Resume

• 2013

  Envision Pharma Group

  Grey Healthcare Group

  NYU School of Medicine

  Grey Healthcare Group

  New York

  NY

  Associate Medical Director

  Greater New York City Area

  Medical Affairs

  Envision Pharma Group

• 2008

  New York University Cancer Institute

  New York University Cancer Institute

  Postdoctoral Fellowship

  Molecular Oncology

  NYU School of Medicine

  Sackler Institute of Graduate Biomedical Sciences

• 2002

  Doctor of Philosophy (Ph.D.)

  Molecular Oncology

  City University of New York

• 1999

  Bachelor of Arts (B.A.)

  Biochemistry

  City University of New York-Hunter College

• 1997

  Biotechnology

  Università di Bologna / University of Bologna

• HPLC

  Animal Models

  Molecular Biology

  Lifesciences

  Science

  PCR

  Immunohistochemistry

  Italian languages

  Western Blotting

  Cell Biology

  Tissue Culture

  Life Sciences

  Neuroscience

  Research

  Biochemistry

  Pharmaceutical Industry

  Scientific Writing

  Oncology

  Cell Culture

  Medical Writing

  Targeting mTOR with rapamycin: one dose does not fit all.

  Foster David

  A puzzling aspect of rapamycin-based therapeutic strategies is the wide disparity in the doses needed to suppress mTOR under different circumstances. A recent study revealing mechanistically how rapamycin suppresses mTOR provides two explanations for the differential sensitivities to rapamycin. First

  mTOR exists as two functionally distinct complexes (mTORC1 and mTORC2)

  and while rapamycin suppresses both

  it does so at very different concentrations. Whereas mTORC1 is suppressed by concentrations of rapamycin in the low nM range

  mTORC2 generally requires low muM concentrations. Second

  the efficacy of rapamycin is dependent on the level of phosphatidic acid (PA)

  which is required for the assembly of both mTORC1 and mTORC2 complexes. Rapamycin interacts with mTOR in a manner that is competitive with PA. Therefore

  elevated levels of PA

  which is common in cancer cells

  increases the level of rapamycin needed to suppress both mTORC1 and mTORC2. A practical outcome of the recent study is that if PA levels are suppressed

  mTORC2 becomes sensitive to concentrations of rapamycin that can be achieved clinically. Since mTORC2 is likely more critical for survival signals in cancer cells

  the recent findings suggest new strategies for enhancing the efficacy of rapamycin-based therapeutic approaches in cancer cells.

  Targeting mTOR with rapamycin: one dose does not fit all.

  Evan Lee

  Limei Xu

  Avalon Garcia

  Noga Gadir

  David Foster

  mTOR

  the mammalian target of rapamycin

  is a critical node for control of cell growth and survival and has widely been implicated in cancer survival signals. mTOR exists in two complexes: mTORC1 and mTORC2. Phospholipase D (PLD) and its metabolite phosphatidic acid (PA) have been implicated in the regulation of mTOR; however

  their role has been controversial. We report here that suppression of PLD prevents phosphorylation of the mTORC1 substrate S6 kinase (S6K) at Thr389 and the mTORC2 substrate Akt at Ser473. Suppression of PLD also blocked insulin-stimulated Akt phosphorylation at Ser473 and the mTORC2-dependent phosphorylation of PRAS40. Importantly

  PA was required for the association of mTOR with Raptor to form mTORC1 and that of mTOR with Rictor to form mTORC2. The effect of PA was competitive with rapamycin-with much higher concentrations of rapamycin needed to compete with the PA-mTORC2 interaction than with PA-mTORC1. Suppressing PA production substantially increased the sensitivity of mTORC2 to rapamycin. Data provided here demonstrate a PA requirement for the stabilization of both mTORC1 and mTORC2 complexes and reveal a mechanism for the inhibitory effect of rapamycin on mTOR. This study also suggests that by suppressing PLD activity

  mTORC2 could be targeted therapeutically with rapamycin.

