Neal Rosen

Summary

Affiliation: Memorial Sloan-Kettering Cancer Center
Country: USA

Publications

  1. ncbi request reprint AKT and cancer--is it all mTOR?
    Neal Rosen
    Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Cancer Cell 10:254-6. 2006
  2. pmc Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism
    Piro Lito
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
    Science 351:604-8. 2016
  3. pmc Inhibitors of HSP90 block p95-HER2 signaling in Trastuzumab-resistant tumors and suppress their growth
    S Chandarlapaty
    Department of Medicine, Memorial Sloan Kettering Cancer Center MSKCC, New York, NY 10065, USA
    Oncogene 29:325-34. 2010
  4. pmc The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner
    Eric W Joseph
    Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA
    Proc Natl Acad Sci U S A 107:14903-8. 2010
  5. pmc Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel
    Ayana Sawai
    Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    Cancer Res 68:589-96. 2008
  6. pmc Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation
    Debyani Chakravarty
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    J Clin Invest 121:4700-11. 2011
  7. pmc Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors
    Piro Lito
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Cancer Cell 25:697-710. 2014
  8. pmc 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors
    Qing Bai She
    Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Cancer Cell 18:39-51. 2010
  9. doi request reprint HER kinase activation confers resistance to MET tyrosine kinase inhibition in MET oncogene-addicted gastric cancer cells
    Thomas Bachleitner-Hofmann
    Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
    Mol Cancer Ther 7:3499-508. 2008
  10. pmc BRAFV600E mutation is associated with preferential sensitivity to mitogen-activated protein kinase kinase inhibition in thyroid cancer cell lines
    Rebecca Leboeuf
    Department of Medicine and Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
    J Clin Endocrinol Metab 93:2194-201. 2008

Research Grants

Detail Information

Publications101 found, 100 shown here

  1. ncbi request reprint AKT and cancer--is it all mTOR?
    Neal Rosen
    Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Cancer Cell 10:254-6. 2006
    ..Moreover, the effects of AKT are mediated predominantly or solely via mTORC1. This suggests that AKT or mTOR inhibitors will be useful treatments for many cancers...
  2. pmc Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism
    Piro Lito
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
    Science 351:604-8. 2016
    ..These findings reveal that KRAS(G12C) undergoes nucleotide cycling in cancer cells and provide a basis for developing effective therapies to treat KRAS(G12C)-driven cancers. ..
  3. pmc Inhibitors of HSP90 block p95-HER2 signaling in Trastuzumab-resistant tumors and suppress their growth
    S Chandarlapaty
    Department of Medicine, Memorial Sloan Kettering Cancer Center MSKCC, New York, NY 10065, USA
    Oncogene 29:325-34. 2010
    ..HSP90 inhibition is therefore a potentially effective therapeutic strategy for p95-HER2-mediated Trastuzumab-resistant breast cancer...
  4. pmc The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner
    Eric W Joseph
    Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA
    Proc Natl Acad Sci U S A 107:14903-8. 2010
    ..This selectivity may lead to a broader therapeutic index and help explain the greater antitumor activity observed with this drug than with MEK inhibitors...
  5. pmc Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel
    Ayana Sawai
    Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    Cancer Res 68:589-96. 2008
    ....
  6. pmc Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation
    Debyani Chakravarty
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    J Clin Invest 121:4700-11. 2011
    ..These findings have potentially significant clinical ramifications...
  7. pmc Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors
    Piro Lito
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Cancer Cell 25:697-710. 2014
    ..Newer MEK inhibitors target MEK catalytic activity and also impair its reactivation by CRAF, either by disrupting RAF-MEK complexes or by interacting with Ser 222 to prevent MEK phosphorylation by RAF. ..
  8. pmc 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors
    Qing Bai She
    Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Cancer Cell 18:39-51. 2010
    ..Thus, 4E-BP1 plays a prominent role in mediating the effects of these pathways in tumors in which they are activated by mutation...
  9. doi request reprint HER kinase activation confers resistance to MET tyrosine kinase inhibition in MET oncogene-addicted gastric cancer cells
    Thomas Bachleitner-Hofmann
    Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
    Mol Cancer Ther 7:3499-508. 2008
    ....
