelosuppression had a significant increase in the time with ANC in goal (mean increase 26.4%, P = .0004). CONCLUSIONS: Allopurinol during ALL maintenance chemotherapy is a safe, feasible, and effective intervention for those who have altered metabolism of 6MP causing toxicity or inadequate myelosuppression.


Subject(s)
Allopurinol/therapeutic use , Antimetabolites/therapeutic use , Bone Marrow Diseases/drug therapy , Gastrointestinal Diseases/drug therapy , Mercaptopurine/metabolism , Neoplasm Recurrence, Local/prevention & control , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Bone Marrow Diseases/etiology , Bone Marrow Diseases/metabolism , Bone Marrow Diseases/pathology , Child , Child, Preschool , Female , Follow-Up Studies , Gastrointestinal Diseases/etiology , Gastrointestinal Diseases/metabolism , Gastrointestinal Diseases/pathology , Humans , Infant , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis , Retrospective Studies , Survival Rate
2.
Pediatr Hematol Oncol ; 34(6-7): 365-378, 2017.
Article in English | MEDLINE | ID: mdl-29211600

ABSTRACT

Signaling between leukemia cells and nonhematopoietic cells in the bone marrow microenvironment contributes to leukemia cell growth and survival. This complicated extrinsic mechanism of chemotherapy resistance relies on a number of pathways and factors, some of which have yet to be determined. Research on cell-cell crosstalk the bone marrow microenvironment in acute leukemia was presented at the 2016 annual Therapeutic Advances in Childhood Leukemia (TACL) investigator meeting. This review summarizes the mini-symposium proceedings and focuses on chemokine signaling via the cell surface receptor CXCR4, adhesion molecule signaling via integrin α4, and crosstalk between leukemia cells and the bone marrow microenvironment that is mediated through extracellular vesicles.


Subject(s)
Bone Marrow/metabolism , Chemokines/metabolism , Hematologic Neoplasms/metabolism , Integrins/metabolism , Neoplasm Proteins/metabolism , Signal Transduction , Tumor Microenvironment , Animals , Bone Marrow/pathology , Hematologic Neoplasms/pathology , Humans
3.
Pediatr Blood Cancer ; 64(8)2017 Aug.
Article in English | MEDLINE | ID: mdl-28409853

ABSTRACT

BACKGROUND: Plerixafor, a reversible CXCR4 antagonist, inhibits interactions between leukemic blasts and the bone marrow stromal microenvironment and may enhance chemosensitivity. A phase 1 trial of plerixafor in combination with intensive chemotherapy in children and young adults with relapsed or refractory acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS) was performed to determine a tolerable and biologically active dose. PROCEDURE: Plerixafor was administered daily for 5 days at four dose levels (6, 9, 12, and 15 mg/m2 /dose) followed 4 hr later by high-dose cytarabine (every 12 hr) and etoposide (daily). RESULTS: Nineteen patients (13 with AML, 5 with ALL, 1 with MDS) were treated. The most common grade 3 or greater nonhematologic toxicities attributable to plerixafor were febrile neutropenia and hypokalemia. There were no dose-limiting toxicities (DLTs). Plerixafor exposure increased with increasing dose levels and clearance was similar on days 1 and 5. Eighteen patients were evaluable for response. Two patients achieved complete remission (CR) and one patient achieved CR with incomplete hematologic recovery (CRi): all three had AML. No responses were seen in patients with ALL or MDS. Plerixafor mobilized leukemic blasts into the peripheral blood in 14 of 16 evaluable patients (median 3.4-fold increase), and the degree of mobilization correlated with surface CXCR4 expression. CONCLUSIONS: Plerixafor, in combination with high-dose cytarabine and etoposide, was well tolerated in children and young adults with relapsed/refractory acute leukemias and MDS. While biologic responses were observed, clinical responses in this heavily pretreated cohort were modest.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Heterocyclic Compounds/administration & dosage , Myelodysplastic Syndromes/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzylamines , Child , Child, Preschool , Cyclams , Cytarabine/administration & dosage , Cytarabine/adverse effects , Etoposide/administration & dosage , Etoposide/adverse effects , Female , Heterocyclic Compounds/adverse effects , Humans , Leukemia, Myeloid, Acute/drug therapy , Male , Neoplasm Recurrence, Local/drug therapy , Receptors, CXCR4/antagonists & inhibitors , Treatment Outcome , Young Adult
4.
Angew Chem Int Ed Engl ; 54(44): 13085-9, 2015 Oct 26.
Article in English | MEDLINE | ID: mdl-26480340