  Regulation of mTORC1 and mTORC2 Complex Assembly by Phosphatidic Acid

  a Competition with Rapamycin

  Evan Lee

  Noga Gadir

  David Foster

  Constitutive expression of hypoxia-inducible factor (HIF) has been implicated in several proliferative disorders. Constitutive expression of HIF1 alpha and HIF2 alpha has been linked to a number of human cancers

  especially renal cell carcinoma (RCC)

  in which HIF2 alpha expression is the more important contributor. Expression of HIF1 alpha is dependent on the mammalian target of rapamycin (mTOR) and is sensitive to rapamycin. In contrast

  there have been no reports linking HIF2 alpha expression with mTOR. mTOR exists in two complexes

  mTORC1 and mTORC2

  which are differentially sensitive to rapamycin. We report here that although there are clear differences in the sensitivity of HIF1 alpha and HIF2 alpha to rapamycin

  both HIF1 alpha and HIF2 alpha expression is dependent on mTOR. HIF1 alpha expression was dependent on both Raptor (a constituent of mTORC1) and Rictor (a constitutive of mTORC2). In contrast

  HIF2 alpha was dependent only on the mTORC2 constituent Rictor. These data indicate that although HIF1 alpha is dependent on both mTORC1 and mTORC2

  HIF2 alpha is dependent only on mTORC2. We also examined the dependence of HIF alpha expression on the mTORC2 substrate Akt

  which exists as three different isoforms

  Akt1

  Akt2

  and Akt3. Interestingly

  the expression of HIF2 alpha was dependent on Akt2

  whereas that of HIF1 alpha was dependent on Akt3. Because HIF2 alpha is apparently more critical in RCC

  this study underscores the importance of targeting mTORC2 and perhaps Akt2 signaling in RCC and other proliferative disorders in which HIF2 alpha has been implicated.

  Differential Dependence of HIF1α and HIF2α on mTORC1 and mTORC2.

  Jake Edelstein

  Patricia Rockwell

  David Foster

  Loss of the von Hippel-Lindau (VHL) tumor suppressor gene contributes to proliferative disorders including renal cell carcinoma. The consequence of VHL loss is increased levels of hypoxia-inducible factor-alpha (HIFalpha)

  which is targeted for proteolytic degradation by the VHL gene product pVHL. HIF is a transcription factor that increases the expression of factors critical for tumorigenesis in renal cell carcinoma. We report here another regulatory component of HIFalpha expression in renal cancer cells. Phospholipase D (PLD)

  which is commonly elevated in renal and other cancers

  is required for elevated levels of both HIF1alpha and HIF2alpha in VHL-deficient renal cancer cells. The induction of both HIF1alpha and HIF2alpha by hypoxic mimetic conditions was also dependent on PLD in renal cancer cells with restored pVHL expression. The effect of PLD activity upon HIFalpha expression was at the level of translation. PLD activity also provides a survival signal that suppresses apoptosis induced by serum deprivation in the renal cancer cells. Suppression of HIF2alpha has been shown to reverse tumorigenesis with renal cancer cells. The finding here that HIF2alpha expression is dependent on PLD in renal cancer cells suggests that targeting PLD signals may represent an alternative therapeutic strategy for targeting HIF2alpha in renal cancers where HIF2alpha is critical for tumorigenesis and elevated PLD activity is common.

  HIF alpha expression in VHL-deficient renal cancer cells is dependent on phospholipase D

  Evan Lee

  Sebastian Thompson

  Noga Gadir

  Paige Yellen

  Michael Drain

  Michael Ohh

  David Foster

  A characteristic of cancer cells is the generation of lactate from glucose in spite of adequate oxygen for oxidative phosphorylation. This property - known as the \"Warburg effect\" or aerobic glycolysis - contrasts with anaerobic glycolysis

  which is triggered in hypoxic normal cells. The Warburg effect is thought to provide a means for cancer cells to survive under conditions where oxygen is limited and to generate metabolites necessary for cell growth. The shift from oxidative phosphorylation to glycolysis in response to hypoxia is mediated by the production of hypoxia-inducible factor (HIF) - a transcription factor family that stimulates the expression of proteins involved in glucose uptake and glycolysis. We reported previously that elevated phospholipase D (PLD) activity in renal and breast cancer cells is required for the expression of the α subunits of HIF1 and HIF2. We report here that the aerobic glycolysis observed in human breast and renal cancer cells is dependent on the elevated PLD activity. Intriguingly

  the effect of PLD on the Warburg phenotype was dependent on the mammalian target of rapamycin complex 1 (mTORC1) in the breast cancer cells and on mTORC2 in the renal cancer cells. These data indicate that elevated PLD-mTOR signaling

  which is common in human cancer cells

  is critical for the metabolic shift to aerobic glycolysis.

  Phospholipase D-mTOR requirement for the Warburg effect in human cancer cells

  NYU School of Medicine