Search

Your search keyword '"Mitchell, Shaneice"' showing total 30 results
Start Over Author "Mitchell, Shaneice"
30 results on '"Mitchell, Shaneice"'

1. The multi-CDK inhibitor dinaciclib reverses bromo- and extra-terminal domain (BET) inhibitor resistance in acute myeloid leukemia via inhibition of Wnt/β-catenin signaling

Author

Marr, Alexander R., Halpin, Madeline, Corbin, Dominique L., Asemelash, Yerdanos, Sher, Steven, Gordon, Britten K., Whipp, Ethan C., Mitchell, Shaneice, Harrington, Bonnie K., Orwick, Shelley, Benrashid, Samon, Goettl, Virginia M., Yildiz, Vedat, Mitchell, Andrew D., Cahn, Olivia, Mims, Alice S., Larkin, Karilyn T. M., Long, Meixao, Blachly, James, Woyach, Jennifer A., Lapalombella, Rosa, and Grieselhuber, Nicole R.

Published
2024
Full Text
View/download PDF

2. Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.

Author

Weinstock, Joshua, Gopakumar, Jayakrishnan, Burugula, Bala, Uddin, Md, Jahn, Nikolaus, Belk, Julia, Bouzid, Hind, Daniel, Bence, Miao, Zhuang, Ly, Nghi, Mack, Taralynn, Luna, Sofia, Prothro, Katherine, Mitchell, Shaneice, Laurie, Cecelia, Broome, Jai, Taylor, Kent, Guo, Xiuqing, Sinner, Moritz, von Falkenhausen, Aenne, Kääb, Stefan, Shuldiner, Alan, OConnell, Jeffrey, Lewis, Joshua, Boerwinkle, Eric, Barnes, Kathleen, Chami, Nathalie, Kenny, Eimear, Loos, Ruth, Fornage, Myriam, Hou, Lifang, Lloyd-Jones, Donald, Redline, Susan, Cade, Brian, Psaty, Bruce, Bis, Joshua, Brody, Jennifer, Silverman, Edwin, Yun, Jeong, Qiao, Dandi, Palmer, Nicholette, Freedman, Barry, Bowden, Donald, Cho, Michael, DeMeo, Dawn, Vasan, Ramachandran, Yanek, Lisa, Becker, Lewis, Kardia, Sharon, Peyser, Patricia, He, Jiang, Rienstra, Michiel, Van der Harst, Pim, Kaplan, Robert, Heckbert, Susan, Smith, Nicholas, Wiggins, Kerri, Arnett, Donna, Irvin, Marguerite, Tiwari, Hemant, Cutler, Michael, Knight, Stacey, Muhlestein, J, Correa, Adolfo, Raffield, Laura, Gao, Yan, de Andrade, Mariza, Rotter, Jerome, Rich, Stephen, Tracy, Russell, Konkle, Barbara, Johnsen, Jill, Wheeler, Marsha, Smith, J, Melander, Olle, Nilsson, Peter, Custer, Brian, Duggirala, Ravindranath, Curran, Joanne, Blangero, John, McGarvey, Stephen, Williams, L, Xiao, Shujie, Yang, Mao, Gu, C, Chen, Yii-Der, Lee, Wen-Jane, Kane, John, Pullinger, Clive, Shoemaker, M, Darbar, Dawood, Roden, Dan, Albert, Christine, Kooperberg, Charles, Zhou, Ying, Manson, JoAnn, Desai, Pinkal, Johnson, Andrew, Mathias, Rasika, and Blackwell, Thomas

Subjects
Animals, Humans, Mice, Alleles, Clonal Hematopoiesis, Genome-Wide Association Study, Hematopoiesis, Hematopoietic Stem Cells, Mutation, Promoter Regions, Genetic
Abstract

