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Hunter, Zachary

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Hunter

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Zachary

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Hunter, Zachary
Author's Publications: search.filters.isAuthorOfPublication.d3dd738a-1157-4194-aea3-3dfba428dde6

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    The Cyclophilin A-CD147 complex promotes bone marrow colonization of B-cell malignancies: implications for therapy
    (2015) Zhu, Di; Wang, Zhongqiu; Zhao, Jian-Jun; Calimeri, Teresa; Meng, Jiang; Hideshima, Teru; Fulciniti, Mariateresa; Kang, Yue; Ficarro, Scott; Tai, Yu-Tzu; Hunter, Zachary; McMilin, Douglas; Tong, Haoxuan; Mitsiades, Constantine; Wu, Catherine; Treon, Steven; Dorfman, David M.; Pinkus, Geraldine; Munshi, Nikhil; Tassone, Pierfrancesco; Marto, Jarrod; Anderson, Kenneth; Carrasco, Ruben
    B-cell malignancies frequently colonizes the bone marrow (BM). The mechanisms responsible for this preferential homing are not entirely known. Using multiple myeloma (MM) as a model of a terminally differentiated B-cell malignancy that selectively colonizes the BM, we demonstrated that BM endothelial cells (BMECs), secrete cyclophilin A (eCyPA), which promotes migration, proliferation, and BM colonization of MM cells via binding to its receptor, CD147, on MM cells. The clinical and translational implications of this work are highlighted by the observation of significantly higher eCyPA levels in BM serum than in peripheral blood (PB) in MM persons, and that eCyPA-CD147 blockade supresses BM-homing and tumor growth in a mouse xenograft model of MM. eCyPA also promoted migration of CLL and LPL cells, two other B-cell malignancies that colonize the BM and express CD147. These findings offer a compelling rationale for exploring the eCyPA-CD147 axis as therapeutic target for these malignancies.
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    Ibrutinib in Previously Treated Waldenström’s Macroglobulinemia
    (Massachusetts Medical Society, 2015-04-09) Treon, Steven; Tripsas, Christina K.; Meid, Kirsten; Warren, Diane; Varma, Gaurav; Green, Rebecca; Argyropoulos, Kimon V.; Yang, Guang; Cao, Yang; Xu, Lian; Patterson, Christopher J.; Rodig, Scott; Zehnder, James L.; Aster, Jon; Harris, Nancy; Kanan, Sandra; Ghobrial, Irene; Castillo, Jorge; Laubach, Jacob; Hunter, Zachary; Salman, Zeena; Li, Jianling; Cheng, Mei; Clow, Fong; Graef, Thorsten; Palomba, M. Lia; Advani, Ranjana H.
    Background: MYD88(L265P) and CXCR4(WHIM) mutations are highly prevalent in Waldenström's macroglobulinemia. MYD88(L265P) triggers tumor-cell growth through Bruton's tyrosine kinase, a target of ibrutinib. CXCR4(WHIM) mutations confer in vitro resistance to ibrutinib. Methods: We performed a prospective study of ibrutinib in 63 symptomatic patients with Waldenström's macroglobulinemia who had received at least one previous treatment, and we investigated the effect of MYD88 and CXCR4 mutations on outcomes. Ibrutinib at a daily dose of 420 mg was administered orally until disease progression or the development of unacceptable toxic effects. Results: After the patients received ibrutinib, median serum IgM levels decreased from 3520 mg per deciliter to 880 mg per deciliter, median hemoglobin levels increased from 10.5 g per deciliter to 13.8 g per deciliter, and bone marrow involvement decreased from 60% to 25% (P<0.01 for all comparisons). The median time to at least a minor response was 4 weeks. The overall response rate was 90.5%, and the major response rate was 73.0%; these rates were highest among patients with MYD88(L265P)CXCR4(WT) (with WT indicating wild-type) (100% overall response rate and 91.2% major response rate), followed by patients with MYD88(L265P)CXCR4(WHIM) (85.7% and 61.9%, respectively) and patients with MYD88(WT)CXCR4(WT) (71.4% and 28.6%). The estimated 2-year progression-free and overall survival rates among all patients were 69.1% and 95.2%, respectively. Treatment-related toxic effects of grade 2 or higher included neutropenia (in 22% of the patients) and thrombocytopenia (in 14%), which were more common in heavily pretreated patients; postprocedural bleeding (in 3%); epistaxis associated with the use of fish-oil supplements (in 3%); and atrial fibrillation associated with a history of arrhythmia (5%). Conclusions: Ibrutinib was highly active, associated with durable responses, and safe in pretreated patients with Waldenström's macroglobulinemia. MYD88 and CXCR4 mutation status affected responses to this drug.
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    Clonal Architecture of CXCR4 WHIM-Like Mutations in Waldenström Macroglobulinaemia
    (Wiley, 2016-03) Xu, Lian; Hunter, Zachary; Tsakmaklis, Nicholas; Cao, Yang; Yang, Guang; Chen, Jie; Liu, Xia; Kanan, Sandra; Castillo, Jorge; Tai, Yu-Tzu; Zehnder, James L.; Brown, Jennifer; Carrasco, Ruben; Advani, Ranjana; Sabile, Jean M.; Argyropoulos, Kimon; Lia Palomba, M.; Morra, Enrica; Trojani, Alessandra; Greco, Antonino; Tedeschi, Alessandra; Varettoni, Marzia; Arcaini, Luca; Munshi, Nikhil; Anderson, Kenneth; Treon, Steven
    CXCR4WHIM somatic mutations are distinctive to Waldenstrom Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4WHIM mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction(AS-PCR) assays for detecting the most common CXCR4WHIM mutations (CXCR4S338X C>A and C>G) in WM. The AS-PCR assays detected CXCR4S338X mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4WHIM mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%)untreated WM, previously treated WM, IgM MGUS and marginal zonelymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cellfraction analysis in WM and IgM MGUS patients showed CXCR4S338X mutations were primarily subclonal, with highly variable clonal distribution(median 35·1%, range 1·2–97·5%). Combined AS-PCR and Sangersequencing revealed multiple CXCR4WHIM mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show thatCXCR4WHIM mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88L265P in WM oncogenesis. The presence of multiple CXCR4WHIM mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability.