Clinical Focus


  • Medical Oncology
  • Cancer

Academic Appointments


Honors & Awards


  • NIH Director's New Innovator Award, NIH (2012)
  • Distinguished Scientist Award, Sontag Foundation (2010)
  • Basil O' Connor Starter Scholar Award, March of Dimes Foundation (2010-2012)
  • Stand Up To Cancer Innovation Research Grant, American Association for Cancer Research (2010-2013)
  • Martin D. Abeloff Scholar, V Foundation for Cancer Research (2009-2011)
  • Josephine Q. Berry Faculty Scholar in Cancer Research, Stanford University (2009)
  • Howard Temin Pathway to Independance Award (K99/R00), NCI/NIH (2007)
  • Young Investigator Award, American Society for Clinical Oncology (2007)
  • Fellowship Award, Damon Runyon Cancer Research Fund (2006)

Professional Education


  • Fellowship:Stanford University - CAPS (2008) CA
  • Residency:Stanford University - CAPS (2004) CA
  • Board Certification: Medical Oncology, American Board of Internal Medicine (2008)
  • Board Certification: Internal Medicine, American Board of Internal Medicine (2005)
  • Medical Education:Harvard Medical School (2002) MA
  • Fellowship, Stanford Hospital, Medical Oncology (2008)
  • Residency, Stanford Hospital, Internal Medicine (2004)
  • Ph.D., Harvard Medical School, Cell Biology (2002)
  • M.D., Harvard Medical School (2002)
  • A.B., Harvard University, Biochemical Sciences (1994)

Current Research and Scholarly Interests


We are working to elucidate the biochemical and cell biological principles that govern signaling pathways that sit at the intersection between developmental biology and cancer. Our toolkit combines bulk biochemical techniques, such as cell-free reconstitution, with microscopy using novel optical probes to study the dynamics of signal propagation in cells. We strive to develop novel strategies for the manipulation of these pathways for cancer therapies and applications in regenerative medicine.

Clinical Trials


  • Molecular Analysis of Thoracic Malignancies Recruiting

    Primary Objective: To collect detailed clinical information on patients with thoracic malignancies via the electronic medical record and a detailed patient questionnaire, collect blood samples, retrieve paraffin embedded tissue if not collected at Stanford, and perform exploratory molecular analysis of tumor tissues.

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  • Erlotinib Plus Tivantinib (ARQ 197) Versus Single Agent Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer Not Recruiting

    The purpose of this study is to evaluate progression-free survival among subjects with KRAS mutation positive Non-Small Cell Lung Cancer (NSCLC) treated with erlotinib plus tivantinib (ARQ 197) compared to single agent chemotherapy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lei Shura, 650-723-2312.

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  • Erlotinib in Patients With Resected, Early Stage NSCLC With Confirmed Mutations in the EGFR Not Recruiting

    In this research study erlotinib will be given to eligible participants whose lung cancer has been removed by surgery. Eligible patients have adenocarcinoma, a type of non-small lung cancer, and must have 1 or more of the following characteristics: be female, be of Asian or Pacific Rim descent and/or be a never smoker. The potential participant's tumor will be examined for Epidermal growth factor (EGFR) mutations. EGFR is a protein that is overexpressed in most non-small cell lung cancers. Some EGFR has been found to have specific mutations and the participant must have one of these mutations in his tumor. Erlotinib blocks this protein and may control tumor growth and increase survival. Previous research has shown that erlotinib is most effective for people who have these specific mutations in the EGFR.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lei Shura, 650-723-2312.

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  • Erlotinib With or Without Hydroxychloroquine in Chemo-Naive Advanced NSCLC and (EGFR) Mutations Not Recruiting

    The purpose of this research study is to learn if adding hydroxychloroquine (HCQ) to erlotinib helps treat non-small cell lung cancer (NSCLC). Another goal of this research study is to learn more about NSCLC and how it may respond to study treatment. Erlotinib (Tarceva) is a type of drug called a tyrosine kinase inhibitor (TKI). TKIs block a protein called the epidermal growth factor receptor (EGFR). EGFR may control tumor growth and tumor cell survival. However, although TKI drugs can work for some lung cancer patients for a period of time, eventually the tumor finds a way to resist or counteract the TKI treatment and it begins to grow again. Hydroxychloroquine (HCQ) is a drug approved by the FDA for treating malaria, rheumatoid arthritis, and several other diseases. Laboratory research suggests that when HCQ is given with a TKI, it may help delay or prevent TKI resistance from developing.