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

Published
2023

6. Data from BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor

Author

Ozer, Hatice Gulcin, primary, El-Gamal, Dalia, primary, Powell, Ben, primary, Hing, Zachary A., primary, Blachly, James S., primary, Harrington, Bonnie, primary, Mitchell, Shaneice, primary, Grieselhuber, Nicole R., primary, Williams, Katie, primary, Lai, Tzung-Huei, primary, Alinari, Lapo, primary, Baiocchi, Robert A., primary, Brinton, Lindsey, primary, Baskin, Elizabeth, primary, Cannon, Matthew, primary, Beaver, Larry, primary, Goettl, Virginia M., primary, Lucas, David M., primary, Woyach, Jennifer A., primary, Sampath, Deepa, primary, Lehman, Amy M., primary, Yu, Lianbo, primary, Zhang, Jiazhong, primary, Ma, Yan, primary, Zhang, Ying, primary, Spevak, Wayne, primary, Shi, Songyuan, primary, Severson, Paul, primary, Shellooe, Rafe, primary, Carias, Heidi, primary, Tsang, Garson, primary, Dong, Ken, primary, Ewing, Todd, primary, Marimuthu, Adhirai, primary, Tantoy, Christina, primary, Walters, Jason, primary, Sanftner, Laura, primary, Rezaei, Hamid, primary, Nespi, Marika, primary, Matusow, Bernice, primary, Habets, Gaston, primary, Ibrahim, Prabha, primary, Zhang, Chao, primary, Mathé, Ewy A., primary, Bollag, Gideon, primary, Byrd, John C., primary, and Lapalombella, Rosa, primary

Published
2023
Full Text
View/download PDF

7. Supplementary Methods from BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor

Author

Ozer, Hatice Gulcin, primary, El-Gamal, Dalia, primary, Powell, Ben, primary, Hing, Zachary A., primary, Blachly, James S., primary, Harrington, Bonnie, primary, Mitchell, Shaneice, primary, Grieselhuber, Nicole R., primary, Williams, Katie, primary, Lai, Tzung-Huei, primary, Alinari, Lapo, primary, Baiocchi, Robert A., primary, Brinton, Lindsey, primary, Baskin, Elizabeth, primary, Cannon, Matthew, primary, Beaver, Larry, primary, Goettl, Virginia M., primary, Lucas, David M., primary, Woyach, Jennifer A., primary, Sampath, Deepa, primary, Lehman, Amy M., primary, Yu, Lianbo, primary, Zhang, Jiazhong, primary, Ma, Yan, primary, Zhang, Ying, primary, Spevak, Wayne, primary, Shi, Songyuan, primary, Severson, Paul, primary, Shellooe, Rafe, primary, Carias, Heidi, primary, Tsang, Garson, primary, Dong, Ken, primary, Ewing, Todd, primary, Marimuthu, Adhirai, primary, Tantoy, Christina, primary, Walters, Jason, primary, Sanftner, Laura, primary, Rezaei, Hamid, primary, Nespi, Marika, primary, Matusow, Bernice, primary, Habets, Gaston, primary, Ibrahim, Prabha, primary, Zhang, Chao, primary, Mathé, Ewy A., primary, Bollag, Gideon, primary, Byrd, John C., primary, and Lapalombella, Rosa, primary

Published
2023
Full Text
View/download PDF

8. Supplementary Figures & Tables from BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor

Author

Ozer, Hatice Gulcin, primary, El-Gamal, Dalia, primary, Powell, Ben, primary, Hing, Zachary A., primary, Blachly, James S., primary, Harrington, Bonnie, primary, Mitchell, Shaneice, primary, Grieselhuber, Nicole R., primary, Williams, Katie, primary, Lai, Tzung-Huei, primary, Alinari, Lapo, primary, Baiocchi, Robert A., primary, Brinton, Lindsey, primary, Baskin, Elizabeth, primary, Cannon, Matthew, primary, Beaver, Larry, primary, Goettl, Virginia M., primary, Lucas, David M., primary, Woyach, Jennifer A., primary, Sampath, Deepa, primary, Lehman, Amy M., primary, Yu, Lianbo, primary, Zhang, Jiazhong, primary, Ma, Yan, primary, Zhang, Ying, primary, Spevak, Wayne, primary, Shi, Songyuan, primary, Severson, Paul, primary, Shellooe, Rafe, primary, Carias, Heidi, primary, Tsang, Garson, primary, Dong, Ken, primary, Ewing, Todd, primary, Marimuthu, Adhirai, primary, Tantoy, Christina, primary, Walters, Jason, primary, Sanftner, Laura, primary, Rezaei, Hamid, primary, Nespi, Marika, primary, Matusow, Bernice, primary, Habets, Gaston, primary, Ibrahim, Prabha, primary, Zhang, Chao, primary, Mathé, Ewy A., primary, Bollag, Gideon, primary, Byrd, John C., primary, and Lapalombella, Rosa, primary

