المؤلفون: Zeidan, Amer M, DeAngelo, Daniel J, Palmer, Jeanne, Seet, Christopher S, Tallman, Martin S, Wei, Xin, Raymon, Heather, Sriraman, Priya, Kopytek, Stephan, Bewersdorf, Jan Philipp, Burgess, Michael R, Hege, Kristen, Stock, Wendy

المصدر: Annals of Hematology. 101(3)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Clinical Trials and Supportive Activities, Pediatric, Cancer, Clinical Research, Hematology, Pediatric Research Initiative, Pediatric Cancer, Evaluation of treatments and therapeutic interventions, 6.2 Cellular and gene therapies, Adult, Aged, Aged, 80 and over, Animals, Female, Humans, Male, Mice, Middle Aged, Antineoplastic Agents, Immunological, CD47 Antigen, Leukemia, Myeloid, Acute, Macaca fascicularis, Maximum Tolerated Dose, Mice, SCID, Myelodysplastic Syndromes, Neoplasm Recurrence, Local, Safety, SIRP alpha, IgG4PE, Macrophages, Hematological cancer, SIRPα, Cardiorespiratory Medicine and Haematology, Immunology, Cardiovascular medicine and haematology

الوصف: CC-90002 is an anti-CD47 antibody that inhibits CD47-SIRPα interaction and enables macrophage-mediated killing of tumor cells in hematological cancer cell lines. In this first clinical, phase 1, dose-escalation and -expansion study (CC-90002-AML-001; NCT02641002), we evaluated CC-90002 in patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). CC-90002 was administered in escalating doses of 0.1-4.0 mg/kg, using a modified 3 + 3 design. Primary endpoints included dose-limiting toxicities (DLTs), non-tolerated dose (NTD), maximum tolerated dose (MTD), and recommended phase 2 dose. Secondary endpoints included preliminary efficacy, pharmacokinetics, and presence/frequency of anti-drug antibodies (ADAs). Between March 2016 and July 2018, 28 patients were enrolled (24 with AML and 4 with MDS) at 6 sites across the USA. As of July 18, 2018, all patients had discontinued, mainly due to death or progressive disease. The most common treatment-emergent adverse events were diarrhea (46.4%), thrombocytopenia (39.3%), febrile neutropenia (35.7%), and aspartate aminotransferase increase (35.7%). Four patients experienced DLTs (1 patient had grade 4 disseminated intravascular coagulation and grade 5 cerebral hemorrhage, 1 had grade 3 purpura, 1 had grade 4 congestive cardiac failure and grade 5 acute respiratory failure, and another had grade 5 sepsis). The NTD and MTD were not reached. No objective responses occurred. CC-90002 serum exposure was dose-dependent. ADAs were present across all doses, and the proportion of ADA-positive patients in cycle 1 increased over time. Despite no unexpected safety findings, the CC-90002-AML-001 study was discontinued in dose escalation for lack of monotherapy activity and evidence of ADAs. However, as other anti-CD47 agents in clinical trials are showing promising early results for AML and MDS, understanding preclinical and clinical differences between individual agents in this class will be of high importance.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/92r962wxTest

المؤلفون: Wong, Sandy W., Bar, Noffar, Victoria Mateos, María, Ribas, Paz, Hansson, Markus, Paris, Laura, Hofmeister, Craig, Rodriguez-Otero, Paula, Aranzazu Bermúdez, Maria, Santoro, Armando, Yee, Andrew J., Creignou, Maria, Encinas, Cristina, Cerchione, Claudio, de la Rubia, Javier, Oriol, Albert, Ferstl, Barbara, Besemer, Britta, Chen, Jinjie, Chung, Alexander, Boss, Isaac W., Gaudy, Allison, LI, Shaoyi, Hsu, Kevin, Godwin, Colin, Burgess, Michael R., San-Miguel, Jesús, Jose Costa, Luciano

المصدر: HemaSphere ; volume 7, issue S3, page e1220745 ; ISSN 2572-9241

الإتاحة: https://doi.org/10.1097/01.hs9.0000970436.12207.45Test

المؤلفون: Burgess, Michael R, Hwang, Eugene, Mroue, Rana, Bielski, Craig M, Wandler, Anica M, Huang, Benjamin J, Firestone, Ari J, Young, Amy, Lacap, Jennifer A, Crocker, Lisa, Asthana, Saurabh, Davis, Elizabeth M, Xu, Jin, Akagi, Keiko, Le Beau, Michelle M, Li, Qing, Haley, Benjamin, Stokoe, David, Sampath, Deepak, Taylor, Barry S, Evangelista, Marie, Shannon, Kevin