ABSTRACT

Nearly 40 % of children with acute myeloid leukemia (AML) suffer relapse arising from chemoresistance, often involving upregulation of the oncoprotein STAT3 (signal transducer and activator of transcription 3). Herein, rhodium(II)-catalyzed, proximity-driven modification identifies the STAT3 coiled-coil domain (CCD) as a novel ligand-binding site, and we describe a new naphthalene sulfonamide inhibitor that targets the CCD, blocks STAT3 function, and halts its disease-promoting effects in vitro, in tumor growth models, and in a leukemia mouse model, validating this new therapeutic target for resistant AML.


Subject(s)
Antineoplastic Agents/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Naphthalenes/pharmacology , Rhodium/chemistry , STAT3 Transcription Factor/antagonists & inhibitors , Sulfonamides/pharmacology , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Binding Sites/drug effects , Catalysis , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Leukemia, Myeloid, Acute/pathology , Mice , Naphthalenes/chemistry , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , STAT3 Transcription Factor/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry
5.
Oncotarget ; 6(31): 30902-18, 2015 Oct 13.
Article in English | MEDLINE | ID: mdl-26360610

ABSTRACT

The importance of the cell surface receptor CXCR4 and the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) is well-established in normal and malignant hematopoiesis. The Protein Epitope Mimetic POL5551 is a novel and potent antagonist of CXCR4. POL5551 efficiently mobilizes hematopoietic stem and progenitor cells, but its effects in acute lymphoblastic leukemia (ALL) have not been reported. Here, we demonstrate that POL5551 is a potent antagonist of CXCR4 in pre-B and T cell ALL cell lines and pediatric ALL primary samples. POL5551 has activity at nanomolar concentrations in decreasing CXCR4 antibody binding, blocking SDF-1α-mediated phosphorylation of ERK1/2, inhibiting SDF-1α-induced chemotaxis, and reversing stromal-mediated protection from chemotherapy. POL5551 is significantly more effective at inhibiting CXCR4 antibody binding than the FDA-approved CXCR4 inhibitor plerixafor in ALL cell lines and primary samples. We also show that treatment with POL5551 in vitro and cytarabine +/- POL5551 in vivo modulates surface expression of adhesion molecules, findings that may guide the optimal clinical use of POL5551. Finally, we demonstrate that POL5551 increases sensitivity to cytarabine in a xenograft model of a high-risk pediatric ALL, infant MLL-rearranged (MLL-R) ALL. Therefore, disruption of the CXCR4/SDF-1 axis with POL5551 may improve outcomes in children with high-risk ALL.


Subject(s)
Cell Movement/drug effects , Drug Resistance, Neoplasm/drug effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Proteins/pharmacology , Receptors, CXCR4/antagonists & inhibitors , Stromal Cells/drug effects , Animals , Apoptosis/drug effects , Cell Proliferation/drug effects , Chemotaxis/drug effects , Child , Flow Cytometry , Humans , Mice , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Stromal Cells/metabolism , Stromal Cells/pathology , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
6.
Oncotarget ; 5(19): 8947-58, 2014 Oct 15.
Article in English | MEDLINE | ID: mdl-25333254

