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Author Lori A Hazlehurst

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Contribution of the bone marrow stromal cells in mediating drug resistance in hematopoietic tumors.

Wei-Chih Chen, Gangqing Hu, Lori A Hazlehurst,

The bone marrow microenvironment (BMM) provides input via production of cytokines, chemokines, extracellular matrixes in the context of lower oxygen levels that influences self-renewal, survival, differentiation, progression, and therapeutic resistance of multiple myeloma and leukemic cells. Within the context of the BMM, tumor cells are supported by osteoblasts, bone marrow ... Read more >>

Curr Opin Pharmacol (Current opinion in pharmacology)
[2020, 54:36-43]

Cited: 0 times

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The Role of TRPC1 in Modulating Cancer Progression.

Osama M Elzamzamy, Reinhold Penner, Lori A Hazlehurst,

Calcium ions (Ca2+) play an important role as second messengers in regulating a plethora of physiological and pathological processes, including the progression of cancer. Several selective and non-selective Ca2+-permeable ion channels are implicated in mediating Ca2+ signaling in cancer cells. In this review, we are focusing on TRPC1, a member ... Read more >>

Cells (Cells)
[2020, 9(2):]

Cited: 1 time

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Hypoxia-induced PIM kinase and laminin-activated integrin α6 mediate resistance to PI3K inhibitors in bone-metastatic CRPC.

Rachel K Toth, Jack D Tran, Michelle T Muldong, Eric A Nollet, Veronique V Schulz, Corbin C Jensen, Lori A Hazlehurst, Eva Corey, Donald Durden, Christina Jamieson, Cindy K Miranti, Noel A Warfel,

Bone-metastatic castration-resistant prostate cancer (CRPC) is lethal due to inherent resistance to androgen deprivation therapy, chemotherapy, and targeted therapies. Despite the fact that a majority of CRPC patients (approximately 70%) harbor a constitutively active PI3K survival pathway, targeting the PI3K/mTOR pathway has failed to increase overall survival in clinical trials. ... Read more >>

(American journal of clinical and experimental urology)
[2019, 7(4):297-312]

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Crystal structure of the mitochondrial protein mitoNEET bound to a benze-sulfonide ligand.

Werner J Geldenhuys, Timothy E Long, Pushkar Saralkar, Toshio Iwasaki, Raisa A A Nuñez, Rajesh R Nair, Mary E Konkle, Michael A Menze, Mark V Pinti, John M Hollander, Lori A Hazlehurst, Aaron R Robart,

MitoNEET (gene cisd1) is a mitochondrial outer membrane [2Fe-2S] protein and is a potential drug target in several metabolic diseases. Previous studies have demonstrated that mitoNEET functions as a redox-active and pH-sensing protein that regulates mitochondrial metabolism, although the structural basis of the potential drug binding site(s) remains elusive. Here ... Read more >>

Commun Chem (Communications chemistry)
[2019, 2:]

Cited: 0 times

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Emerging combination therapies for the management of multiple myeloma: the role of elotuzumab.

Wei-Chih Chen, Abraham S Kanate, Michael Craig, William P Petros, Lori A Hazlehurst,

Treatment options for patients with multiple myeloma (MM) have increased during the past decade. Despite the significant advances, challenges remain on which combination strategies will provide the optimal response for any given patient. Defining optimal combination strategies and corresponding companion diagnostics, that will guide clinical decisions are required to target ... Read more >>

(Cancer management and research)
[2017, 9:307-314]

Cited: 5 times

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MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma.

Michael F Emmons, Nagaraju Anreddy, Javier Cuevas, Kayla Steinberger, Shengyu Yang, Mark McLaughlin, Ariosto Silva, Lori A Hazlehurst,

The emergence of drug resistance continues to be a major hurdle towards improving patient outcomes for the treatment of Multiple Myeloma. MTI-101 is a first-in-class peptidomimetic that binds a CD44/ITGA4 containing complex and triggers necrotic cell death in multiple myeloma cell lines. In this report, we show that acquisition of ... Read more >>

Sci Rep (Scientific reports)
[2017, 7(1):2685]

Cited: 4 times

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Selective inhibition of matrix metalloproteinase-2 in the multiple myeloma-bone microenvironment.