  10. pmc BRAFV600E mutation is associated with preferential sensitivity to mitogen-activated protein kinase kinase inhibition in thyroid cancer cell lines
    Rebecca Leboeuf
    Department of Medicine and Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
    J Clin Endocrinol Metab 93:2194-201. 2008
    ..Although the signal output common to these oncoproteins is ERK, a recent report showed that only BRAF mutations consistently predicted responsiveness to MAPK kinase (MEK) inhibitors...
  11. ncbi request reprint 17AAG: low target binding affinity and potent cell activity--finding an explanation
    Gabriela Chiosis
    Program in Cell Biology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Mol Cancer Ther 2:123-9. 2003
    ..We suggest that in the clinic, micromolar concentrations of 17AAG must accumulate in the tumor cells to achieve antitumor effects in patients comparable with ones achieved in tissue culture settings...
  12. ncbi request reprint Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol
    David B Solit
    Department of Medicine, Program in Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Cancer Res 63:2139-44. 2003
    ..These results suggest that Hsp90 inhibitors can effectively suppress Akt activity in animal models of human cancer at nontoxic doses, thus sensitizing tumor cells to proapoptotic stimuli...
  13. pmc PIK3CA mutation uncouples tumor growth and cyclin D1 regulation from MEK/ERK and mutant KRAS signaling
    Ensar Halilovic
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
    Cancer Res 70:6804-14. 2010
    ....
  14. pmc 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography is a sensitive method for imaging the response of BRAF-dependent tumors to MEK inhibition
    David B Solit
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Cancer Res 67:11463-9. 2007
    ..The data suggest that [(18)F]FLT PET can effectively image induction of G(1) arrest by MEK inhibitors in mutant BRAF tumors and may be a useful noninvasive method for assessing the early biological response to this class of drugs...
  15. pmc Antitumor activity of SNX-2112, a synthetic heat shock protein-90 inhibitor, in MET-amplified tumor cells with or without resistance to selective MET Inhibition
    Thomas Bachleitner-Hofmann
    Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    Clin Cancer Res 17:122-33. 2011
    ..MET, a tyrosine kinase that is constitutively active in tumor cells with MET oncogene amplification, has recently been identified as another HSP-90 client...
  16. pmc Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2
    Andrea D Basso
    Program in Pharmacology, Weill Graduate School of Medical Sciences, Cornell University, 1300 York Avenue, New York, NY 10021, USA
    Oncogene 21:1159-66. 2002
    ..Thus, pharmacological inhibition of Akt activation is achievable with ansamycins and may be useful for the treatment of HER2 driven tumors...
  17. pmc Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas
    Piro Lito
    Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Cancer Cell 22:668-82. 2012
    ..In this state, ERK signaling is RAF inhibitor resistant, and MEK inhibitor sensitive, and combined inhibition results in enhancement of ERK pathway inhibition and antitumor activity...
  18. pmc RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF
    Poulikos I Poulikakos
    Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    Nature 464:427-30. 2010
    ..In agreement with this prediction, RAF inhibitors do not inhibit ERK signalling in cells that coexpress BRAF(V600E) and mutant RAS...
  19. pmc Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer
    Brett S Carver
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Cancer Cell 19:575-86. 2011
    ....
  20. pmc Early tumor response to Hsp90 therapy using HER2 PET: comparison with 18F-FDG PET
    Peter M Smith-Jones
    Nuclear Medicine Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    J Nucl Med 47:793-6. 2006
    ....
  21. ncbi request reprint New efficient synthesis of resorcinylic macrolides via ynolides: establishment of cycloproparadicicol as synthetically feasible preclinical anticancer agent based on Hsp90 as the target
    Zhi Qiang Yang
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA
    J Am Chem Soc 126:7881-9. 2004
    ..The potency of their cytotoxicity was found to be consistent with their ability to degrade the oncogenic protein, Her2. From these assays, cycloproparadicicol was identified as a most promising candidate for further development...
  22. ncbi request reprint Safety and biologic activity of intravenous BCL-2 antisense oligonucleotide (G3139) and taxane chemotherapy in patients with advanced cancer
    Michael J Morris
    Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Appl Immunohistochem Mol Morphol 13:6-13. 2005
    ..These data support the dose selection of ongoing phase 2 studies of G3139 at 7 mg/kg/d and docetaxel 75 mg/m2...
  23. pmc mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling
    Vanessa S Rodrik-Outmezguine
    Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    Cancer Discov 1:248-59. 2011
    ..These findings reveal the adaptive capabilities of oncogenic signaling networks and the limitations of monotherapy for inhibiting feedback-regulated pathways...
  24. pmc A phase I trial of docetaxel and pulse-dose 17-allylamino-17-demethoxygeldanamycin in adult patients with solid tumors
    Gopa Iyer
    Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
    Cancer Chemother Pharmacol 69:1089-97. 2012
    ....
  25. pmc SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase-dependent cancers
    Sarat Chandarlapaty
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Clin Cancer Res 14:240-8. 2008
    ..However, the utility of these drugs has been limited by their hepatotoxicity, poor solubility, and poorly tolerated formulations...
  26. pmc Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling
    Qing Bai She
    Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
    PLoS ONE 3:e3065. 2008
    ..The objective of this study was to determine the role of Akt activation in breast cancer as a function of mechanism of activation and whether inhibition of Akt signaling is a feasible approach to therapy...
  27. ncbi request reprint Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function
    Andrea D Basso
    Program in Pharmacology, Weill Graduate School of Medical Sciences, Cornell University and the Program in Cell Biology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    J Biol Chem 277:39858-66. 2002
    ..Thus, transduction of growth factor signaling via the Akt and Raf pathways requires functional Hsp90 and can be coordinately blocked by its inhibition...
  28. pmc Progression of RAS-mutant leukemia during RAF inhibitor treatment
    Margaret K Callahan
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    N Engl J Med 367:2316-21. 2012
    ..Exposure to vemurafenib induced hyperactivation of ERK signaling and proliferation of the leukemic cell population, an effect that was reversed on drug withdrawal...
  29. ncbi request reprint Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study
    Shanu Modi
    Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    J Clin Oncol 25:5410-7. 2007
    ..This phase I study examined whether a heat shock protein (Hsp) 90 inhibitor tanespimycin (17-AAG; KOS-953) could be administered safely in combination with trastuzumab at a dose that inhibits Hsp90 function in vivo in lymphocytes...
  30. pmc Randomized phase II study of pulse erlotinib before or after carboplatin and paclitaxel in current or former smokers with advanced non-small-cell lung cancer
    Gregory J Riely
    Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10022, USA
    J Clin Oncol 27:264-70. 2009
    ..However, preclinical data support the hypothesis that intermittent administration of erlotinib before or after chemotherapy may improve efficacy. We tested this hypothesis in patients with advanced NSCLC...
  31. ncbi request reprint 17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts
    David B Solit
    Program in Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Clin Cancer Res 8:986-93. 2002
    ....
  32. pmc Genetic predictors of MEK dependence in non-small cell lung cancer
    Christine A Pratilas
    Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Cancer Res 68:9375-83. 2008
    ....
  33. pmc (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway
    Christine A Pratilas
    Department of Pediatrics, Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Proc Natl Acad Sci U S A 106:4519-24. 2009
    ..Physiologic feedback inhibition of RAF/MEK signaling down-regulates ERK output in RTK cells; evasion of this feedback in mutant BRAF cells is associated with increased transcriptional output and MEK/ERK-dependent transformation...
  34. pmc AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity
    Sarat Chandarlapaty
    Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Cancer Cell 19:58-71. 2011
    ..Consistent with this model, we find that, in tumors in which AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone...
  35. pmc Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors
    Lucia Regales
    Pao Lab, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America
    PLoS ONE 2:e810. 2007
    ..The EGFR T790M mutation confers acquired resistance to kinase inhibitors in human EGFR mutant lung adenocarcinoma, is occasionally detected before treatment, and may confer genetic susceptibility to lung cancer...
  36. ncbi request reprint Evaluation of 8-arylsulfanyl, 8-arylsulfoxyl, and 8-arylsulfonyl adenine derivatives as inhibitors of the heat shock protein 90
    Laura Llauger
    Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    J Med Chem 48:2892-905. 2005
    ....
  37. pmc The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells
    Qing Bai She
    Program in Molecular Pharmacology and Chemistry, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    Cancer Cell 8:287-97. 2005
    ..Thus, BAD integrates the antiapoptotic effects of both pathways. Combined inhibition of EGFR and PI3K signaling may be a useful therapeutic strategy...
  38. pmc Proton MRS detects metabolic changes in hormone sensitive and resistant human prostate cancer models CWR22 and CWR22r
    H Carl Le
    Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Magn Reson Med 62:1112-9. 2009
    ..01). Metabolic changes in total choline by proton MRSI can be used as an early biomarker of response for advanced-stage prostate cancer in targeted therapy such as 17-allylamino, 17-demethoxygeldanamycin...
  39. doi request reprint ERK pathway inhibitors: how low should we go?
    Moriah H Nissan
    Louis V Gerstner, Jr Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    Cancer Discov 3:719-21. 2013
    ..SCH772984 may also have a role in the treatment of tumors in which ERK is dysregulated by mutant RAS, NF1, or activated receptor tyrosine kinases, settings in which current RAF inhibitors are ineffective...
  40. ncbi request reprint Total synthesis as a resource in the discovery of potentially valuable antitumor agents: cycloproparadicicol
    Kana Yamamoto
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10021, USA
    Angew Chem Int Ed Engl 42:1280-4. 2003
  41. pmc Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast tumors
    Paola de Candia
    Program in Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    Proc Natl Acad Sci U S A 100:12337-42. 2003
    ..Thus angiogenesis inhibitors in combination with inhibitors of Hsp90 function should be evaluated for the treatment of advanced breast cancer...
  42. pmc Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas
    Cristina Montero-Conde
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
    Cancer Discov 3:520-33. 2013
    ..The determinants of primary resistance to MAPK inhibitors vary between cancer types, due to preferential upregulation of specific receptor tyrosine kinases, and the abundance of their respective ligands...
  43. ncbi request reprint Hsp90: a novel target for cancer therapy
    David B Solit
    Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
    Curr Top Med Chem 6:1205-14. 2006
    ..This article will review the preclinical data which supports the testing of Hsp90 inhibitors as cancer drugs and update the reader on the current status of the ongoing clinical trials of Hsp90 inhibitors...
  44. pmc Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer
    David B Solit
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    Clin Cancer Res 13:1775-82. 2007
    ..To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules...
  45. ncbi request reprint Association with HSP90 inhibits Cbl-mediated down-regulation of mutant epidermal growth factor receptors
    Seungchan Yang
    Department of Medicine, Breast Cancer Research Program, Vanderbilt Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 6307, USA
    Cancer Res 66:6990-7. 2006
    ..These results suggest that EGFR mutants form defective endocytic complexes. In addition, HSP90 plays a role in maintaining the functional conformation of EGFR mutants and protecting activated receptors from LIRD...
  46. ncbi request reprint Combination treatment with 17-N-allylamino-17-demethoxy geldanamycin and acute irradiation produces supra-additive growth suppression in human prostate carcinoma spheroids
    Richard Enmon
    Memorial Sloan Kettering Cancer Center, New York, New York, USA
    Cancer Res 63:8393-9. 2003
    ..These results suggest that significant gains in treatment effectiveness may be obtained by combining these treatment modalities, warranting additional preclinical investigation...
  47. ncbi request reprint Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90
    Maria Vilenchik
    Program in Cell Biology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021 USA
    Chem Biol 11:787-97. 2004
    ..Concentrations achieved in vivo in tumors lead to single-agent anti-tumor activity at non-toxic doses...
  48. pmc BRAF mutation predicts sensitivity to MEK inhibition
    David B Solit
    Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
    Nature 439:358-62. 2006
    ..These data suggest an exquisite dependency on MEK activity in BRAF mutant tumours, and offer a rational therapeutic strategy for this genetically defined tumour subtype...
  49. pmc Phase II trial of MEK inhibitor selumetinib (AZD6244, ARRY-142886) in patients with BRAFV600E/K-mutated melanoma
    Federica Catalanotti
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    Clin Cancer Res 19:2257-64. 2013
    ..Test the hypothesis that in BRAF-mutated melanomas, clinical responses to selumetinib, a MEK inhibitor, will be restricted to tumors in which the PI3K/AKT pathway is not activated...
  50. pmc Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence
    Moriah H Nissan
    Authors Affiliations Louis V Gerstner, Jr Graduate School of Biomedical Science Human Oncology and Pathogenesis Program Departments of Pediatrics, Pathology, and Medicine Programs in Molecular Pharmacology and Chemistry Computational Biology Ludwig Collaborative Lab, Memorial Sloan Kettering Cancer Center, New York, New York Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles Departments of Epidemiology and Biostatistics and Medicine, and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California
    Cancer Res 74:2340-50. 2014
    ..We conclude that loss of NF1 is common in cutaneous melanoma and is associated with RAS activation, MEK-dependence, and resistance to RAF inhibition...
  51. pmc RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer
    Rona Yaeger
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
    Cancer 121:1195-203. 2015
    ..We sought to evaluate the impact of RAS and PIK3CA mutations on cumulative incidence of metastasis to potentially curable sites of liver and lung and other sites such as bone and brain...
  52. doi request reprint Tumor adaptation and resistance to RAF inhibitors
    Piro Lito
    1 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA 2 Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    Nat Med 19:1401-9. 2013
    ....
  53. pmc Frequent mutational activation of the PI3K-AKT pathway in trastuzumab-resistant breast cancer
    Sarat Chandarlapaty
    Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    Clin Cancer Res 18:6784-91. 2012
    ..We conducted a prospective tissue acquisition study to determine if there is evidence for these lesions in metastatic tumors that have progressed on trastuzumab-containing therapy...
  54. pmc RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)
    Poulikos I Poulikakos
    Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    Nature 480:387-90. 2011
    ....
  55. doi request reprint HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab
    Shanu Modi
    Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Clin Cancer Res 17:5132-9. 2011
    ..On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer...
  56. ncbi request reprint Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors
    Peter M Smith-Jones
    Department of Radiology, Memorial Sloan Kettering Cancer Center, New York 10021, USA
    Nat Biotechnol 22:701-6. 2004
    ..This approach allows noninvasive imaging of the pharmacodynamics of a targeted drug and will facilitate the rational design of combination therapy based on target inhibition...
  57. ncbi request reprint Pulsatile administration of the epidermal growth factor receptor inhibitor gefitinib is significantly more effective than continuous dosing for sensitizing tumors to paclitaxel
    David B Solit
    Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
    Clin Cancer Res 11:1983-9. 2005
    ..Furthermore, we hypothesized that intermittent dosing would allow for dose escalation and greater inhibition of EGFR-dependent antiapoptotic pathways...
  58. pmc mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt
    Kathryn E O'Reilly
    Program in Molecular Pharmacy and Chemistry, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
    Cancer Res 66:1500-8. 2006
    ..Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity...
  59. pmc Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma
    David B Solit
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    Clin Cancer Res 14:8302-7. 2008
    ..We conducted a phase II trial using the hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in melanoma patients. The primary end points were clinical responses and whether treatment inhibited MAPK pathway activity...
  60. ncbi request reprint Development of a purine-scaffold novel class of Hsp90 binders that inhibit the proliferation of cancer cells and induce the degradation of Her2 tyrosine kinase
    Gabriela Chiosis
    Program in Cell Biology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA
    Bioorg Med Chem 10:3555-64. 2002
    ..Induces the degradation of Her2 tyrosine kinase and arrests the MCF-7 breast cancer cell line at low micromolar concentrations (IC50=2 microM)...
  61. pmc Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma
    Jonathan H Schatz
    Cancer Biology and Genetics Program, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA
    J Exp Med 208:1799-807. 2011
    ..Hence, targeting the convergence of oncogenic survival signals on translation initiation is an effective alternative to combinations of kinase inhibitors...
  62. pmc Phosphorylated 4E-BP1 is associated with poor survival in melanoma
    Kathryn E O'Reilly
    Department of Dermatology, New York University School of Medicine, New York, NY 10016, USA
    Clin Cancer Res 15:2872-8. 2009
    ..We then tested the association between amounts of total and p-4E-BP1 and patient survival...
  63. ncbi request reprint A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors
    Matthew G Fury
    Division of Solid Tumor Oncology, Head and Neck Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY 10021, USA
    Cancer Chemother Pharmacol 59:467-75. 2007
    ....
  64. pmc Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms
    Eli L Diamond
    Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York
    Cancer Discov 6:154-65. 2016
    ..Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders...
  65. pmc BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition
    Zhan Yao
    Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Cancer Cell 28:370-83. 2015
    ..A compound that equally inhibits both sites of mutant RAF dimers inhibits tumors driven by either class of mutants or those BRAF V600E tumors with dimer-dependent acquired resistance to monomer-specific inhibitors. ..
  66. pmc Uncoupling of hormone-dependence from chaperone-dependence in the L701H mutation of the androgen receptor
    Kenneth Robzyk
    Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    Mol Cell Endocrinol 268:67-74. 2007
    ....
  67. pmc Everolimus combined with gefitinib in patients with metastatic castration-resistant prostate cancer: Phase 1/2 results and signaling pathway implications
    Dana E Rathkopf
    Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
    Cancer 121:3853-61. 2015
    ..Thus, this study tested the combination of mTOR inhibition (everolimus) and epidermal growth factor receptor inhibition (gefitinib) in castration-resistant prostate cancer (CRPC)...
  68. ncbi request reprint Development of a fluorescence polarization assay for the molecular chaperone Hsp90
    Joungnam Kim
    Program in Cell Biology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    J Biomol Screen 9:375-81. 2004
    ..These data demonstrate that the Hsp90-FP-based assay can be used for high-throughput screening in aiding the identification of novel Hsp90 inhibitors...
  69. doi request reprint Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo
    Erik Henke
    Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, 1270 York Ave, New York, New York 10021, USA
    Nat Biotechnol 26:91-100. 2008
    ..Combination with the Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin yielded virtually complete growth suppression of aggressive breast tumors...
  70. pmc mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer
    Moshe Elkabets
    Human Oncology and Pathogenesis Program and Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA
    Sci Transl Med 5:196ra99. 2013
    ..Our findings suggest that simultaneous administration of mTORC1 inhibitors may enhance the clinical activity of p110α-targeted drugs and delay the appearance of resistance...
  71. pmc Efficacy of intermittent combined RAF and MEK inhibition in a patient with concurrent BRAF- and NRAS-mutant malignancies
    Omar Abdel-Wahab
    1Human Oncology and Pathogenesis Program, 2Leukemia Service, 3Gastrointestinal Oncology Service, 4Melanoma and Immunotherapeutics Service, Department of Medicine, 5Molecular Diagnostics Service, Department of Pathology, 6Department of Radiology, 7Center for Molecular Oncology, 8Ludwig Center for Cancer Immunotherapy, and 9Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center and 10Weill Cornell Medical College, New York, New York
    Cancer Discov 4:538-45. 2014
    ..These data support testing of intermittent ERK pathway inhibition in the therapy for both RAS-mutant leukemia and BRAF-mutant melanoma...
  72. ncbi request reprint Microtiter cell-based assay for detection of agents that alter cellular levels of Her2 and EGFR
    Henri Huezo
    Program in Cell Biology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
    Chem Biol 10:629-34. 2003
    ..The method gives results comparable to Western blot, but it is faster, less labor intensive, and amenable to high throughput...
  73. ncbi request reprint Development of purine-scaffold small molecule inhibitors of Hsp90
    Gabriela Chiosis
    Department of Medicine and Cell Biology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA
    Curr Cancer Drug Targets 3:371-6. 2003
    ..The development of novel agents that lack the drawbacks of the natural products is thus necessary. Here we present an overview of such efforts with focus on a new class of purine-scaffold Hsp90 inhibitors developed by rational design...
  74. pmc Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumor initiation in mice
    Aime T Franco
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Proc Natl Acad Sci U S A 108:1615-20. 2011
    ....
  75. pmc AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas
    Moshe Elkabets
    Human Oncology and Pathogenesis Program HOPP, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA
    Cancer Cell 27:533-46. 2015
    ..Combined treatment with PI3Kα and either EGFR, AXL, or PKC inhibitors reverts this resistance. ..
  76. ncbi request reprint Hsp90 as a therapeutic target in prostate cancer
    David B Solit
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    Semin Oncol 30:709-16. 2003
    ..These data suggest that inhibitors of Hsp90 may represent a novel strategy for the treatment of patients with prostate cancer and clinical trials to test this hypothesis are currently ongoing...
  77. pmc Feedback suppression of PI3Kα signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3Kβ
    Sarit Schwartz
    Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Cancer Cell 27:109-22. 2015
    ..In PTEN-deficient models of prostate cancer, this effective inhibition of PI3K causes marked activation of androgen receptor activity. Combined inhibition of both PI3K isoforms and androgen receptor results in major tumor regressions. ..
  78. doi request reprint Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients
    Rona Yaeger
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
    Clin Cancer Res 21:1313-20. 2015
    ..These data suggest that combined therapy with RAF and EGFR inhibitors could be an effective strategy for treating BRAF V600E mCRC...
  79. pmc Models from experiments: combinatorial drug perturbations of cancer cells
    Sven Nelander
    Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
    Mol Syst Biol 4:216. 2008
    ..Possible applications include the discovery of regulatory interactions, the design of targeted combination therapies and the engineering of molecular biological networks...
  80. pmc Inhibition of mycobacterial infection by the tumor suppressor PTEN
    Guochang Huang
    Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
    J Biol Chem 287:23196-202. 2012
    ..The relationship of PTEN-PI3K-Akt mTOR status and susceptibility to mycobacterial infection suggests that the interaction of mycobacterial pathogens with cancer cells may be influenced by genetic alterations in the tumor cells...
  81. pmc Akt phosphorylates the transcriptional repressor bmi1 to block its effects on the tumor-suppressing ink4a-arf locus
    Yan Liu
    Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Sci Signal 5:ra77. 2012
    ....
  82. ncbi request reprint Phase I trial of BCL-2 antisense oligonucleotide (G3139) administered by continuous intravenous infusion in patients with advanced cancer
    Michael J Morris
    Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Clin Cancer Res 8:679-83. 2002
    ..To evaluate the safety and pharmacokinetics of BCL-2 antisense oligonucleotide (G3139) administered by prolonged i.v. infusion in patients with advanced cancer...
  83. ncbi request reprint The use of molecular markers in farnesyltransferase inhibitor (FTI) therapy of breast cancer
    M M Moasser
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    Breast Cancer Res Treat 73:135-44. 2002
    ..Although these studies do not identify any single molecular marker that can accurately predict FTI sensitivity in breast tumors, they highlight the potential roles of FPTase activity and p53 function for further analysis...
  84. ncbi request reprint A novel pyridopyrimidine inhibitor of abl kinase is a picomolar inhibitor of Bcr-abl-driven K562 cells and is effective against STI571-resistant Bcr-abl mutants
    David R Huron
    Department of Medicine, Memorial Sloan Kettering Cancer Center and Program in Pharmacology, New York, New York 10021, USA
    Clin Cancer Res 9:1267-73. 2003
    ..PD166326 is a prototype of a new generation of anti-Bcr-abl compounds with picomolar potency and substantial activity against STI571-resistant mutants...
  85. pmc Monitoring the induction of heat shock factor 1/heat shock protein 70 expression following 17-allylamino-demethoxygeldanamycin treatment by positron emission tomography and optical reporter gene imaging
    Mikhail Doubrovin
    Department of Neurology, Memorial Hospital, Sloan KetteringInstitute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Mol Imaging 11:67-76. 2012
    ..The HSF1 reporter system can be used to screen anticancer drugs for induction of cytotoxic stress and HSF1 activation both in vitro and in vivo...
  86. doi request reprint Mutant BRAF melanomas--dependence and resistance
    Poulikos I Poulikakos
    Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan Kettering Cancer Center, NY, NY 10065, USA
    Cancer Cell 19:11-5. 2011
    ....
  87. pmc Genomic complexity and AKT dependence in serous ovarian cancer
    Aphrothiti J Hanrahan
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10471, USA
    Cancer Discov 2:56-67. 2012
    ....
  88. pmc Towards a unified model of RAF inhibitor resistance
    David B Solit
    1Department of Medicine, 2Human Oncology and Pathogenesis Program, and 3Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York
    Cancer Discov 4:27-30. 2014
    ..Mutations in the phosphoinositide 3-kinase/AKT pathway that enhance the adaptive response to RAF inhibitors also contribute to RAF inhibitor resistance in a subset of patients...
