Biography:Lewis C. Cantley

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Short description: American biochemist
Lewis C. Cantley
Born (1949-02-20) February 20, 1949 (age 75)
West Virginia, U.S.
NationalityAmerican
Alma materWest Virginia Wesleyan College
Cornell University
Known forPI-3-kinase
Phosphatidylinositol (3,4,5)-trisphosphate
Oriented Peptide Libraries/Scansite
Phosphatidylinositol 5-phosphate
Scientific career
FieldsBiochemistry
Cell Biology
Systems Biology
InstitutionsWeill Cornell Medical College
Harvard Medical School
Beth Israel Deaconess Medical Center
Tufts University
Harvard University
Doctoral advisorGordon Hammes
Other academic advisorsGuido Guidotti

Lewis C. Cantley (born February 20, 1949) is an American cell biologist and biochemist who has made significant advances to the understanding of cancer metabolism. Among his most notable contributions are the discovery and study of the enzyme PI-3-kinase, now known to be important to understanding cancer and diabetes mellitus.[1][2] He is currently Meyer Director and Professor of Cancer Biology at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine in New York City. He was formerly a professor in the Departments of Systems Biology and Medicine at Harvard Medical School, and the Director of Cancer Research at the Beth Israel Deaconess Medical Center, in Boston, Massachusetts. In 2016, he was elected Chairman of the Board for the Hope Funds for Cancer Research.

Biography

Cantley grew up in West Virginia, remaining there at Wesleyan College where he graduated summa cum laude in chemistry in 1971. Cantley obtained his PhD at Cornell University in Ithaca, New York, where he worked with Gordon Hammes on enzyme kinetics, using FRET to study enzyme conformational changes. In 1975 he moved to Harvard University for a postdoctoral fellowship under Guido Guidotti, where he discovered that an impurity in commercial preparations of ATP, vanadate, acts as a transition state analog for phosphate hydrolysis. 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 University School of Medicine. In 1985 Cantley and colleagues Malcolm Whitman, David Kaplan, Tom Roberts, and Brian Schaffhausen 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 (now Beth Israel Deaconess Medical Center). In 2003, Cantley became a founding member of the newly formed Department of Systems Biology at Harvard Medical School. In 2007, Cantley also became the Director of Cancer Research at the Beth Israel Deaconess Medical Center. He joined the faculty of Weill Cornell Medicine and NewYork–Presbyterian Hospital in 2012.[1][2][3][4] Dr. Cantley was elected the Chairman of the Board of the Hope Funds for Cancer Research in 2016.[5]

Cantley is married to Vicki Sato, herself a prominent figure in the pharmaceutical industry and a professor at Harvard University in both the Business and Medical Schools.

Research

Discovery of PI-3-kinase and PtdIns(3,4)P2[1][2][6]

In a series of studies spanning several years, Cantley and colleagues demonstrated that a kinase activity associated with the middle T oncoprotein is a phosphoinositide kinase,[7] that it is a novel type of phosphoinositide kinase that phosphorylates the 3' position on the inositol ring,[8] and that this phosphatidylinositol-3-kinase (PI-3-kinase) is activated by growth factors to produce novel 3'-phosphorylated phosphoinositides, in particularly PtdIns(3,4,5)P3[9] that had previously been identified in physiologically stimulated human neutrophils.[10] In subsequent years Cantley and colleagues identified critical aspects of the regulation of PI-3-kinase by growth factor receptors. Specifically, they discovered that the catalytic subunit p110 dimerizes with the regulatory subunit p85,[11] and that the SH2 domain of p85 specifically recognized phosphotyrosines[12] on growth factor receptors or adaptor proteins via the pY-X-X-M motif.[13][14]

The Cantley lab has also made seminal contributions to understanding signaling downstream of PI-3-kinase. They discovered that the Pleckstrin Homology domain of AKT binds to PtdIns(3,4,5)P3 (and PtdIns(3,4)P2) and that this binding is critical for activation of AKT catalytic activity.[15][16] They further demonstrated that tuberin/TSC2 is a critical substrate of AKT,[17] and together with the laboratory of John Blenis they discovered that AKT phosphorylation of tuberin/TSC2 is required for activation of mTOR TORC1 kinase activity[18] via regulation of the small GTPase rheb.[19] The Cantley lab also was one of a few labs that nearly simultaneously identified LKB1 as a regulator of AMPK that also serves to regulate TORC1.[20][21]

For the discovery of PI-3-Kinase and its role in cancer metabolism, Cantley was one of eleven recipients of the inaugural Breakthrough Prize in Life Sciences, "the world's richest academic prize for medicine and biology. The prize, which carries a $3 million cash award, recognizes excellence in research aimed at curing intractable diseases and human life."[22] The fundamental and far-reaching nature of the discovery of PI-3-kinase, together with Cantley's role in mapping the upstream regulation of PI-3-kinase and the downstream signaling pathways, have led to speculation that Cantley is a likely candidate for the Nobel prize in Medicine or Physiology.[23] The growing evidence for a primary role for PI-3-kinase in cancer[24][25] and its critical role in insulin signaling[26] have served to strengthen the significance of this fundamentally important discovery.