المصدر: Cell. 168(5)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Digestive Diseases, Genetics, Pediatric, Colo-Rectal Cancer, Cancer, Pediatric Cancer, Orphan Drug, Rare Diseases, Biotechnology, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Animals, Antineoplastic Agents, Benzamides, Cell Line, Tumor, Clonal Evolution, Colorectal Neoplasms, Diphenylamine, Drug Resistance, Neoplasm, Humans, Leukemia, Myeloid, Acute, MAP Kinase Signaling System, Mice, Mutation, Proto-Oncogene Proteins p21(ras), Retroviridae, AML, KRAS, MEK inhibition, allelic imbalance, colorectal cancer, drug resistance, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences

الوصف: Investigating therapeutic "outliers" that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D "knockin" mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse. Loss of wild-type (WT) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition. Similarly, human colorectal cancer cell lines with increased KRAS mutant allele frequency were more sensitive to MAP kinase inhibition, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized heterozygous mutant HCT116 cells to treatment. In a prospectively characterized cohort of patients with advanced cancer, 642 of 1,168 (55%) with KRAS mutations exhibited allelic imbalance. These studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer and modulate competitive fitness and MEK dependency.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2mz8t47dTest

المؤلفون: Burgess, Michael R, Hwang, Eugene, Firestone, Ari J, Huang, Tannie, Xu, Jin, Zuber, Johannes, Bohin, Natacha, Wen, Tiffany, Kogan, Scott C, Haigis, Kevin M, Sampath, Deepak, Lowe, Scott, Shannon, Kevin, Li, Qing

المصدر: Blood. 124(26)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Childhood Leukemia, Pediatric Cancer, Stem Cell Research - Nonembryonic - Non-Human, Stem Cell Research, Rare Diseases, Hematology, Cancer, Stem Cell Research - Nonembryonic - Human, Orphan Drug, Genetics, Regenerative Medicine, Pediatric, Aetiology, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Cell Survival, Genes, ras, Hematopoietic Stem Cells, Humans, Leukemia, Myeloid, Acute, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Mice, Mice, Inbred C57BL, Monomeric GTP-Binding Proteins, Mutation, Protein Kinase Inhibitors, RNA, Small Interfering, Signal Transduction, Stem Cells, Transgenes, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine, Immunology, Biochemistry and cell biology, Cardiovascular medicine and haematology, Paediatrics

الوصف: Oncogenic NRAS mutations are highly prevalent in acute myeloid leukemia (AML). Genetic analysis supports the hypothesis that NRAS mutations cooperate with antecedent molecular lesions in leukemogenesis, but have limited independent prognostic significance. Using short hairpin RNA-mediated knockdown in human cell lines and primary mouse leukemias, we show that AML cells with NRAS/Nras mutations are dependent on continued oncogene expression in vitro and in vivo. Using the Mx1-Cre transgene to inactivate a conditional mutant Nras allele, we analyzed hematopoiesis and hematopoietic stem and progenitor cells (HSPCs) under normal and stressed conditions and found that HSPCs lacking Nras expression are functionally equivalent to normal HSPCs in the adult mouse. Treating recipient mice transplanted with primary Nras(G12D) AMLs with 2 potent allosteric mitogen-activated protein kinase kinase (MEK) inhibitors (PD0325901 or trametinib/GlaxoSmithKline 1120212) significantly prolonged survival and reduced proliferation but did not induce apoptosis, promote differentiation, or drive clonal evolution. The phosphatidylinositol 3-kinase inhibitor GDC-0941 was ineffective as a single agent and did not augment the activity of PD0325901. All mice ultimately succumbed to progressive leukemia. Together, these data validate oncogenic N-Ras signaling as a therapeutic target in AML and support testing combination regimens that include MEK inhibitors.

الوصول الحر: https://escholarship.org/uc/item/337137dqTest

المؤلفون: Diaz-Flores, Ernesto, Goldschmidt, Hana, Depeille, Philippe, Ng, Victor, Akutagawa, Jon, Krisman, Kimberly, Crone, Michael, Burgess, Michael R, Williams, Olusegun, Houseman, Benjamin, Shokat, Kevan, Sampath, Deepak, Bollag, Gideon, Roose, Jeroen P, Braun, Benjamin S, Shannon, Kevin

المصدر: Science Signaling. 6(304)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biological Sciences, Cancer, Rare Diseases, Hematology, Stem Cell Research, 1.1 Normal biological development and functioning, Underpinning research, Amino Acid Substitution, Animals, Cells, Cultured, Cytokines, Extracellular Signal-Regulated MAP Kinases, Hematopoietic Stem Cells, Leukemia, MAP Kinase Signaling System, Mice, Mutation, Missense, Neoplastic Stem Cells, Phosphatidylinositol 3-Kinases, Phospholipase C gamma, Proto-Oncogene Proteins p21(ras), Second Messenger Systems, TOR Serine-Threonine Kinases, Biochemistry and cell biology