    Stanford is currently not accepting patients for this trial. For more information, please contact Zeina Babetty, (650) 723 - 2983.

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  • Identification of Circulating Tumor Cells in the Peripheral Blood of Lung Cancer Patients Recruiting

    The primary aim of this study is to determine whether we can identify human lung cancer tumor cells in the peripheral blood of lung cancer patients.

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2013-14 Courses


Graduate and Fellowship Programs


Journal Articles


  • Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling. eLife Nachtergaele, S., Whalen, D. M., Mydock, L. K., Zhao, Z., Malinauskas, T., Krishnan, K., Ingham, P. W., Covey, D. F., Siebold, C., Rohatgi, R. 2013; 2

    Abstract

    The Hedgehog (Hh) signal is transduced across the membrane by the heptahelical protein Smoothened (Smo), a developmental regulator, oncoprotein and drug target in oncology. We present the 2.3 Å crystal structure of the extracellular cysteine rich domain (CRD) of vertebrate Smo and show that it binds to oxysterols, endogenous lipids that activate Hh signaling. The oxysterol-binding groove in the Smo CRD is analogous to that used by Frizzled 8 to bind to the palmitoleyl group of Wnt ligands and to similar pockets used by other Frizzled-like CRDs to bind hydrophobic ligands. The CRD is required for signaling in response to native Hh ligands, showing that it is an important regulatory module for Smo activation. Indeed, targeting of the Smo CRD by oxysterol-inspired small molecules can block signaling by all known classes of Hh activators and by clinically relevant Smo mutants. DOI:http://dx.doi.org/10.7554/eLife.01340.001.

    View details for DOI 10.7554/eLife.01340

    View details for PubMedID 24171105

  • A Smoothened-Evc2 Complex Transduces the Hedgehog Signal at Primary Cilia DEVELOPMENTAL CELL Dorn, K. V., Hughes, C. E., Rohatgi, R. 2012; 23 (4): 823-835

    Abstract

    Vertebrate Hedgehog (Hh) signaling is initiated at primary cilia by the ligand-triggered accumulation of Smoothened (Smo) in the ciliary membrane. The underlying biochemical mechanisms remain unknown. We find that Hh agonists promote the association between Smo and Evc2, a ciliary protein that is defective in two human ciliopathies. The formation of the Smo-Evc2 complex is under strict spatial control, being restricted to a distinct ciliary compartment, the EvC zone. Mutant Evc2 proteins that localize in cilia but are displaced from the EvC zone are dominant inhibitors of Hh signaling. Disabling Evc2 function blocks Hh signaling at a specific step between Smo and the downstream regulators protein kinase A and Suppressor of Fused, preventing activation of the Gli transcription factors. Our data suggest that the Smo-Evc2 signaling complex at the EvC zone is required for Hh signal transmission and elucidate the molecular basis of two human ciliopathies.

    View details for DOI 10.1016/j.devcel.2012.07.004

    View details for Web of Science ID 000310036200017

    View details for PubMedID 22981989

  • Oxysterols are allosteric activators of the oncoprotein Smoothened NATURE CHEMICAL BIOLOGY Nachtergaele, S., Mydock, L. K., Krishnan, K., Rammohan, J., Schlesinger, P. H., Covey, D. F., Rohatgi, R. 2012; 8 (2): 211-220

    Abstract

    Oxysterols are a class of endogenous signaling molecules that can activate the Hedgehog pathway, which has critical roles in development, regeneration and cancer. However, it has been unclear how oxysterols influence Hedgehog signaling, including whether their effects are mediated through a protein target or indirectly through effects on membrane properties. To answer this question, we synthesized the enantiomer and an epimer of the most potent oxysterol, 20(S)-hydroxycholesterol. Using these molecules, we show that the effects of oxysterols on Hedgehog signaling are exquisitely stereoselective, consistent with the hypothesis that they function through a specific protein target. We present several lines of evidence that this protein target is the seven-pass transmembrane protein Smoothened, a major drug target in oncology. Our work suggests that these enigmatic sterols, which have multiple effects on cell physiology, may act as ligands for signaling receptors and provides a generally applicable framework for probing sterol signaling mechanisms.