Gemma Shay, Marilena Tauro, Fulvio Loiodice, Paolo Tortorella, Daniel M Sullivan, Lori A Hazlehurst, Conor C Lynch,

Multiple myeloma is a plasma cell malignancy that homes aberrantly to bone causing extensive skeletal destruction. Despite the development of novel therapeutic agents that have significantly improved overall survival, multiple myeloma remains an incurable disease. Matrix metalloproteinase-2 (MMP-2) is associated with cancer and is significantly overexpressed in the bone marrow ... Read more >>

Oncotarget (Oncotarget)
[2017, 8(26):41827-41840]

Cited: 3 times

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High-content screen using zebrafish (Danio rerio) embryos identifies a novel kinase activator and inhibitor.

Werner J Geldenhuys, Sadie A Bergeron, Jackie E Mullins, Rowaa Aljammal, Briah L Gaasch, Wei-Chi Chen, June Yun, Lori A Hazlehurst,

In this report we utilized zebrafish (Danio rerio) embryos in a phenotypical high-content screen (HCS) to identify novel leads in a cancer drug discovery program. We initially validated our HCS model using the flavin adenosine dinucleotide (FAD) containing endoplasmic reticulum (ER) enzyme, endoplasmic reticulum oxidoreductase (ERO1) inhibitor EN460. EN460 showed ... Read more >>

Bioorg Med Chem Lett (Bioorganic & medicinal chemistry letters)
[2017, 27(9):2029-2037]

Cited: 0 times

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Targeting Intrinsic and Extrinsic Vulnerabilities for the Treatment of Multiple Myeloma.

Nagaraju Anreddy, Lori A Hazlehurst,

Multiple myeloma (MM) is a malignant plasma cell disorder, clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. Over the past decade, MM therapy is significantly improved by the introduction of novel therapeutics such as immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide), proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), monoclonal antibodies (daratumumab ... Read more >>

J Cell Biochem (Journal of cellular biochemistry)
[2017, 118(1):15-25]

Cited: 5 times

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The one-two punch: combination treatment in chronic myeloid leukemia.

Kendra L Sweet, Lori A Hazlehurst, Javier Pinilla-Ibarz,

Despite the success of tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML), minimal residual disease persists, requiring indefinite treatment. Accumulated evidence has shown that leukemic stem cells (LSCs) in the bone marrow can survive TKI treatment via downstream BCR-ABL1-independent signaling pathways that are activated by soluble ... Read more >>

Crit. Rev. Oncol. Hematol. (Critical reviews in oncology/hematology)
[2013, 88(3):667-679]

Cited: 3 times

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CRM1 Inhibition Sensitizes Drug Resistant Human Myeloma Cells to Topoisomerase II and Proteasome Inhibitors both In Vitro and Ex Vivo.

Joel G Turner, Jana Dawson, Michael F Emmons, Christopher L Cubitt, Michael Kauffman, Sharon Shacham, Lori A Hazlehurst, Daniel M Sullivan,

Multiple myeloma (MM) remains an incurable disease despite improved treatments, including lenalidomide/pomalidomide and bortezomib/carfilzomib based therapies and high-dose chemotherapy with autologous stem cell rescue. New drug targets are needed to further improve treatment outcomes. Nuclear export of macromolecules is misregulated in many cancers, including in hematological malignancies such as MM. ... Read more >>

(Journal of Cancer)
[2013, 4(8):614-625]

Cited: 27 times

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Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases.

Ernst Schonbrunn, Stephane Betzi, Riazul Alam, Mathew P Martin, Andreas Becker, Huijong Han, Rawle Francis, Ramappa Chakrasali, Sudhakar Jakkaraj, Aslamuzzaman Kazi, Said M Sebti, Christopher L Cubitt, Anthony W Gebhard, Lori A Hazlehurst, Joseph S Tash, Gunda I Georg,

Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that act as key regulatory elements in cell cycle progression. We describe the development of highly potent diaminothiazole inhibitors of CDK2 (IC50 = 0.0009-0.0015 μM) from a single hit compound with weak inhibitory activity (IC50 = 15 μM), discovered by high-throughput screening. Structure-based ... Read more >>

J Med Chem (Journal of medicinal chemistry)
[2013, 56(10):3768-3782]

Cited: 13 times

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Tipifarnib-induced apoptosis in acute myeloid leukemia and multiple myeloma cells depends on Ca2+ influx through plasma membrane Ca2+ channels.

