Klaus Hoeflich

Senior Scientist, Oncology

POSTDOC MENTOR

"I greatly value the collaborative environment within Genentech, the excellent postdoctoral research program, and also that external collaboration with academia is encouraged."

• 10
  years at Genentech
• 21
  publications (2010-12)
• 8
  awards & honors

I spent my early years in Vancouver, British Columbia and attended Simon Fraser University and University of Toronto for my education. I was fortunate to have great scientific mentors that provided me with training and encouragement to pursue a career in biomedical research. I joined Genentech as a postdoctoral fellow in 2003 and performed early investigation into the role of BRAF (v-Raf murine sarcoma viral oncogene homolog B1) in malignant melanoma. I had the opportunity to transition to a permanent position in 2005 and continued to work on mitogen-activated protein kinase (MAPK) pathway biology and therapeutic intervention.

In terms of drug discovery efforts, my lab has supported BRAF and MEK projects with various in vivo and in vitro studies. We contributed to interesting observations during the formative years of these projects, including BRAF/KRAS genotype-dependent efficacy and mechanisms of action, combinatorial efficacy for MEK1/2 and class Ia PI-3 kinase inhibition at tolerated doses, and the feasibility and molecular mechanism of intermittent scheduling. Small molecule inhibitors for these projects have advanced into clinical development. More recently, I have been interested in regulators of the actin cytoskeleton as potential anti-tumor targets and we devote part of our discretionary research time to that area of biology.

• My Focus

  My laboratory supports small molecule drug discovery efforts for several intracellular kinases. In this capacity, we investigate cellular signaling, predictive diagnostics and combination therapies to advance new development candidates and support clinical planning for these targets.

  Over the past years, we have also focused on two major basic science areas:

  Mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling network. We are interested in understanding crosstalk, feedback and points of convergence for the RAS/RAF/MEK and PI3K/AKT/mTOR pathways. These studies have been aided by use of novel investigational drugs: GDC-0973, an allosteric inhibitor of MEK1/2, and GDC-0941, an inhibitor of class I PI-3 kinases, both of which are in Phase I and II clinical trials. We have also completed a mass spectrometry-based phosphoproteomic analysis of MEK and PI3K signaling in tumor cells and biological characterization of novel targets is ongoing.

  P21-activated kinases. PAK family serine/threonine kinases are important mediators of Rac and Cdc42 GTPases, however the contribution of these kinases to tumorigenesis has not been well defined. Together with collaborators in academia, we are comprehensively examining the expression and prognostic significance of PAK1 in human tumors and genetically engineered mouse models. The functional requirement and signaling mechanisms for PAK1 in cellular proliferation, survival and morphogenesis in select tumor indications is being investigated using genetic and pharmacologic approaches both in vitro and in vivo.

• Publications

  • Systems-wide analysis of K-Ras, Cdc42 and PAK4 signaling by quantitative phosphoproteomics

    Molecular and Cellular Proteomics, 2013, ISSN: 1535-9476

    Gnad, Florian; Young, Amy; Zhou, Wei; Lyle, Karen; Ong, Christy C; Stokes, Matthew P; Silva, Jeffrey C; Belvin, Marcia; Friedman, Lori S; Koeppen, Hartmut; Minden, Audrey; Hoeflich, Klaus

     View on PubMed

  • PAK1 kinase links ErbB2 to β-catenin in transformation of breast epithelial cells

    Cancer Research, 2013, ISSN: 1538-7445

    Arias-Romero, Luis; Villamar-Cruz, Olga; Huang, Min; Hoeflich, Klaus; Chernoff, Jonathan;

     View on PubMed

  • P21-Activated Kinase 1 (PAK1) as a Therapeutic Target in BRAF Wild-Type Melanoma

    Journal of the National Cancer Institute, 2013, ISSN: 0027-8874

    Ong, Christy C; Jubb, Adrian M; Jakubiak, Diana; Zhou, Wei; Rudolph, Joachim; Haverty, Peter M; Kowanetz, Marcin; Yan, Yibing; Tremayne, Jarrod; Lisle, Richard; Harris, Adrian L; Friedman, Lori S; Belvin, Marcia; Middleton, Mark R; Blackwood, Elizabeth M; Koeppen, Hartmut; Hoeflich, Klaus P

     View on PubMed

  • p21-activated kinase 1 is required for efficient tumor formation and progression in a ras-mediated skin cancer model

    Cancer Research, 2012, ISSN: 0008-5472

    Chow, Hoi Yee; Jubb, Adrian M.; Koch, Jennifer N.; Jaffer, Zahara M.; Stepanova, Dina; Campbell, David A.; Duron, Sergio G.; O'Farrell, Marie; Cai, Kathy Q.; Klein-Szanto, Andres J. P.; Gutkind, J. Silvio; Hoeflich, Klaus P.; Chernoff, Jonathan

     View on PubMed

  • FDG-PET is a good biomarker of both early response and acquired resistance in BRAFV600 mutant melanomas treated with vemurafenib and the MEK inhibitor GDC-0973

    European Journal of Nuclear Medicine and Molecular Imaging Research, 2012, ISSN:

    Baudy, Andreas; Dogan, Taner; Flores-Mercado, Judith; Hoeflich, Klaus; Su, Fei; Van Bruggen, Nicholas; Williams, Simon

     View on PubMed

  • ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors

    Molecular Cancer Therapeutics, 2012, ISSN: 1535-7163

    Hatzivassiliou, Georgia; Liu, Bonnie; O'Brien, Carol; Spoerke, Jill M; Hoeflich, Klaus P; Haverty, Peter M; Soriano, Robert; Forrest, William F; Heldens, Sherry; Chen, Huifen; Toy, Karen; Ha, Connie; Zhou, Wei; Song, Kyung; Friedman, Lori S; Amler, Lukas C; Hampton, Garret M; Moffat, John; Belvin, Marcia; Lackner, Mark R;

     View on PubMed

  • Active PI3K Pathway Causes an Invasive Phenotype Which Can Be Reversed or Promoted by Blocking the Pathway at Divergent Nodes

    PLoS ONE, 2012, ISSN: 1932-6203

    Wallin, Jeffrey J; Guan, Jane; Edgar, Kyle A; Zhou, Wei; Francis, Ross; Torres, Anthony C; Haverty, Peter M; Eastham-Anderson, Jeffrey; Arena, Sabrina; Bardelli, Alberto; Griffin, Sue; Goodall, John E; Grimshaw, Kyla M; Hoeflich, Klaus P; Torrance, Christopher; Belvin, Marcia; Friedman, Lori S

     View on PubMed

  • Preclinical Disposition of GDC-0973 and Prospective and Retrospective Analysis of Human Dose and Efficacy Predictions

    Drug Metabolism and Pharmacokinetics, 2012, ISSN: 0090-9556

    Choo, Edna F; Belvin, Marcia; Boggs, Jason; Deng, Yuzhong; Hoeflich, Klaus P; Ly, Justin; Merchant, Mark; Orr, Christine; Plise, Emile; Robarge, Kirk; Martini, Jean F; Kassees, Robert; Aoyama, Ron G; Ramaiya, Atulkumar; Johnston, Stuart H;

     View on PubMed

  • p21-Activated kinase inhibitors: a patent review

    Expert Opinion on Therapeutic Patents, 2012, ISSN: 1354-3776

    Crawford, James J; Hoeflich, Klaus P; Rudolph, Joachim;

     View on PubMed

  • PPM1H Is a p27 Phosphatase Implicated in Trastuzumab Resistance.

    Cancer Discovery, 2011, V1, N4, SEP, pp 326-337, ISSN: 2159-8274.

    Lee, Hoeflich Si Tuen; Thinh, Q Pham; Dowbenko, Don; Munroe, Xander; Lee, James; Li, Li; Zhou, Wei; Haverty, Peter M; Pujara, Kanan; Stinson, Jeremy; Chan, Sara M; Eastham, Anderson Jeffrey; Pandita, Ajay; Seshagiri, Somasekar; Hoeflich, Klaus P; Turashvili, Gulisa; Gelmon, Karen A; Aparicio, Samuel A; Davis, David P; Sliwkowski, Mark X; Stern, Howard M

     View on PubMed

  • p21-activated kinase 1: PAK'ed with potential.

    Oncotarget, {Oncotarget}, 7 Jun 2011 (epub: 7 6 2011), ISSN: 1949-2553.

    Ong, Christy C; Jubb, Adrian M; Zhou, Wei; Haverty, Peter M; Harris, Adrian L; Belvin, Marcia; Friedman, Lori S; Koeppen, Hartmut; Hoeflich, Klaus P

  • PK-PD Modeling of Combination Efficacy Effect from Administration of a MEK Inhibitor, GDC-0973 and PI3K Inhibitor, GDC-0941 in A2058 Xenografts.

    Drug Metabolism Reviews, 2010, ISSN: 0360-2532

    Choo, E.F.; Belvin, M.; Hoeflich, K.; Merchant, M.; Otter, D.D.; Salphati, L.

  • Preclinical disposition and pharmacokinetics-pharmacodynamic modeling of biomarker response and tumour growth inhibition in xenograft mouse models of G-573, a MEK inhibitor.

    Xenobiotica, 2010, ISSN: 0049-8254

    Choo, E.; Belvin, M.; Chan, J.; Hoeflich, K.; Orr, C.; Robarge, K.; Yang, X.; Zak, M.; Boggs, J.