Published
2023
Full Text
View/download PDF

10. Supplementary Figure S3 from Targeting DNA Damage Repair Functions of Two Histone Deacetylases, HDAC8 and SIRT6, Sensitizes Acute Myeloid Leukemia to NAMPT Inhibition

Author

Zhang, Pu, primary, Brinton, Lindsey T., primary, Williams, Katie, primary, Sher, Steven, primary, Orwick, Shelley, primary, Tzung-Huei, Lai, primary, Mims, Alice S., primary, Coss, Christopher C., primary, Kulp, Samuel K., primary, Youssef, Youssef, primary, Chan, Wing Keung, primary, Mitchell, Shaneice, primary, Mustonen, Allison, primary, Cannon, Matthew, primary, Phillips, Hannah, primary, Lehman, Amy M., primary, Kauffman, Tierney, primary, Beaver, Larry, primary, Canfield, Daniel, primary, Grieselhuber, Nicole R., primary, Alinari, Lapo, primary, Sampath, Deepa, primary, Yan, Pearlly, primary, Byrd, John C., primary, Blachly, James S., primary, and Lapalombella, Rosa, primary

Published
2023
Full Text
View/download PDF

11. The Multi-CDK Inhibitor Dinaciclib Shows Synergistic Activity with the BET Inhibitor PLX51107 and Reverses BET Resistance through Inhibition of Canonical Wnt Signaling in Acute Myeloid Leukemia (AML)

Author

Marr, Alexander, primary, Karmahapatra, Soumendrakrishna, additional, Corbin, Dominique, additional, Asemelash, Yerdanos, additional, Sher, Steven, additional, Mitchell, Shaneice Renee, additional, Harrington, Bonnie K, additional, Orwick, Shelley, additional, Beaver, Larry, additional, Wasmuth, Ronni, additional, Goettl, Virginia, additional, Mims, Alice S., additional, Larkin, Karilyn T., additional, Vasu, Sumithira, additional, Long, Meixiao, additional, Blachly, James S., additional, Garzon, Ramiro, additional, Byrd, John C., additional, Lapalombella, Rosa, additional, and Grieselhuber, Nicole, additional

Published
2022
Full Text
View/download PDF

13. Additional file 1 of Red blood cells differentiated in vitro using sequential liquid and semi-solid culture as a pre-clinical model

Author

Cannon, Matthew, Phillips, Hannah, Smith, Sidney, Mitchell, Shaneice, Landes, Kristina, Desai, Payal, Byrd, John, and Lapalombella, Rosa

Abstract

Additional file 1: Figure S1. Establishment of original two-stage culture methods. a Timeline schematic adapted from original in vitro erythroid culture system Migliaccio et al. [5]. Expansion phase cytokines are added after isolation. After 1 week, cells are cultured with differentiation phase cytokines. b CD45/CD235/CD71 positivity of patient derived PBMCs measured after 1 week in expansion phase cytokines (measured at day 8). c CD45/CD235/CD71 positivity of patient derived cells after 1 week in differentiation phase cytokines (measured at day 14). d Quantification of CD45/CD235/CD71 positivity at day 8 and day 14. e Quantification of differentiation status by CD235/CD71 status (Early E. blast: CD235+/CD71+, Mature E. blast: CD235+/CD71dim, Late E. blast: CD235+). Figure S2. Extension of two-stage culture methodology yields mixed results. a Timeline schematic for extension of two-stage culture system adapted from previously published methodology (Top-panel: Miharada et al. [6], Bottom-panel: Giarratana et al. [2]. b CD45/CD235 positivity for cells measured after final collection of both extended protocols. Figure S3. Semi-solid media demonstrates relationship between differentiation efficiency and cell viability. a CD235/CD71 erythroid profiles of semi-solid plated cells at various concentrations. b Quantification of CD235/CD71 erythroid profiles of various concentrations in semi-solid medium. c Viability of cells grown at various concentrations in semi-solid medium. Figure S4. Advantages and disadvantages at-a-glance between semi-solid and liquid culture for terminal stages of in vitro differentiation method.