The first drug targeting the PI-3-kinase pathway as a treatment for cancer - Idelalisib (PI3K Delta inhibitor) - was approved by the FDA as a treatment for leukemia and two types of lymphoma in July 2014.[27] Other drugs are currently in clinical development.

Use of Oriented Peptide Libraries to determine phosphopeptide binding specificity and protein kinase substrate specificity

In 1994, the Cantley lab published a novel strategy to determine the sequence specificity of phosphopeptide binding domains (initially SH2 domains).[13] Subsequently, the oriented peptide library approach was extended to identify the substrate specificity of protein kinases toward synthetic peptides.[28] This approach was then extended to characterize the specificity of Ser/Thr kinases and phospho-Ser/Thr binding domains.[29] This approach was used to characterize the substrate specificity of a large number of protein kinases. The kinase specificity matrices generated from these experiments served as the basis for creating the website Scansite, allowing the de novo identification of candidate phosphorylation sites in an arbitrary protein.[30][31]

In later research, the oriented peptide library approach has also been used to characterize protease cleavage specificity.[32] Modification of the original oriented peptide approach has allowed for large scale, kinome-wide determination of protein kinase specificity.[33]

Discovery of PtdIns(5)P

In 1997, the Cantley lab discovered that the enzymes that had been referred to as type II PIP-kinases, instead of using PtdIns(4)P as a substrate, in fact required PtdIns(5)P as a substrate to produce PtdIns(4,5)P2.[34] Further research demonstrated that PtdIns(5)P is naturally occurring in all eukaryotes.

It is remarkable that of the seven naturally occurring phosphoinositides, the existence of four of them (PtdIns(5)P, PtdIns(3)P, PtdIns(3,4)P2, and PtdIns(3,4,5)P3) was discovered by Cantley and colleagues.[8][9][34][35]

Role of metabolism in cancer

The role of PI-3-kinase in anabolic signaling by insulin, IGF-1, and other growth factors makes a straightforward link between metabolism and cancer, especially in light of the discovery that the PIK3CA gene encoding PI-3-kinase is an oncogene.[36]

In recent years Cantley and colleagues have made additional links between metabolic regulation and oncogenic transformation with their discovery that the M2 isoform of pyruvate kinase is associated with cancer.[37][38] This discovery provides a molecular basis for understanding the Warburg effect. Cantley is now a major player in the resurgence of the importance of the Warburg effect in the process of oncogenesis.[39]

Role of PI-3-kinase in different cancers

Cantley was part of the Stand Up to Cancer "dream team" that was brought together to investigate ways to target PI-3-kinase as a way to treat women's cancers, and he now leads a national effort targeting triple-negative breast cancer and ovarian cancer with novel drug combinations.[40] Recent research found that high levels of Vitamin C halted the growth of aggressive forms of colorectal tumors.[41] His lab also elucidated the role of Nrf2 in serine production in non-small cell lung cancer, with potential implications for pancreatic and other cancers as well.[42]

Industrial activities

Lewis C. Cantley has been involved in numerous companies. Recent examples include the following:

  • Co-founder of Petra Pharma (with Nathanael Gray)[43]
  • Co-founder of Agios Pharmaceuticals (with Tak Mak and Craig B. Thompson)[44]
  • Co-founder of Volastra Therapeutics (with Sam Bakhoum and Olivier Elemento)[45]
  • Advisory Board of AVEO Pharmaceuticals [46]
  • Advisory Board of TransMolecular, Inc.[47]

Awards, honors and media appearances

Cantley has received numerous awards and honors, including:

  • ASBMB Avanti Award for Lipid Research (1998)[48]
  • Elected to the American Academy of Arts and Sciences (1999)[49]
  • Heinrich Wieland Prize for Lipid Research (2000)
  • Elected to the National Academy of Sciences (2001) [1]
  • Caledonian Prize from the Royal Society of Edinburgh (2002)[50]
  • Pezcoller-AACR International Award for Cancer Research (2005)[51]
  • Rolf Luft Award of the Karolinska Institute (2009)[52]
  • Pasrow Prize for Cancer Research (2011)
  • Breakthrough Prize in Life Sciences (2013)
  • Jacobaeus Prize for Diabetes Research, from the Karolinska Institute (2013) [53]
  • Elected to the Institute of Medicine of the National Academies (2014)[54]
  • AACR Princess Takamatsu Memorial Lectureship (2015) [55]
  • Ross Prize in Molecular Medicine (2015) [56]
  • Canada Gairdner International Award (2015) [57]
  • Elected to European life sciences academy EMBO (2015) [58]
  • The Association of American Cancer Institutes Distinguished Scientist Award (2015) [59]
  • Thomson Reuter's "The World's Most Influential Scientific Minds 2015".[60]
  • The Wolf Prize in Medicine (2016) [61]
  • The Hope Funds Award of Excellence in Basic Science (2016)
  • Louisa Gross Horwitz Prize (2019) [62]

He appeared in the 60 Minutes program "Is sugar toxic?".[63]