    View details for DOI 10.1038/nchembio.765

    View details for Web of Science ID 000299323200014

    View details for PubMedID 22231273

  • The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins GENES & DEVELOPMENT Humke, E. W., Dorn, K. V., Milenkovic, L., Scott, M. P., Rohatgi, R. 2010; 24 (7): 670-682

    Abstract

    The transcriptional program orchestrated by Hedgehog signaling depends on the Gli family of transcription factors. Gli proteins can be converted to either transcriptional activators or truncated transcriptional repressors. We show that the interaction between Gli3 and Suppressor of Fused (Sufu) regulates the formation of either repressor or activator forms of Gli3. In the absence of signaling, Sufu restrains Gli3 in the cytoplasm, promoting its processing into a repressor. Initiation of signaling triggers the dissociation of Sufu from Gli3. This event prevents formation of the repressor and instead allows Gli3 to enter the nucleus, where it is converted into a labile, differentially phosphorylated transcriptional activator. This key dissociation event depends on Kif3a, a kinesin motor required for the function of primary cilia. We propose that the Sufu-Gli3 interaction is a major control point in the Hedgehog pathway, a pathway that plays important roles in both development and cancer.

    View details for DOI 10.1101/gad.1902910

    View details for Web of Science ID 000276235400006

    View details for PubMedID 20360384

  • Lateral transport of Smoothened from the plasma membrane to the membrane of the cilium JOURNAL OF CELL BIOLOGY Milenkovic, L., Scott, M. P., Rohatgi, R. 2009; 187 (3): 365-374

    Abstract

    The function of primary cilia depends critically on the localization of specific proteins in the ciliary membrane. A major challenge in the field is to understand protein trafficking to cilia. The Hedgehog (Hh) pathway protein Smoothened (Smo), a 7-pass transmembrane protein, moves to cilia when a ligand is received. Using microscopy-based pulse-chase analysis, we find that Smo moves through a lateral transport pathway from the plasma membrane to the ciliary membrane. Lateral movement, either via diffusion or active transport, is quite distinct from currently studied pathways of ciliary protein transport in mammals, which emphasize directed trafficking of Golgi-derived vesicles to the base of the cilium. We anticipate that this alternative route will be used by other signaling proteins that function at cilia. The path taken by Smo may allow novel strategies for modulation of Hh signaling in cancer and regeneration.

    View details for DOI 10.1083/jcb.200907126

    View details for Web of Science ID 000271374200008

    View details for PubMedID 19948480

  • Hedgehog signal transduction by smoothened: pharmacological evidence for a two-step activation process. Proceedings of the National Academy of Sciences USA Rohatgi R, M., Corcoran RB, Scott MP 2009; 106: 3196-3201
  • Patched1 regulates Hedgehog signaling at the primary cilium. Science Rohatgi R, M., Scott MP 2007; 317 (5836): 372-376
  • Cancer risk after use of recombinant bone morphogenetic protein-2 for spinal arthrodesis. journal of bone and joint surgery. American volume Carragee, E. J., Chu, G., Rohatgi, R., Hurwitz, E. L., Weiner, B. K., Yoon, S. T., Comer, G., Kopjar, B. 2013; 95 (17): 1537-1545

    Abstract

    Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a growth factor known to have in vitro effects on the growth and invasiveness of cancer. It has been approved by the U.S. Food and Drug Administration in limited doses for single-level anterior spinal arthrodesis, but it is commonly used off-label and at high doses. The effect of rhBMP-2 on the risk of cancer has been a concern. We sought to evaluate the risk of new cancers in patients receiving high-dose rhBMP-2.We used publicly available data from a pivotal, multicenter, randomized controlled trial of patients with degenerative lumbar spine conditions who underwent a single-level instrumented posterolateral arthrodesis with either high-dose rhBMP-2 in a compression-resistant matrix (CRM) (rhBMP-2/CRM; n = 239) or autogenous bone graft (control group; n = 224). We compared the risks of new cancers in the rhBMP-2/CRM and control groups at two and five years after surgery.At two years, with 86% follow-up, there were fifteen new cancer events in eleven patients in the rhBMP-2/CRM group compared with two new cancer events in two patients in the control group treated with autogenous bone graft. The incidence rate of new cancer events per 100 person-years was 3.37 (95% confidence interval [CI], 1.89 to 5.56) in the rhBMP-2/CRM group at two years compared with 0.50 (95% CI, 0.06 to 1.80) in the control group. The incidence rate ratio was 6.75 (95% CI, 1.57 to 60.83; p = 0.0026) at two years. Calculated in terms of the number of patients with one or more cancer events two years after the surgery, the incidence rate per 100 person-years was 2.54 (95% CI, 1.27 to 4.54) in the rhBMP-2/CRM group compared with 0.50 (95% CI, 0.06 to 1.82) in the control group at two years; the incidence rate ratio was 5.04 (95% CI, 1.10 to 46.82; p = 0.0194). At five years, there was a 37% loss of follow-up, but a significantly greater incidence of cancer events was still observed in the rhBMP-2/CRM group.A high dose of 40 mg of rhBMP-2/CRM in lumbar spinal arthrodesis was associated with an increased risk of new cancer.Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