Published
2021
Full Text
View/download PDF

15. Targeting DNA Damage Repair Functions of Two Histone Deacetylases, HDAC8 and SIRT6, Sensitizes Acute Myeloid Leukemia to NAMPT Inhibition

Author

Zhang, Pu, primary, Brinton, Lindsey T., additional, Williams, Katie, additional, Sher, Steven, additional, Orwick, Shelley, additional, Tzung-Huei, Lai, additional, Mims, Alice S., additional, Coss, Christopher C., additional, Kulp, Samuel K., additional, Youssef, Youssef, additional, Chan, Wing Keung, additional, Mitchell, Shaneice, additional, Mustonen, Allison, additional, Cannon, Matthew, additional, Phillips, Hannah, additional, Lehman, Amy M., additional, Kauffman, Tierney, additional, Beaver, Larry, additional, Canfield, Daniel, additional, Grieselhuber, Nicole R., additional, Alinari, Lapo, additional, Sampath, Deepa, additional, Yan, Pearlly, additional, Byrd, John C., additional, Blachly, James S., additional, and Lapalombella, Rosa, additional

Published
2021
Full Text
View/download PDF

17. HSP90 inhibition depletes DNA repair proteins to sensitize acute myelogenous leukemia to nucleoside analog chemotherapeutics

Author

Lai, Tzung-Huei, primary, Mitchell, Shaneice, additional, Wu, Pei-Jung, additional, Orwick, Shelley, additional, Liu, Chaomei, additional, Ravikrishnan, Janani, additional, Woyach, Jennifer, additional, Mims, Alice, additional, Plunkett, William, additional, Puduvalli, Vinay K., additional, Byrd, John C., additional, Lapalombella, Rosa, additional, and Sampath, Deepa, additional

Published
2019
Full Text
View/download PDF

18. Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia

Author

Mitchell, Shaneice R., primary, Larkin, Karilyn, additional, Grieselhuber, Nicole R., additional, Lai, Tzung-Huei, additional, Cannon, Matthew, additional, Orwick, Shelley, additional, Sharma, Pratibha, additional, Asemelash, Yerdanose, additional, Zhang, Pu, additional, Goettl, Virginia M., additional, Beaver, Larry, additional, Mims, Alice, additional, Puduvalli, Vinay K., additional, Blachly, James S., additional, Lehman, Amy, additional, Harrington, Bonnie, additional, Henderson, Sally, additional, Breitbach, Justin T., additional, Williams, Katie E., additional, Dong, Shuai, additional, Baloglu, Erkan, additional, Senapedis, William, additional, Kirschner, Karl, additional, Sampath, Deepa, additional, Lapalombella, Rosa, additional, and Byrd, John C., additional

Published
2019
Full Text
View/download PDF

19. Using HSP90 Inhibitors to Target DNA Repair Proteins in AML

Author

Ravikrishnan, Janani, primary, Lai, Tzung-Huei, additional, Mitchell, Shaneice Renee, additional, Wu, Pei-Jung, additional, Orwick, Shelley, additional, Liu, Chaomei, additional, Woyach, Jennifer A., additional, Mims, Alice S., additional, Plunkett, William, additional, Puduvalli, Vinay K, additional, Byrd, John C., additional, Lapalombella, Rosa, additional, and Sampath, Deepa, additional

Published
2018
Full Text
View/download PDF

20. NAMPT Inhibitor KPT-9274 Selectively Targets Self-Renewal Capacity in Acute Myeloid Leukemia

Author

Mitchell, Shaneice Renee, primary, Grieselhuber, Nicole, additional, Asemelash, Yerdanos, additional, Cannon, Matthew, additional, Orwick, Shelley, additional, Sharma, Pratibha, additional, Goettl, Virginia, additional, Puduvalli, Vinay K, additional, Sampath, Deepa, additional, Mims, Alice S., additional, Blachly, James S., additional, Lehman, Amy M., additional, Harrington, Bonnie K., additional, Breitbach, Justin, additional, Baloglu, Erkan, additional, Senapedis, William, additional, Lapalombella, Rosa, additional, and Byrd, John C., additional

Published
2018
Full Text
View/download PDF

21. Abstract 1882: Preclinical evaluation of the tyrosine kinase inhibitor ARQ 531 in AML

Author

Elgamal, Ola A., primary, Carmichael, Bridget, additional, Lehman, Amy, additional, Orwick, Shelley J., additional, Tran, Minh, additional, Goettl, Virginia M., additional, Mitchell, Shaneice, additional, Lapalombella, Rosa, additional, Jeon, Jae Yoon, additional, Baker, Sharyn D., additional, Eathiraj, Sudharshan, additional, Schwartz, Brian, additional, Hertlein, Erin, additional, and Byrd, John C., additional