الوصف: Oncogenic K-Ras proteins, such as K-Ras(G12D), accumulate in the active, guanosine triphosphate (GTP)-bound conformation and stimulate signaling through effector kinases. The presence of the K-Ras(G12D) oncoprotein at a similar abundance to that of endogenous wild-type K-Ras results in only minimal phosphorylation and activation of the canonical Raf-mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling cascades in primary hematopoietic cells, and these pathways remain dependent on growth factors for efficient activation. We showed that phospholipase C-γ (PLC-γ), PI3K, and their generated second messengers link activated cytokine receptors to Ras and ERK signaling in differentiated bone marrow cells and in a cell population enriched for leukemia stem cells. Cells expressing endogenous oncogenic K-Ras(G12D) remained dependent on the second messenger diacylglycerol for the efficient activation of Ras-ERK signaling. These data raise the unexpected possibility of therapeutically targeting proteins that function upstream of oncogenic Ras in cancer.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8w66v2d3Test

المؤلفون: Burgess, Michael R., Skaggs, Brian J., Shah, Neil P., Lee, Francis Y., Sawyers, Charles L., Kuriyan, John

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2005 Mar 01. 102(9), 3395-3400.

الوصول الحر: https://www.jstor.org/stable/3374937Test

المؤلفون: Balbas, Minna D., Burgess, Michael R., Murali, Rajmohan, Wongvipat, John, Skaggs, Brian J., Mundel, Peter, Weins, Astrid, Sawyers, Charles L.

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2014 Oct . 111(41), 14876-14881.

الوصول الحر: https://www.jstor.org/stable/43190170Test

المؤلفون: Skaggs, Brian J., Gorre, Mercedes E., Ryvkin, Ann, Burgess, Michael R., Xie, Yongming, Han, Yun, Komisopoulou, Evangelia, Brown, Lauren M., Loo, Joseph A., Landaw, Elliot M., Sawyers, Charles L., Graeber, Thomas G.

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2006 Dec . 103(51), 19466-19471.

الوصول الحر: https://www.jstor.org/stable/30051323Test

المؤلفون: Wong, Jasmine C, Weinfurtner, Kelley M, Alzamora, Maria del pilar, Kogan, Scott C, Burgess, Michael R, Zhang, Yan, Nakitandwe, Joy, Ma, Jing, Cheng, Jinjun, Chen, Shann-Ching, Ho, Theodore T, Flach, Johanna, Reynaud, Damien, Passegué, Emmanuelle, Downing, James R, Shannon, Kevin

المساهمون: National Cancer Institute, St. Baldrick's Foundation, Leukemia and Lymphoma Society, St. Jude Children's Research Hospital, National Heart, Lung, and Blood Institute, American Cancer Society

المصدر: eLife ; volume 4 ; ISSN 2050-084X

الوصف: Chromosome 7 deletions are highly prevalent in myelodysplastic syndrome (MDS) and likely contribute to aberrant growth through haploinsufficiency. We generated mice with a heterozygous germ line deletion of a 2-Mb interval of chromosome band 5A3 syntenic to a commonly deleted segment of human 7q22 and show that mutant hematopoietic cells exhibit cardinal features of MDS. Specifically, the long-term hematopoietic stem cell (HSC) compartment is expanded in 5A3 +/del mice, and the distribution of myeloid progenitors is altered. 5A3 +/del HSCs are defective for lymphoid repopulating potential and show a myeloid lineage output bias. These cell autonomous abnormalities are exacerbated by physiologic aging and upon serial transplantation. The 5A3 deletion partially rescues defective repopulation in Gata2 mutant mice. 5A3 +/del hematopoietic cells exhibit decreased expression of oxidative phosphorylation genes, increased levels of reactive oxygen species, and perturbed oxygen consumption. These studies provide the first functional data linking 7q22 deletions to MDS pathogenesis.

الإتاحة: https://doi.org/10.7554/elife.07839Test
https://cdn.elifesciences.org/articles/07839/elife-07839-v2.pdfTest
https://cdn.elifesciences.org/articles/07839/elife-07839-v2.xmlTest
https://elifesciences.org/articles/07839Test

المؤلفون: Bal, Susan, Kocoglu, M. Hakan, Nadeem, Omar, Htut, Myo, Gregory, Tara, Anderson, Larry D., Costa, Luciano J., Buchholz, Tonia J., Ziyad, Safiyyah, Li, Meng, Chen, Yanping, Kaeding, Allison J., Burgess, Michael R., Hege, Kristen, Berdeja, Jesus

المصدر: Blood; November 2022, Vol. 140 Issue: Supplement 1 p883-885, 3p