  • P21-activated kinase-1 (PAK1) as a therapeutic target in cancer.

    Proceedings of the American Association for Cancer Research Annual Meeting, 2010, ISSN: 0197-016X

    Ong, C.; Jubb, A.; Truong, T.; Zhou, W.; Tran, V.; Haverty, P.; Turley, H.; Vucic, D.; Belvin, M.; Blackwood, E.; Harris, A.; Friedman, L.; Koeppen, H.; Hoeflich, K.

  • RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth.

    Nature, 2010, ISSN: 1476-4687

    Hatzivassiliou, G.; Song, K.; Yen, I.; Brandhuber, B.J.; Anderson, D.J.; Alvarado, R.; Ludlam, M.J.; Stokoe, D.; Gloor, S.L.; Vigers, G.; Morales, T.; Aliagas, I.; Liu, B.; Sideris, S.; Hoeflich, K.P.; Jaiswal, B.S.; Seshagiri, S.; Koeppen, H.; Belvin, M.; Friedman, L.S.; Malek, S.

  • Identifying genotype-dependent efficacy of single and combined P13K- and MAPK-pathway inhibition in cancer.

    Proc. Natl. Acad. Sci. USA, 2009, ISSN: 0027-8424

    Sos, M.L.; Fischer, S.; Ullrich, R.; Peifer, M.; Heuckmann, J.M.; Koker, M.; Heynck, S.; Stuckrath, I.S; Weiss, J.; ....Shokat, K.M.; Sellers, W.R.; Rauh, D.; Orr, C.; Hoeflich, K.P.; Friedman, L.; Wong, K.-K.; Pao, W.; Thomas, R.K.

  • In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models

    Clinical Cancer Research, 2009, ISSN: 1078-0432

    Hoeflich, K.P.; O'Brien, C.; Boyd, Z.; Cavet, G.; Guerrero, S.; Jung, K.; Januario, T.; Savage, H.; Punnoose, E.; Truong, T.; Zhou, W.; Berry, L.; Murray, L.; Amler, L,; Belvin, M.; Friedman, L.S.; Lackner, M.R.

  • Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab.

    Clinical Cancer Research, 2009, ISSN: 1078-0432

    Yao, E.; Zhou, W.; Lee-Hoeflich, S.T.;Truong T.; Haverty, P.M.;Eastham-Anderson, J.; Lewin-Koh, N.; Gunter, B.; Belvin, M.; Murray, L.J.; Friedman, L.S.; Sliwkowski, M.X.; Hoeflich, K.P.

  • Combined targeting of BRAF and CRAF or BRAF and P13K effector pathways is required for efficacy in NRAS mutant tumors.

    PloS ONE, 2009, ISSN: 1932-6203

    Jaiswal, B.S.; Janakiraman, V.; Klavin, N.M.; Eastham-Anderson, J.; Cupp, J.E.; Liang, Y.; Davis, D.P.; Hoeflich, K.P.; Seshagiri, S.

  • Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAF^V600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression.

    Cancer Research, 2009, ISSN: 1538-7445

    Hoeflich, K.P.; Herter, S.; Tien, J.; Wong, L.; Berry, L.; Chan, J.; O'Brien, C.; Modrusan, Z.; Seshagiri, S.; Lackner, M.; Stern, H.; Choo, E.; Murray, L.; Friedman, L.S.; Belvin, M.

  • Pharmacodynamics of 2-[4-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridine-4-yl)-1H-pyrazol-1-yl]ethan-1-ol (GDC-0879), a potent and selective B-Raf kinase inhibitor: understanding relationships between systemic concentrations, phosphorylated mitogen-activated protein kinase kinase 1 in

    Journal of Pharmacology & Experimental Therapeutics, 2009, ISSN: 1521-0103

    Wong, H.; Belvin, M.; Herter, S.; Hoeflich, K.P.; Murray, L.J.; Wong, L.; Choo, E.F.

• Education
  • Genentech, Department of Molecular Biology, Postdoctoral Fellow – 2005
  • Ontario Cancer Institute, Toronto, Canada, Caven Postdoctoral Fellow – 2003
  • University of Toronto, Canada, Medical Biophysics, Ph.D. – 2001
  • Simon Fraser University, Canada, B.Sc. – 1994
• Awards & Honors
  • Genentech Postdoctoral Research Prize – 2005
  • National Cancer Institute (NCI) Postdoctoral Fellowship – 2002
  • Caven Postdoctoral Fellowship – 2001
  • Canadian Institutes of Health Research (CIHR) Next Generation Award – 2000
  • Medical Research Council (MRC) Studentship – 1996
  • Simon Fraser University Honor Roll – 1994
  • Natural Science and Engineering Research Council of Canada (NSERC) Award – 1993
  • Simon Fraser University Dean's Scholarship – 1990