Niranjan Yanamandra, Robert W Buzzeo, Mark Gabriel, Lori A Hazlehurst, Yelenis Mari, Darrin M Beaupre, Javier Cuevas,

A major contributing factor to the high mortality rate associated with acute myeloid leukemia and multiple myeloma is the development of resistance to chemotherapy. We have shown that the combination of tipifarnib, a nonpeptidomimetic farnesyltransferase inhibitor (FTI), with bortezomib, a proteosome inhibitor, promotes synergistic death and overcomes de novo drug ... Read more >>

J. Pharmacol. Exp. Ther. (The Journal of pharmacology and experimental therapeutics)
[2011, 337(3):636-643]

Cited: 15 times

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Emerging strategies for targeting cell adhesion in multiple myeloma.

Rajesh R Nair, Anthony W Gebhard, Michael F Emmons, Lori A Hazlehurst,

Multiple myeloma (MM) is an incurable hematological cancer involving proliferation of abnormal plasma cells that infiltrate the bone marrow (BM) and secrete monoclonal antibodies. The disease is clinically characterized by bone lesions, anemia, hypercalcemia, and renal failure. MM is presently treated with conventional therapies like melphalan, doxorubicin, and prednisone; or ... Read more >>

Adv. Pharmacol. (Advances in pharmacology (San Diego, Calif.))
[2012, 65:143-189]

Cited: 7 times

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Role of STAT3 in Transformation and Drug Resistance in CML.

Rajesh R Nair, Joel H Tolentino, Lori A Hazlehurst,

Chronic myeloid leukemia (CML) is initially driven by the bcr-abl fusion oncoprotein. The identification of bcr-abl led to the discovery and rapid translation into the clinic of bcr-abl kinase inhibitors. Although, bcr-abl inhibitors are efficacious, experimental evidence indicates that targeting bcr-abl is not sufficient for elimination of minimal residual disease ... Read more >>

(Frontiers in oncology)
[2012, 2:30]

Cited: 28 times

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Acquisition of resistance toward HYD1 correlates with a reduction in cleaved α4 integrin expression and a compromised CAM-DR phenotype.

Michael F Emmons, Anthony W Gebhard, Rajesh R Nair, Rachid Baz, Mark L McLaughlin, Anne E Cress, Lori A Hazlehurst,

We recently reported that the β1 integrin antagonist, referred to as HYD1, induces necrotic cell death in myeloma cell lines as a single agent using in vitro and in vivo models. In this article, we sought to delineate the determinants of sensitivity and resistance toward HYD1-induced cell death. To this ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2011, 10(12):2257-2266]

Cited: 17 times

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The bone marrow microenvironment as a sanctuary for minimal residual disease in CML.

Rajesh R Nair, Joel Tolentino, Lori A Hazlehurst,

Bcr-abl kinase inhibitors have provided proof of principal that targeted therapy holds great promise for the treatment of cancer. However, despite the success of these agents in treating chronic myelogenous leukemia (CML), the majority of patients continue to present with minimal residual disease contained within the bone marrow microenvironment. These ... Read more >>

Biochem Pharmacol (Biochemical pharmacology)
[2010, 80(5):602-612]

Cited: 44 times

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Targeting the Fanconi anemia/BRCA pathway circumvents drug resistance in multiple myeloma.

Danielle N Yarde, Vasco Oliveira, Linda Mathews, Xingyu Wang, Alejandro Villagra, David Boulware, Kenneth H Shain, Lori A Hazlehurst, Melissa Alsina, Dung-Tsa Chen, Amer A Beg, William S Dalton,

The Fanconi anemia/BRCA (FA/BRCA) DNA damage repair pathway plays a pivotal role in the cellular response to replicative stress induced by DNA alkylating agents and greatly influences drug response in cancer treatment. We recently reported that FA/BRCA genes are overexpressed and causative for drug resistance in human melphalan-resistant multiple myeloma ... Read more >>

Cancer Res (Cancer research)
[2009, 69(24):9367-9375]

Cited: 60 times

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Human multiple myeloma cells are sensitized to topoisomerase II inhibitors by CRM1 inhibition.