Published
2018
Full Text
View/download PDF

22. BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor

Author

Ozer, Hatice Gulcin, primary, El-Gamal, Dalia, additional, Powell, Ben, additional, Hing, Zachary A., additional, Blachly, James S., additional, Harrington, Bonnie, additional, Mitchell, Shaneice, additional, Grieselhuber, Nicole R., additional, Williams, Katie, additional, Lai, Tzung-Huei, additional, Alinari, Lapo, additional, Baiocchi, Robert A., additional, Brinton, Lindsey, additional, Baskin, Elizabeth, additional, Cannon, Matthew, additional, Beaver, Larry, additional, Goettl, Virginia M., additional, Lucas, David M., additional, Woyach, Jennifer A., additional, Sampath, Deepa, additional, Lehman, Amy M., additional, Yu, Lianbo, additional, Zhang, Jiazhong, additional, Ma, Yan, additional, Zhang, Ying, additional, Spevak, Wayne, additional, Shi, Songyuan, additional, Severson, Paul, additional, Shellooe, Rafe, additional, Carias, Heidi, additional, Tsang, Garson, additional, Dong, Ken, additional, Ewing, Todd, additional, Marimuthu, Adhirai, additional, Tantoy, Christina, additional, Walters, Jason, additional, Sanftner, Laura, additional, Rezaei, Hamid, additional, Nespi, Marika, additional, Matusow, Bernice, additional, Habets, Gaston, additional, Ibrahim, Prabha, additional, Zhang, Chao, additional, Mathé, Ewy A., additional, Bollag, Gideon, additional, Byrd, John C., additional, and Lapalombella, Rosa, additional

Published
2018
Full Text
View/download PDF

23. The Novel BET Inhibitor PLX51107 Has In Vitro and In Vivo Activity Against Acute Myeloid Leukemia

Author

Grieselhuber, Nicole R., primary, Mitchell, Shaneice R., additional, Orwick, Shelley, additional, Harrington, Bonnie K., additional, Goettl, Virginia M., additional, Walker, Alison R., additional, Bhatnagar, Bhavana, additional, Mims, Alice S., additional, Klisovic, Rebecca B., additional, Vasu, Sumithra, additional, Blum, William, additional, Blachly, James S., additional, Lucas, David M., additional, Garzon, Ramiro, additional, Lapalombella, Rosa, additional, and Byrd, John C., additional

Published
2016
Full Text
View/download PDF

25. A Novel Inhibitor of BET Family Bromodomains Demonstrates In Vivo and I n Vi tro Potency in B-Cell Malignancies

Author

El-Gamal, Dalia, primary, Hing, Zachary A., additional, Mitchell, Shaneice, additional, LaFollette, Taylor D., additional, Brennan, Paul J., additional, Flynn, Joseph M., additional, Jones, Jeffrey A., additional, Awan, Farrukh, additional, Andritsos, Leslie A., additional, Blachly, James S., additional, Williams, Katie, additional, Harrington, Bonnie K., additional, Goettl, Virginia M., additional, Woyach, Jennifer A., additional, Lehman, Amy M., additional, Yu, Lianbo, additional, Byrd, John C., additional, and Lapalombella, Rosa, additional

Published
2015
Full Text
View/download PDF

26. Next Generation XPO1 Inhibitor Shows Improved Efficacy and In Vivo Tolerability in Hematologic Malignancies

Author

Hing, Zachary A., primary, Fung, Ho Yee Joyce, additional, Ranganathan, Parvathi, additional, Mitchell, Shaneice, additional, El-Gamal, Dalia, additional, Woyach, Jennifer A., additional, Williams, Katie, additional, Goettl, Virginia M., additional, Smith, Jordan L., additional, Yu, Xueyan, additional, Meng, Xiaomei, additional, Sun, Qingxiang, additional, Cagatay, Tolga, additional, MacMillan, John B., additional, Lehman, Amy M., additional, Lucas, David M., additional, Baloglu, Erkan, additional, Shacham, Sharon, additional, Kauffman, Michael, additional, Byrd, John C., additional, Chook, Yuh Min, additional, Garzon, Ramiro, additional, and Lapalombella, Rosa, additional

Published
2015
Full Text
View/download PDF

27. In Vitro and In Vivo Anti-Leukemic Effects of KPT-9274, a Reported PAK4 Allosteric Modulator, in Acute Myeloid Leukemia: Promising Results Justifying Further Development in This Disease

Author

Mitchell, Shaneice, primary, Orwick, Shelley, additional, Cannon, Matthew, additional, Goettl, Virginia M., additional, LaFollette, Taylor D., additional, Baloglu, Erkan, additional, Senapedis, William, additional, Walker, Alison R., additional, Bhatnagar, Bhavana, additional, Mims, Alice S., additional, Klisovic, Rebecca B., additional, Vasu, Sumithira, additional, Blum, William, additional, Lucas, David M., additional, Blachly, James S., additional, Garzon, Ramiro, additional, Bloomfield, Clara D., additional, Lapalombella, Rosa, additional, and Byrd, John C., additional

Published
2015
Full Text
View/download PDF

28. Preclinical evaluation of NAMPT inhibitor KPT-9274 in Acute Myeloid Leukemia

Author

Mitchell, Shaneice Renee

Subjects
Biomedical Research, Oncology, Pharmacology, NAMPT, AML, acute myeloid leukemia, leukemia, hematologic malignancies, metabolism, nicotinamide phosphoribosyltransferase, nicotinamide, NAD, nicotinamide dinucleotide
Abstract

Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults affecting almost 12,000 people each year in the US. This disease is collectively characterized by an accumulation of rapidly proliferating neoplastic cells of the myeloid lineage with differentiation defects. In spite of the vast amount of information known about AML and the identification of favorable prognosis factors, a large percentage of patients relapse and succumb to this disease. In addition, the inter- and intra-tumor heterogeneity of AML makes the identification of therapeutic targets for this disease particularly challenging. Future studies are warranted to identify multi-targeted agents that could influence AML as a composite disease. A target that shows promise in targeting the bulk AML leukemic cell population is nicotinamide phosphoribosyltransferase (NAMPT). NAMPT is a protein involved in the generation of NAD+ in tumor cells, an important mediator of enzymatic reactions involved in various functions of leukemic disease progression. Leukemic blasts show a higher NAD+ turnover rate than normal cells, suggesting that NAD+ biosynthesis could be critically required in hematologic malignancies and therefore targeting the regeneration of NAD+ offers an attractive alternative strategy in AML. Inhibitors of NAMPT that have been described by others have shown potent anti-tumor activity and selectivity of several tumor models, including AML, while preserving the viability and functionality of normal tissues. While two agents targeting NAMPT have been tested in Phase I clinical trials, dose-limiting toxicities including thrombocytopenia and gastrointestinal toxicities led to their clinical discontinuation. Novel compounds with improved tolerability are needed. We sought to determine the mechanism of anti-tumor activity on AML leukemic cell population using a novel compound, KPT-9274, targeting NAMPT. We will also highlight several mechanisms used to antagonize AML disease progression via NAMPT inhibition that are cancer cell intrinsic and extrinsic, while minimizing toxicity in normal cells. To this end, I begin my studies by characterizing KPT-9274 as a selective target of AML leukemic cells. KPT-9274 was able to induce potent cytotoxicity of AML patient cells and significantly increase overall survival in murine models of disseminated AML. In addition, the selectivity of KPT-9274 allow for the overall preservation of the viability and function of normal hematopoietic cells. Further studies demonstrate that NAMPT inhibition is able to selectively target resistant-deriving leukemic stem cell population in vitro and in vivo using AML patient derived xenograft models (PDX), a more sophisticated AML mouse model to study therapeutic efficacy. Finally, I was able to demonstrate that on-target unwanted toxic effects of KPT-9274 is mitigated by the selective activation of an alternative pathway of NAD+ production via NAPRT1 and niacin supplementation. Overall, KPT-9274 demonstrates broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML. The knowledge gained from this work will facilitate the clinical development of a promising therapeutic in AML, a disease in dire need new therapeutic options.

Published
2019

30. A Novel Inhibitor of BET Family Bromodomains Demonstrates In Vivoand I n Vi troPotency in B-Cell Malignancies

Author

El-Gamal, Dalia, Hing, Zachary A., Mitchell, Shaneice, LaFollette, Taylor D., Brennan, Paul J., Flynn, Joseph M., Jones, Jeffrey A., Awan, Farrukh, Andritsos, Leslie A., Blachly, James S., Williams, Katie, Harrington, Bonnie K., Goettl, Virginia M., Woyach, Jennifer A., Lehman, Amy M., Yu, Lianbo, Byrd, John C., and Lapalombella, Rosa

Published
2015
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results