ABSTRACT

In spite of advances in the treatment of pediatric acute lymphoblastic leukemia (ALL), a significant number of children with ALL are not cured of their disease. We and others have shown that signaling from the bone marrow microenvironment confers therapeutic resistance, and that the interaction between CXCR4 and stromal cell-derived factor-1 (SDF-1 or CXCL12) is a key mediator of this effect. We demonstrate that ALL cells that upregulate surface CXCR4 in response to chemotherapy treatment are protected from chemotherapy-induced apoptosis when co-cultured with bone marrow stroma. Treatment with the CXCR4 inhibitor plerixafor diminishes stromal protection and confers chemosensitivity. Using xenograft models of high-risk pediatric ALL, plerixafor plus chemotherapy induces significantly decreased leukemic burden, compared to chemotherapy alone. Further, treatment with plerixafor and chemotherapy influences surface expression of CXCR4, VLA-4, and CXCR7 in surviving ALL blasts. Finally, prolonged exposure of ALL blasts to plerixafor leads to a persistent increase in surface CXCR4 expression, along with modulation of surface expression of additional adhesion molecules, and enhanced SDF-1α-induced chemotaxis, findings that may have implications for therapeutic resistance. Our results suggest that while CXCR4 inhibition may prove useful in ALL, further study is needed to understand the full effects of targeting the leukemic microenvironment.


Subject(s)
Apoptosis/drug effects , Cytarabine/pharmacology , Heterocyclic Compounds/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Receptors, CXCR4/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacology , Benzylamines , Cell Adhesion Molecules/biosynthesis , Cell Line, Tumor , Chemokine CXCL12/metabolism , Chemotaxis/drug effects , Coculture Techniques , Cyclams , Heterografts , Humans , Infant , Infant, Newborn , Integrin alpha4beta1/biosynthesis , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Transplantation , Receptors, CXCR/biosynthesis , Receptors, CXCR4/biosynthesis , Receptors, CXCR4/metabolism , Up-Regulation
8.
Article in English | MEDLINE | ID: mdl-24319238

ABSTRACT

A 6-month-old girl was diagnosed with acute lymphoblastic leukemia (ALL). She has completed induction therapy and is currently in first complete remission (CR1). You are asked by your resident if hematopoietic stem cell transplantation (HSCT) would benefit infants with acute leukemia.


Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia/therapy , Acute Disease , Allografts , Female , Humans , Infant , Infant, Newborn , Male , Remission Induction
9.
Mol Cancer Res ; 11(9): 1004-16, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23754844

ABSTRACT

UNLABELLED: Cure rates in pediatric acute leukemias remain suboptimal. Overexpression of the cell-surface chemokine receptor CXCR4 is associated with poor outcome in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Certain nonchemotherapeutic agents have been shown to modulate CXCR4 expression and alter leukemia interactions with stromal cells in the bone marrow microenvironment. Because chemotherapy is the mainstay of AML treatment, it was hypothesized that standard cytotoxic chemotherapeutic agents induce dynamic changes in leukemia surface CXCR4 expression, and that chemotherapy-induced upregulation of CXCR4 represents a mechanism of acquired therapeutic resistance. Here, it was shown that cell lines variably upregulate CXCR4 with chemotherapy treatment. Those that showed upregulation were differentially protected from chemotherapy-induced apoptosis when cocultured with stroma. The functional effects of chemotherapy-induced CXCR4 upregulation in an AML cell line (MOLM-14, which harbors consistent upregulated CXCR4) and clinical specimens were explored. Importantly, enhanced stromal-cell derived factor-1α (SDF1A/CXCL12)-mediated chemotaxis and stromal protection from additional chemotherapy-induced apoptosis was found. Furthermore, treatment with plerixafor, a CXCR4 inhibitor, preferentially decreased stromal protection with higher chemotherapy-induced upregulation of surface CXCR4. Thus, increased chemokine receptor CXCR4 expression after treatment with conventional chemotherapy may represent a mechanism of therapeutic resistance in pediatric AML. IMPLICATIONS: CXCR4 may be a biomarker for the stratification and optimal treatment of patients using CXCR4 inhibitors.


Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Receptors, CXCR4/genetics , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Apoptosis/genetics , Benzylamines , Cell Line, Tumor , Cell Movement/drug effects , Chemokine CXCL12/metabolism , Chemotaxis/drug effects , Chemotaxis/genetics , Child , Cyclams , Drug Resistance, Neoplasm , Gene Expression Regulation, Leukemic , Heterocyclic Compounds/therapeutic use , Humans , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Receptors, CXCR4/antagonists & inhibitors , Receptors, CXCR4/metabolism , Stromal Cells/drug effects , Stromal Cells/metabolism , Up-Regulation
10.
Br J Haematol ; 160(6): 785-97, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23294096

ABSTRACT

Infants with MLL-rearranged (MLL-R) acute lymphoblastic leukaemia (ALL) have a dismal prognosis. While most patients achieve remission, approximately half of patients recur with a short latency to relapse. This suggests that chemotherapy-resistant leukaemia stem cells (LSCs) survive and can recapitulate the leukaemia. We hypothesized that interactions between LSCs and the bone marrow microenvironment mediate survival and chemotherapy resistance in MLL-R ALL. Using primary samples of infant MLL-R ALL, we studied the influence of bone marrow stroma on apoptosis, proliferation, and cytotoxicity induced by the FLT3 inhibitor lestaurtinib. MLL-R ALL were differentially protected by stroma from spontaneous apoptosis compared to non-MLL-R ALL. Co-culture of bulk MLL-R ALL in direct contact with stroma or with stroma-produced soluble factors promoted proliferation and cell cycle entry. Stroma also protected bulk MLL-R ALL cells and MLL-R ALL LSCs from lestaurtinib-mediated cytotoxicity. Previous studies have demonstrated that CXCR4 mediates bone marrow microenvironment signalling. Using a xenograft model of MLL-R ALL, we demonstrated that CXCR4 inhibition with AMD3100 (plerixafor) led to markedly enhanced efficacy of lestaurtinib. Therefore, the bone marrow microenvironment is a mediator of chemotherapy resistance in MLL-R ALL and targeting leukaemia-stroma interactions with CXCR4 inhibitors may prove useful in this high-risk subtype of paediatric ALL.


Subject(s)
Bone Marrow Cells/pathology , Cell Communication/physiology , Myeloid-Lymphoid Leukemia Protein/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Receptors, CXCR4/antagonists & inhibitors , Stromal Cells/pathology , Animals , Apoptosis/genetics , Cell Growth Processes/genetics , Cell Line, Tumor , Coculture Techniques , Histone-Lysine N-Methyltransferase , Humans , Infant , Mice , Mice, Inbred NOD , Mice, SCID , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Prognosis , Receptors, CXCR4/genetics , Receptors, CXCR4/metabolism , Survival Analysis , Tumor Microenvironment , Xenograft Model Antitumor Assays
11.
Expert Rev Hematol ; 4(3): 271-83, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21668393

ABSTRACT

Multiple studies have demonstrated that interaction with the bone marrow stromal microenvironment contributes to the survival of leukemia cells. One explanation for this phenomenon is the interaction between the cell surface receptors CXCR4 and CXCL12. Through CXCL12/CXCR4-mediated chemotaxis, leukemia cells migrate to microscopic niches within the bone marrow, which leads to increased proliferation and survival. Several studies have suggested that increased CXCR4 expression may portend a poor prognosis in various types of leukemia, possibly due to increased protection of leukemia cells by bone marrow stroma. A potential therapeutic strategy to overcome this stromal-mediated survival advantage is to target CXCR4. Inhibition of CXCR4 may allow leukemia cells to be released from bone marrow niches that confer resistance to chemotherapy and negate the survival benefit imparted by bone marrow stroma.


Subject(s)
Bone Marrow/metabolism , Leukemia/therapy , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Chemokine CXCL12/metabolism , Clinical Trials as Topic , Drug Evaluation, Preclinical , Hematopoiesis , Humans , Peptides/chemistry , Peptides/therapeutic use , Receptors, CXCR4/antagonists & inhibitors , Receptors, CXCR4/metabolism
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