小议恶性肿瘤的代谢异常

1、 Robert A. Weinberg CD19 CAR-T Cell Therapy Adapted from 周鹏辉教授 Carl June, MD Director, Translational Research Program Abramson Family Cancer Research Institute Perelman School of Medicine The University of Pennsylvania Emily Emma Whitehead, 2015 Macroscale Metabolic Imaging MRI System PET Scanner Tu

2、mor-associated metabolic disorder Fludeoxyglucose (18F-FDG) Schematic representation of the differences between oxidative phosphorylation, anaerobic glycolysis, and aerobic glycolysis (Warburg effect). Dr. Otto Warburg in his laboratory of the Kaiser Wilhelm Institute for Biology in Berlin-Dahlem, 1

3、931. Grant proposal submitted by Otto Warburg to the Emergency Association of German Science in 1921. The application, which consisted of a single sentence, “I require 10,000 marks”, was funded in full. The citric acid (Krebs) cycle. (GTP) Variables Affecting Traffic Flow Are Analogous to the Regula

4、tion of Metabolic Flux Lewis Cantley obtained his Ph.D. at Cornell University in Ithaca, New York. In 1978 Cantley became assistant professor of Biochemistry and Molecular Biology at Harvard, being promoted to associate professor in 1981. In 1985 he became a full professor in physiology at Tufts Uni

5、versity School of Medicine. In 1985 Cantley made the seminal discovery of the existence of phosphoinositide-3-kinase (PI3K). In 1992 Cantley moved to Harvard Medical School as a Professor of Cell Biology and the Director of the Division of Signal Transduction at the former Beth Israel Hospital. 1. S

6、ongyang, Z., Shoelson, SE, Chadhuri, M., Gish, G., Pawson, T., Haser, WG, King, F., Roberts, T., Ratnofsky, S., Lechleider, RJ, Neel, BG, Birge, RB, Fajardo JE, Chou, MM, Hanafusa, H., Schaffhausen, B. and Cantley, LC (1993) SH2 Domains Recognize Specific Phosphopeptide Sequences. Cell 72, 767-778.

7、(Cell杂志 30年最佳30篇文章之一） 2. Songyang, Z., Shoelson, SE, McGlade, Olivier, JP, Pawson, T., Bustelo, XR, Barbacid, M., Sabe, H., Hanafusa, H., Yi, T., Ren, R., Baltimore, D., Ratnofsky, S., Feldman, RA, and Cantley, LC (1994) Specific Motifs Recognized by the SH2 Domains of Csk, 3BP2, fps/fes, GRB-2, SHP

8、TP1, SHC, Syk and Vav. Mol. Cell. Biol.14, 2777-2785. (Scientist报年度最佳论文奖） 3. Songyang, Z., Blechner, S., Hoagland, N., Hoekstra, M. F., Piwnica-Worms, H., Cantley, L. C. (1994) Use of an oriented peptide library technique for determining the optimal substrates of protein kinases. Curr. Biol. 4, 973-

9、982. 4. Songyang, Z., Carraway, KL III, Eck, MJ, Harrison, SC, Feldman, RA, Mohammodi, M., Schlessinger, J., Hubbard, S., Smith, DP, Eng, C., Lorenzo, M. J., Ponder, BAJ., Mayer, BJ, and Cantley, LC (1995) Catalytic specificity of protein-tyrosine kinases is critical for selective signaling. Nature

10、373, 536-539. 5. Songyang, Z., Fanning, AS, Fu, C., Xu, J., Marfatia, SM, Chishti, AH, Crompton, A., Chan, AC, Anderson, JM, and Cantley, LC (1997) Recognition of unique carboxyl-terminal motifs by distinct PDZ domains. Science 275, 73-77. 1990年获中山大学生物化学理学 学士学位，1995年获美国波士顿 塔夫兹大学生命医学学院分子和 细胞生理学博士学位，

11、1995年到 1998年先后在哈佛大学医学院细 胞生物学系和麻省理工学院(MIT) 生物系做博士后工作。1998年在 美国贝勒医学院生化和分子生物 学系任助理教授。2004年晋升为 终身副教授，2008年晋升为生化 和分子生物学系终身教授。同时 担任贝勒医学院药学系教授，高 通量实验中心主任，2009-2015年 就任中山大学生命科学学院院长。 松阳洲松阳洲 SILAC identities Pyruvate Kinase as a phosphotyrosine-binding protein Phosphopeptide binding is specific to the M2 isof

12、orm of pyruvate kinase Pyruvate kinase (PK) nAllosteric Inhibitors: ATP, alanine nAllosteric activators : F-1,6-BP ADP ATP K+ Mg2+ pyruvate kinase COOH C CH2 P PO pyruvate COOH C=O CH3 phosphoenolpyruvate Phosphotyrosine peptide catalyzes the release of FBP from PKM2 Question: There is still a signi

13、ficant amount of pyruvate in most solid tumors. Mutations were identified in the 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas (星状细胞 瘤)and oligodendrogliomas (寡树突胶质瘤), and in glioblastomas (神经胶母细胞瘤) that developed from these lower-grade lesions. IDH1/2 mutations in brain tumors T

14、he R172 residue in IDH2 is the exact analogue of the R132 residue in IDH1. Two types of mutations are mutually exclusive. Each of IDH1 and IDH2 mutations demonstrate reduced enzymatic activity. However, almost all of them are heterozygous mutations, and no IDH3 mutations are found in brain tumors. F

15、acts and problems Chairman of the Medical Advisory Board of the Howard Hughes Medical Institute, a member of the Lasker Prize Jury, an Associate Editor of Cell, Science, Immunity, and Cancer Cell. an elected member of the National Academy of Sciences, the Institute of Medicine, the American Academy

16、of Arts and Sciences, the American Society for Clinical Investigation, and the American Association of Physicians. Craig B. Thompson, M.D. U87MG glioblastoma cells, transfected with wild- type IDH1or R132H mutant IDH1. Joshua D. Rabinowitz Cells expressing R132H IDH1 contain elevated levels of 2HG T

17、umors with wild-type IDH1 had almost 100-fold 2HG, but why? Gliomas with IDH1 R132 mutations contain increased levels of 2HG AG-221: Phase 1 clinical trial against advanced hematologic malignancies. Overall response rate of 40 percent in U.S. / 31 percent in Europe and a complete remission rate of 1

18、6 percent. Patients responding to AG-221 continue to show durable clinical activity on treatment for more than 15 months. American Cancer Society Fructose-1, 6-bisphosphatase opposes renal carcinoma progression Li et al. Nature (2014) Bonsib, European Urological Review (2009) ccRCC is the predominan

19、t subtype of kidney cancer Subtypes of kidney cancer: Clear cell renal cell carcinoma (ccRCC) 75%; Papillary Transitional cell carcinoma arginine and proline metabolism Nicotinamide (NAD) and Riboflavin (FAD) metabolism Carnitine metabolism Long chain fatty acid Lysolipids Metabolic gene set analysis of the TCGA ccRCC RNAseq data (1) RNAseq data of 480 ccRCC tumors and 69 normal kidney tissues (by TCGA) (2) 2753 metabolic genes, classified