Joel G Turner, Douglas C Marchion, Jana L Dawson, Michael F Emmons, Lori A Hazlehurst, Peter Washausen, Daniel M Sullivan,

Topoisomerase IIalpha (topo IIalpha) is exported from the nucleus of human myeloma cells by a CRM1-dependent mechanism at cellular densities similar to those found in patient bone marrow. When topo IIalpha is trafficked to the cytoplasm, it is not in contact with the DNA; thus, topo IIalpha inhibitors are unable ... Read more >>

Cancer Res (Cancer research)
[2009, 69(17):6899-6905]

Cited: 39 times

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Signaling networks associated with BCR-ABL-dependent transformation.

Lori A Hazlehurst, Nadine N Bewry, Rajesh R Nair, Javier Pinilla-Ibarz,

The fusion protein BCR-ABL results in constitutive tyrosine kinase activity. It also affects downstream targets as well as the subcellular location of the normally tightly regulated Abl tyrosine kinase.The authors review the current knowledge concerning the signaling networks associated with BCR-ABL-dependent transformation.Although BCR-ABL is considered a single genetic change, the ... Read more >>

Cancer Control (Cancer control : journal of the Moffitt Cancer Center)
[2009, 16(2):100-107]

Cited: 32 times

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Detection of DNA damage induced by topoisomerase II inhibitors, gamma radiation and crosslinking agents using the comet assay.

Lori A Hazlehurst,

The comet assay is a simple gel electrophoresis method for visualizing and quantifying DNA damage. The comet assay is sensitive and reproducible and can be used to detect single-strand DNA breaks, double-strand DNA breaks, protein-associated DNA strand breaks and DNA crosslinks. The comet assay uses fluorescent DNA-binding dyes to detect ... Read more >>

Methods Mol. Biol. (Methods in molecular biology (Clifton, N.J.))
[2009, 523:169-176]

Cited: 2 times

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Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance.

Nadine N Bewry, Rajesh R Nair, Michael F Emmons, David Boulware, Javier Pinilla-Ibarz, Lori A Hazlehurst,

Imatinib mesylate is a potent, molecularly targeted therapy against the oncogenic tyrosine kinase BCR-ABL. Although imatinib mesylate has considerable efficacy against chronic myeloid leukemia (CML), advanced-stage CML patients frequently become refractory to this agent. The bone marrow is the predominant microenvironment of CML and is a rich source of both ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2008, 7(10):3169-3175]

Cited: 78 times

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Beta1 integrin adhesion enhances IL-6-mediated STAT3 signaling in myeloma cells: implications for microenvironment influence on tumor survival and proliferation.

Kenneth H Shain, Danielle N Yarde, Mark B Meads, Mei Huang, Richard Jove, Lori A Hazlehurst, William S Dalton,

The bone marrow microenvironmental components interleukin (IL)-6 and fibronectin (FN) individually influence the proliferation and survival of multiple myeloma (MM) cells; however, in vivo, these effectors most likely work together. We examined signaling events, cell cycle progression, and levels of drug response in MM cells either adhered to FN via ... Read more >>

Cancer Res (Cancer research)
[2009, 69(3):1009-1015]

Cited: 108 times

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The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance.

Mark B Meads, Lori A Hazlehurst, William S Dalton,

The bone marrow microenvironment facilitates the survival, differentiation, and proliferation of hematopoietic cells. These cells are supported by fibroblast-like bone marrow stromal cells, osteoblasts, and osteoclasts which secrete soluble factors and extracellular matrix proteins that mediate these functions. This rich environment serves as a safe haven not only for normal ... Read more >>

Clin. Cancer Res. (Clinical cancer research : an official journal of the American Association for Cancer Research)
[2008, 14(9):2519-2526]

Cited: 267 times

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Proteomic contributions to personalized cancer care.

John M Koomen, Eric B Haura, Gerold Bepler, Rebecca Sutphen, Elizabeth R Remily-Wood, Kaaron Benson, Mohamad Hussein, Lori A Hazlehurst, Timothy J Yeatman, Lynne T Hildreth, Thomas A Sellers, Paul B Jacobsen, David A Fenstermacher, William S Dalton,

Cancer impacts each patient and family differently. Our current understanding of the disease is primarily limited to clinical hallmarks of cancer, but many specific molecular mechanisms remain elusive. Genetic markers can be used to determine predisposition to tumor development, but molecularly targeted treatment strategies that improve patient prognosis are not ... Read more >>

Mol. Cell Proteomics (Molecular & cellular proteomics : MCP)
[2008, 7(10):1780-1794]

Cited: 51 times

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