  89. pmc Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity
    Lao H Saal
    Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA
    Proc Natl Acad Sci U S A 104:7564-9. 2007
    ....
  90. ncbi request reprint Synthesis of novel fluorescent probes for the molecular chaperone Hsp90
    Laura Llauger-Bufi
    Program in Cell Biology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    Bioorg Med Chem Lett 13:3975-8. 2003
    ..Here we report the synthesis and characterization of two fluorescent Hsp90 inhibitors and probe their use in an Hsp90 fluorescent polarization assay...
  91. ncbi request reprint General method for the synthesis of 8-arylsulfanyl adenine derivatives
    Huazhong He
    Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
    J Org Chem 69:3230-2. 2004
    ..We report a general method for the synthesis of 8-arylsulfanyl adenine derivatives using a mild protocol of coupling 8-mercaptoadenine with a variety of aryl iodides...
  92. ncbi request reprint Degradation of HER2 by ansamycins induces growth arrest and apoptosis in cells with HER2 overexpression via a HER3, phosphatidylinositol 3'-kinase-AKT-dependent pathway
    Pamela N Munster
    Interdisciplinary Oncology Program, H Lee Moffitt Cancer Center and Research Institute, 12901 Magnolia Drive, Tampa, FL 33612, USA
    Cancer Res 62:3132-7. 2002
    ..These observations have important clinical implications because they may help to identify patients that are most likely to benefit from 17-AAG and may explain resistance to Herceptin as seen in many patients...
  93. ncbi request reprint Consensus statement: Expedition Inspiration fund for breast cancer research meeting 2002
    Christopher Benz
    Buck Institute, Novato, CA, USA
    Breast Cancer Res Treat 78:127-31. 2003
  94. ncbi request reprint Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors
    Roberto Bianco
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
    Oncogene 22:2812-22. 2003
    ..Thus, in EGFR-expressing tumor cells with concomitant amplification(s) of PI3K-Akt signaling, combined blockade of the EGFR tyrosine kinase and Akt should be considered as a therapeutic approach...
  95. ncbi request reprint The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells
    Wanping Xu
    Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute NIH, 9610 Medical Center Drive, Rockville, MD 20850, USA
    Cancer Res 63:7777-84. 2003
    ..ErbB2 thus functions to regulate AKT kinase by simultaneously promoting its activation while inhibiting its inactivation...
  96. ncbi request reprint Targeting HER2 in prostate cancer: where to next?
    David B Solit
    J Clin Oncol 25:241-3. 2007
  97. ncbi request reprint BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90
    Mercedes E Gorre
    Department of Medicine and Molecular Biology Institute, David Geffen School of Medicine at University of California, Los Angeles, CA 900095 1678, USA
    Blood 100:3041-4. 2002
    ..These data support clinical investigations of 17-AAG in imatinib mesylate-resistant Ph(+) leukemias...
  98. ncbi request reprint Fourth International Conference on Innovations and Challenges in Prostate Cancer: Prevention, Detection and Treatment
    Peter R Carroll
    Department of Urology, University of California School of Medicine, San Francisco 94115 1711, USA
    J Urol 172:S3-5. 2004
  99. pmc An acetylation site in the middle domain of Hsp90 regulates chaperone function
    Bradley T Scroggins
    Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA
    Mol Cell 25:151-9. 2007
    ..These data suggest that acetylation/deacetylation of K294 plays an important role in regulating the Hsp90 chaperone cycle...
  100. ncbi request reprint Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress
    Paul Workman
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey UK
    Ann N Y Acad Sci 1113:202-16. 2007
    ..We stress how basic and translational research has been mutually beneficial and indicate future directions to enhance our understanding of molecular chaperones and their exploitation in cancer and other diseases...
  101. doi request reprint Determinants of RASistance to anti-epidermal growth factor receptor agents
    Jose Baselga
    J Clin Oncol 26:1582-4. 2008

Research Grants1

  1. Hsp90s as targets in the development of anticancer drugs
    Neal Rosen; Fiscal Year: 2004
    ..Our goal is to derive selective compounds and use them to determine the biologic effects of inhibiting each of the hsp90 family members and to identify new, target-directed drugs with anticancer activity. ..