References

  1. ↑ 1.0 1.1 1.2 1.3 Bradley D (March 2004). "Biography of Lewis C. Cantley". Proc. Natl. Acad. Sci. U.S.A. 101 (10): 3327–8. doi:10.1073/pnas.0400872101. PMID 14993589. Bibcode: 2004PNAS..101.3327B. 
  2. ↑ 2.0 2.1 2.2 Cantley LC (July 2009). "Lewis C. Cantley". Curr. Biol. 19 (14): R540–1. doi:10.1016/j.cub.2009.06.010. PMID 19655422. 
  3. ↑ "Weill Cornell Medical College and NewYork-Presbyterian Hospital Announce New Powerhouse Recruit for Cancer Research and Patient Care". http://weill.cornell.edu/news/pr/2012/09/weill-cornell-medical-college-and-newyork-presbyterian-hospital-announce-new-powerhouse-recruit-for.html. 
  4. ↑ Alberta Cancer Foundation International Advisory Board
  5. ↑ "Front Page". 30 October 2018. http://www.newportthisweek.com/news/2017-02-09/Around_Town/New_Board_Chair_is_Appointed.html. 
  6. ↑ Cantley, LC. "From Kinase to Cancer." The Scientist, December 2007.
  7. ↑ "Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation". Nature 315 (6016): 239–42. 1985. doi:10.1038/315239a0. PMID 2987699. Bibcode: 1985Natur.315..239W. 
  8. ↑ 8.0 8.1 "Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate". Nature 332 (6165): 644–6. April 1988. doi:10.1038/332644a0. PMID 2833705. Bibcode: 1988Natur.332..644W. 
  9. ↑ 9.0 9.1 "PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells". Cell 57 (1): 167–75. April 1989. doi:10.1016/0092-8674(89)90182-7. PMID 2467744. 
  10. ↑ "An inositol tetrakisphosphate-containing phospholipid in activated neutrophils". Nature 334 (6180): 353–356. July 1988. doi:10.1038/334353a0. PMID 3393226. Bibcode: 1988Natur.334..353T. 
  11. ↑ "Purification and characterization of phosphoinositide 3-kinase from rat liver". J. Biol. Chem. 265 (32): 19704–11. November 1990. doi:10.1016/S0021-9258(17)45429-9. PMID 2174051. 
  12. ↑ "Phosphoinositide 3-kinase is activated by phosphopeptides that bind to the SH2 domains of the 85-kDa subunit". J. Biol. Chem. 268 (13): 9478–83. May 1993. doi:10.1016/S0021-9258(18)98375-4. PMID 7683653. 
  13. ↑ 13.0 13.1 "SH2 domains recognize specific phosphopeptide sequences". Cell 72 (5): 767–78. March 1993. doi:10.1016/0092-8674(93)90404-E. PMID 7680959. 
  14. ↑ "Genetic analysis of a phosphatidylinositol 3-kinase SH2 domain reveals determinants of specificity". Mol. Cell. Biol. 14 (9): 5929–38. September 1994. doi:10.1128/mcb.14.9.5929. PMID 8065326. 
  15. ↑ "Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate". Science 275 (5300): 665–8. January 1997. doi:10.1126/science.275.5300.665. PMID 9005852. 
  16. ↑ "A comparative analysis of the phosphoinositide binding specificity of pleckstrin homology domains". J. Biol. Chem. 272 (35): 22059–66. August 1997. doi:10.1074/jbc.272.35.22059. PMID 9268346. 
  17. ↑ "Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway". Mol. Cell 10 (1): 151–62. July 2002. doi:10.1016/S1097-2765(02)00568-3. PMID 12150915. 
  18. ↑ "Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling". Proc. Natl. Acad. Sci. U.S.A. 99 (21): 13571–6. October 2002. doi:10.1073/pnas.202476899. PMID 12271141. Bibcode: 2002PNAS...9913571T. 
  19. ↑ "Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb". Curr. Biol. 13 (15): 1259–68. August 2003. doi:10.1016/S0960-9822(03)00506-2. PMID 12906785. 
  20. ↑ "The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress". Proc. Natl. Acad. Sci. U.S.A. 101 (10): 3329–35. March 2004. doi:10.1073/pnas.0308061100. PMID 14985505. Bibcode: 2004PNAS..101.3329S. 
  21. ↑ "The LKB1 tumor suppressor negatively regulates mTOR signaling". Cancer Cell 6 (1): 91–9. July 2004. doi:10.1016/j.ccr.2004.06.007. PMID 15261145. 
  22. ↑ "Dr. Lewis Cantley Awarded $3 Million Breakthrough Prize in Life Sciences for Excellence in Cancer Research". Press Release, Weill Cornell Medical College. Feb 21, 2013. http://weill.cornell.edu/news/releases/wcmc/wcmc_2013/02_21_13.shtml. 
  23. ↑ Palazzo, Alex (October 1, 2008). "Gaze into the crystal ball – Nobel Prize Predictions". Transcription and Translation. ScienceBlogs. http://scienceblogs.com/transcript/2008/10/01/gaze-into-the-crystal-ball-nob-2/. 
  24. ↑ "The PI3K pathway as drug target in human cancer". J. Clin. Oncol. 28 (6): 1075–83. February 2010. doi:10.1200/JCO.2009.25.3641. PMID 20085938. 
  25. ↑ "Targeting the PI3K signaling pathway in cancer". Curr. Opin. Genet. Dev. 20 (1): 87–90. February 2010. doi:10.1016/j.gde.2009.11.002. PMID 20006486. 
  26. ↑ Cantley LC (May 2002). "The phosphoinositide 3-kinase pathway". Science 296 (5573): 1655–7. doi:10.1126/science.296.5573.1655. PMID 12040186. Bibcode: 2002Sci...296.1655C. 
  27. ↑ "Press Announcements - FDA approves Zydelig for three types of blood cancers". https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm406387.htm. 
  28. ↑ "Use of an oriented peptide library to determine the optimal substrates of protein kinases". Curr. Biol. 4 (11): 973–82. November 1994. doi:10.1016/S0960-9822(00)00221-9. PMID 7874496. 
  29. ↑ "The structural basis for 14-3-3:phosphopeptide binding specificity". Cell 91 (7): 961–71. December 1997. doi:10.1016/S0092-8674(00)80487-0. PMID 9428519. 
  30. ↑ "A motif-based profile scanning approach for genome-wide prediction of signaling pathways". Nat. Biotechnol. 19 (4): 348–53. April 2001. doi:10.1038/86737. PMID 11283593. 
  31. ↑ "Scansite 2.0: Proteome-wide prediction of cell signaling interactions using short sequence motifs". Nucleic Acids Res. 31 (13): 3635–41. July 2003. doi:10.1093/nar/gkg584. PMID 12824383. 
  32. ↑ "Determination of protease cleavage site motifs using mixture-based oriented peptide libraries". Nat. Biotechnol. 19 (7): 661–7. July 2001. doi:10.1038/90273. PMID 11433279. 
  33. ↑ "A rapid method for determining protein kinase phosphorylation specificity". Nat. Methods 1 (1): 27–9. October 2004. doi:10.1038/nmeth708. PMID 15782149. 
  34. ↑ 34.0 34.1 "A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate". Nature 390 (6656): 192–6. November 1997. doi:10.1038/36621. PMID 9367159. Bibcode: 1997Natur.390..192R. 
  35. ↑ "Phosphatidylinositol 3-kinase and its novel product, phosphatidylinositol 3-phosphate, are present in Saccharomyces cerevisiae". J. Biol. Chem. 264 (34): 20181–4. December 1989. doi:10.1016/S0021-9258(19)47043-9. PMID 2555343. 
  36. ↑ "High frequency of mutations of the PIK3CA gene in human cancers". Science 304 (5670): 554. April 2004. doi:10.1126/science.1096502. PMID 15016963. 
  37. ↑ "The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth". Nature 452 (7184): 230–3. March 2008. doi:10.1038/nature06734. PMID 18337823. Bibcode: 2008Natur.452..230C. 
  38. ↑ "Pyruvate kinase M2 is a phosphotyrosine-binding protein". Nature 452 (7184): 181–6. March 2008. doi:10.1038/nature06667. PMID 18337815. Bibcode: 2008Natur.452..181C. 
  39. ↑ "Understanding the Warburg effect: the metabolic requirements of cell proliferation". Science 324 (5930): 1029–33. May 2009. doi:10.1126/science.1160809. PMID 19460998. Bibcode: 2009Sci...324.1029V. 
  40. ↑ "Pioneering Personalized Medicine | Sandra and Edward Meyer Cancer Center". http://meyercancer.weill.cornell.edu/news/2015-05-26/pioneering-personalized-medicine. 
  41. ↑ "Vitamin C halts growth of aggressive forms of colorectal cancer in preclinical study | Sandra and Edward Meyer Cancer Center". http://meyercancer.weill.cornell.edu/news/2015-11-05/vitamin-c-halts-growth-aggressive-forms-colorectal-cancer-preclinical-study. 
  42. ↑ "Cantley team uncovers vulnerability that can be exploited to kill lung cancer cells | Sandra and Edward Meyer Cancer Center". http://meyercancer.weill.cornell.edu/news/2015-10-22/cantley-team-uncovers-vulnerability-can-be-exploited-kill-lung-cancer-cells. 
  43. ↑ "Eli Lilly, Pfizer, J&J, AbbVie Join $48M Bet On NYC Cancer Drug Startup". https://www.forbes.com/sites/luketimmerman/2016/01/06/eli-lilly-pfizer-jj-abbvie-join-48m-bet-on-nyc-cancer-drug-startup/. 
  44. ↑ Agios Pharmaceuticals
  45. ↑ Volastra Therapeutics
  46. ↑ AVEO Pharmaceuticals
  47. ↑ TransMolecular, Inc.
  48. ↑ [1] AVANTI AWARD IN LIPIDS
  49. ↑ AAAS Membership
  50. ↑ Royal Society of Edinburgh Prizes
  51. ↑ EurekAlert! 7-Apr-2005
  52. ↑ Karolinska Institute
  53. ↑ "American professor awarded the Jacobæus Prize 2013 | Novo Nordisk Fonden". http://www.novonordiskfonden.dk/en/content/american-professor-awarded-jacobaeus-prize-2013. 
  54. ↑ "Dr. Lewis C. Cantley and Dr. Catherine Lord Elected to the Institute of Medicine of the National Academies". http://weill.cornell.edu/news/pr/2014/10/dr-lewis-c-cantley-and-dr-catherine-lord-elected-to-the-institute-of-medicine-of-the-national-academ.html. 
  55. ↑ "Dr. Lewis Cantley Honored With the 2015 AACR Princess Takamatsu Memorial Lectureship | Sandra and Edward Meyer Cancer Center". http://meyercancer.weill.cornell.edu/news/2015-03-27/dr-lewis-cantley-honored-2015-aacr-princess-takamatsu-memorial-lectureship. 
  56. ↑ "Molecular Medicine Awards 3rd Annual Ross Prize to Dr. Lewis C. Cantley, Cancer Researcher at Weill Cornell Medical College and NY Presbyterian Hospital - The Feinstein Institute for Medical Research" (in en-US). http://www.feinsteininstitute.org/2015/04/molecular-medicine-awards-3rd-annual-ross-prize-to-dr-lewis-c-cantley-cancer-researcher-at-weill-cornell-medical-college-and-ny-presbyterian-hospital/. 
  57. ↑ "Lewis Cantley | Gairdner". http://www.gairdner.org/content/lewis-cantley. 
  58. ↑ "Cantley elected to EMBO | Sandra and Edward Meyer Cancer Center". http://meyercancer.weill.cornell.edu/news/2015-05-20/cantley-elected-embo. 
  59. ↑ "Lewis Cantley to receive 2015 AACI distinguished scientist award | Sandra and Edward Meyer Cancer Center". http://meyercancer.weill.cornell.edu/news/2015-10-01/lewis-cantley-receive-2015-aaci-distinguished-scientist-award. 
  60. ↑ "Eloqua - Error Information". http://images.info.science.thomsonreuters.biz/Web/ThomsonReutersScience/%257B37a987a9-e378-4888-8baa-d4ba20efdbfd%257D_tr_scientific_minds_online_final.pdf. 
  61. ↑ "Weill Cornell's Cantley wins Wolf Prize in Medicine | Cornell Chronicle". http://www.news.cornell.edu/stories/2016/01/weill-cornells-cantley-wins-wolf-prize-medicine. 
  62. ↑ Louisa Gross Horwitz Prize 2019
  63. ↑ "Is Sugar Toxic? 60 Minutes report". https://www.youtube.com/watch?v=t9MH_tks_wE. 

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