    View details for DOI 10.2106/JBJS.L.01483

    View details for PubMedID 24005193

  • Chemically inducible diffusion trap at cilia reveals molecular sieve-like barrier. Nature chemical biology Lin, Y., Niewiadomski, P., Lin, B., Nakamura, H., Phua, S. C., Jiao, J., Levchenko, A., Inoue, T., Rohatgi, R., Inoue, T. 2013; 9 (7): 437-443

    Abstract

    Primary cilia function as specialized compartments for signal transduction. The stereotyped structure and signaling function of cilia inextricably depend on the selective segregation of molecules in cilia. However, the fundamental principles governing the access of soluble proteins to primary cilia remain unresolved. We developed a methodology termed 'chemically inducible diffusion trap at cilia' to visualize the diffusion process of a series of fluorescent proteins ranging in size from 3.2 nm to 7.9 nm into primary cilia. We found that the interior of the cilium was accessible to proteins as large as 7.9 nm. The kinetics of ciliary accumulation of this panel of proteins was exponentially limited by their Stokes radii. Quantitative modeling suggests that the diffusion barrier operates as a molecular sieve at the base of cilia. Our study presents a set of powerful, generally applicable tools for the quantitative monitoring of ciliary protein diffusion under both physiological and pathological conditions.

    View details for DOI 10.1038/nchembio.1252

    View details for PubMedID 23666116

  • Singapore signalling: the 2012 hedgehog pathway cocktail EMBO REPORTS Briscoe, J., Rohatgi, R. 2012; 13 (7): 580-583

    Abstract

    The 'Hedgehog Signalling in Development Evolution and Disease' conference took place in Biopolis, Singapore, in March 2012. Organized by Phil Ingham with help from Xinhua Lin, Mary-Ann Price and Fred de Sauvage, it brought leading researchers together to discuss the latest findings and exchange ideas on every aspect of hedgehog signalling.

    View details for DOI 10.1038/embor.2012.79

    View details for Web of Science ID 000306076700004

    View details for PubMedID 22688966

  • Cilia 2010: The Surprise Organelle of the Decade SCIENCE SIGNALING Smith, E. F., Rohatgi, R. 2011; 4 (155)

    Abstract

    Presentations at the 2010 Conference on the Biology of Cilia and Flagella revealed new insights into the functions and assembly of cilia and highlighted their ever-expanding roles in development and disease.

    View details for DOI 10.1126/scisignal.4155mr1

    View details for Web of Science ID 000286102200004

    View details for PubMedID 21224442

  • The ciliary membrane CURRENT OPINION IN CELL BIOLOGY Rohatgi, R., Snell, W. J. 2010; 22 (4): 541-546

    Abstract

    Cilia and flagella are important organizing centers for signaling in both development and disease. A key to their function is a poorly characterized barrier at their base that allows the protein and lipid composition of the ciliary membrane to be distinct from that of the plasma membrane. We review current models of ciliary membrane biogenesis, highlighting several structures, including the ciliary necklace and ciliary pocket, that appear during biogenesis and that likely contribute to the barrier. The regulated movement of membrane proteins and lipids across this barrier is central to the sensory function of these organelles.

    View details for DOI 10.1016/j.ceb.2010.03.010

    View details for Web of Science ID 000280945500017

    View details for PubMedID 20399632

  • Role of Lipid Metabolism in Smoothened Derepression in Hedgehog Signaling DEVELOPMENTAL CELL Yavan, A., Nagaraj, R., Owusu-Ansah, E., Folick, A., Ngo, K., Hillman, T., Call, G., Rohatgi, R., Scott, M. P., Banerjee, U. 2010; 19 (1): 54-65

    Abstract

    The binding of Hedgehog (Hh) to its receptor Patched causes derepression of Smoothened (Smo), resulting in the activation of the Hh pathway. Here, we show that Smo activation is dependent on the levels of the phospholipid phosphatidylinositol-4 phosphate (PI4P). Loss of STT4 kinase, which is required for the generation of PI4P, exhibits hh loss-of-function phenotypes, whereas loss of Sac1 phosphatase, which is required for the degradation of PI4P, results in hh gain-of-function phenotypes in multiple settings during Drosophila development. Furthermore, loss of Ptc function, which results in the activation of Hh pathway, also causes an increase in PI4P levels. Sac1 functions downstream of STT4 and Ptc in the regulation of Smo membrane localization and Hh pathway activation. Taken together, our results suggest a model in which Ptc directly or indirectly functions to suppress the accumulation of PI4P. Binding of Hh to Ptc derepresses the levels of PI4P, which, in turn, promotes Smo activation.

    View details for DOI 10.1016/j.devcel.2010.06.007

    View details for Web of Science ID 000280469100010

    View details for PubMedID 20643350

  • Arrestin? Movement in Cilia. Science Rohatgi R, Scott MP 2008; 320 (5884): 1777-1781
  • Patching the gaps in Hedgehog signaling. Nat Cell Bio Rohatgi R, Scott MP 2007; 9 (9): 1005-1009
  • In vitro reconstitution of cdc42-mediated actin assembly using purified components. Methods in Enzymology Ho HY, Rohatgi R, Lebensohn A, Kirschner MW 2006; 406: 174-190
  • Loss-of-function Analysis of EphA Receptors in Retinotectal mapping. Journal of Neuroscience Feldheim DA, Nakamoto M, Osterfield M, Gale NW, DeChiara TM, Rohatgi R, Yancopoulos GD, Flanagan JG 2004; 24 (10): 2542-2550
  • Toca-1 Mediates Cdc42- Dependent Actin Nucleation by Activating the N-WASP-WIP Complex. Cell Ho HY, R., Lebensohn A, Ma L, Li L, Gygi SP, Kirschner MW 2004; 118 (2): 203-216
  • The Mechanism of Regulation of WAVE1-induced Actin Nucleation by Rac1 and Nck. Nature Eden S, Rohatgi R, Podtelejnikov AV, Mann M, Kirschner MW 2002; 418 (6899): 790-793
  • Nck and Phosphatidylinositol 4,5 Bisphosphate Synergistically Activate Actin Polymerization Through the N-WASP-Arp2/3 Pathway. Journal of Biological Chemistry Rohatgi R, Nollau P, Ho HY, Kirschner MW, Mayer BJ 2001; 276 (28): 26448-26452
  • CR16 Forms a Complex with N-WASP in Brain and is a Novel Member of a Conserved Proline-Rich Actin-Binding Protein Family. Proceedings of the National Academy of Sciences USA Ho HY, R., Ma L, Kirschner MW 2001; 98 (20): 11306-11311
  • WIP Regulates N-WASP-Mediated Actin Polymerization and Filopodium Formation. Nature Cell Biology Martinez-Quiles N, Rohatgi R, Anton IM, Medina M, Saville SP, Miki H, Yamaguchi H, Takenawa T, Hartwig JH, Geha RS, Ramesh N 2001; 3 (5): 484-491
  • Mechanism of N-WASP Activation by CDC42 and Phosphatidylinositol 4, 5-Bisphosphate. Journal of Cell Biology Rohatgi R, H., Kirschner MW 2000; 150 (6): 1299-1310
  • The Interaction Between N-WASP and the Arp2/3 Complex Links Cdc42-Dependent Signals to Actin Assembly. Cell Rohatgi R, M., Miki H, Lopez M, Kirchhausen T, Takenawa T, Kirschner MW 1999; 97 (2): 221-231
  • The Arp2/3 Complex Mediates Actin Polymerization Induced by the Small GTP-Binding Protein Cdc42. Proceedings of the National Academy of Sciences USA Ma L, Rohatgi R, Kirschner MW 1998; 95 (26): 15362-15367
  • Non-Enzymatic, Template-Directed Ligation of Oligoribonucleotides is Highly Regioselective for the Formation of 3'-5'-Phosphodiester Bonds Journal of the American Chemical Society Rohatgi R, Bartel DP, Szostak JW 1996; 118 (14): 3340-3344
  • Kinetic and Mechanistic Analysis of Non-Enzymatic, Template-Directed Oligoribonucleotide Ligation. Journal of the American Chemical Society Rohatgi R, Bartel DP, Szostak JW 1996; 118 (14): 3332-3339