Radioimmunotherapy for Prostate Cancer

Summary

Principal Investigator: M J Morris
Abstract: DESCRIPTION (provided by applicant): Prostate cancer is the second most common cause of cancer-related deaths in American men. Patients with advanced disease are not curable using standard approaches and suffer the effects of metastatic disease to bone, the primary site of distant spread. The candidate's research to date is based on the approach that prostate cancer can be treated by targeting the unique biologic features that characterize the tumor in each clinical state of the disease's natural history. The specific hypothesis of this grant is that techniques applied to hematologic tumors, such as radioimmunotherapy (RIT), can also be applied to prostate cancer, given that the main reservoir of resistant disease is the bone marrow. The proposed target is prostate specific membrane antigen (PSMA), which is present at all phases of the disease, is minimally expressed in non-prostate tissue, and can be modulated. Preliminary studies to define the properties of unlabeled and yttrium-90 labeled anti-PSMA antibodies, such as huJ591, are now being completed. To implement this research, a comprehensive career development plan for the candidate is proposed, that capitalizes on MSKCC's and the Sponsor's resources and expertise. Three years of didactic courses in clinical trial design and nuclear medicine are planned. Mentoring by experts in the field, such as the Sponsor (Dr. Scher, Chief of GU Oncology), Dr. Larson (Chief, Nuclear Medicine), and members of Radiology, Radiochemistry, Pathology, and Biostatistics are incorporated into the plan. Participation in national/international conferences will allow exposure to other experts and to understand the process of bringing trials to a national stage. Through this training, a research plan based on the following three aims will be executed: (1) To test the hypothesis that repetitively dosed RIT can induce antitumor effects that correlate with tumor absorbed dose. In a phase I trial Y-86-huJ591 (a positron emitter) will be administered with repetitively dosed Y-90-huJ591 (a pure beta emitter) to establish the efficacy, dosimetry, and biodistribution of the yttrium conjugate (2) To test the hypothesis that RIT can be optimized by upregulating target expression and/or enhancing tumor radiosensitivity. In a phase 1/11trial, the yttrium conjugate will be combined with PSMA modulation, and (3) to compare RIT with standard chemotherapy in a phase III trial. The acquisition of these skills combined with the completion of the research plan will allow the candidate to pursue such research independently.
Funding Period: 2003-09-01 - 2009-08-31
more information: NIH RePORT

Top Publications

  1. pmc Repetitively dosed docetaxel and ¹⁵³samarium-EDTMP as an antitumor strategy for metastatic castration-resistant prostate cancer
    Karen A Autio
    Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
    Cancer 119:3186-94. 2013
  2. pmc Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer
    Scott T Tagawa
    Authors Affiliations Weill Cornell Medical College WCMC Weill Cornell Cancer Center Memorial Sloan Kettering Cancer Center MSKCC, New York, New York and University of North Carolina Chapel Hill, North Carolina
    Clin Cancer Res 19:5182-91. 2013
  3. pmc A phase I/IIA study of AGS-PSCA for castration-resistant prostate cancer
    M J Morris
    Department of Medicine, Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, NY 10065, USA
    Ann Oncol 23:2714-9. 2012
  4. pmc Bone scan index: a quantitative treatment response biomarker for castration-resistant metastatic prostate cancer
    Elizabeth R Dennis
    Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    J Clin Oncol 30:519-24. 2012
  5. pmc Phase I rapid dose-escalation study of AGS-1C4D4, a human anti-PSCA (prostate stem cell antigen) monoclonal antibody, in patients with castration-resistant prostate cancer: a PCCTC trial
    Emmanuel S Antonarakis
    Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, CRB1 1M59, 1650 Orleans Street, Baltimore, MD 21231, USA
    Cancer Chemother Pharmacol 69:763-71. 2012
  6. pmc Pharmacokinetic assessment of the uptake of 16beta-18F-fluoro-5alpha-dihydrotestosterone (FDHT) in prostate tumors as measured by PET
    Bradley J Beattie
    Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    J Nucl Med 51:183-92. 2010
  7. pmc Phase 1 trial of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer
    Michael J Morris
    Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Eur Urol 56:237-44. 2009
  8. pmc Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer
    Michael J Morris
    Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    J Clin Oncol 27:2436-42. 2009
  9. pmc Novel tracers and their development for the imaging of metastatic prostate cancer
    Andrea B Apolo
    Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    J Nucl Med 49:2031-41. 2008
  10. pmc Assessing outcomes in prostate cancer clinical trials: a twenty-first century tower of Babel
    Gretchen A Gignac
    Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Cancer 113:966-74. 2008

Scientific Experts

  • M J Morris
  • Howard I Scher
  • Neeta Pandit
  • Steven M Larson
  • Neeta Pandit-Taskar
  • Gretchen A Gignac
  • Glenn Heller
  • Karen A Autio
  • Scott T Tagawa
  • Susan F Slovin
  • Ryan D Stephenson
  • Elizabeth R Dennis
  • Emmanuel S Antonarakis
  • Heiko Schoder
  • Bradley J Beattie
  • Andrea B Apolo
  • Lawrence H Schwartz
  • Christina Hong
  • Naveed H Akhtar
  • Neeta Pandit Taskar
  • David M Nanus
  • Steve Larson
  • Stanley J Goldsmith
  • Jorge A Carrasquillo
  • Paul Christos
  • Neil H Bander
  • Matthew I Milowsky
  • Joseph Osborne
  • Shankar Vallabhajosula
  • Dana E Rathkopf
  • Mario A Eisenberger
  • Samuel R Denmeade
  • Martha E Vincent
  • Xiaoyu Jia
  • Josef J Fox
  • Michael A Carducci
  • Kathy Jelaca-Maxwell
  • Irina S Mezheritskiy
  • Yuliya S Jhanwar
  • Peter M Smith-Jones
  • Mohammad Namavari
  • Ron Finn
  • Shangde Cai
  • John L Humm
  • Gustavo S P Meirelles
  • Olivia Squire
  • C Ross Schmidtlein
  • Pat Zanzonico
  • Joseph A O'Donoghue
  • Eze A Wills
  • Chaitanya R Divgi
  • Mithat Gonen
  • Maha Hussain

Detail Information

Publications19

  1. pmc Repetitively dosed docetaxel and ¹⁵³samarium-EDTMP as an antitumor strategy for metastatic castration-resistant prostate cancer
    Karen A Autio
    Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
    Cancer 119:3186-94. 2013
    ..The toxicity and efficacy when each agent is combined at full, recommended doses, in a repetitive fashion is not well established...
  2. pmc Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer
    Scott T Tagawa
    Authors Affiliations Weill Cornell Medical College WCMC Weill Cornell Cancer Center Memorial Sloan Kettering Cancer Center MSKCC, New York, New York and University of North Carolina Chapel Hill, North Carolina
    Clin Cancer Res 19:5182-91. 2013
    ....
  3. pmc A phase I/IIA study of AGS-PSCA for castration-resistant prostate cancer
    M J Morris
    Department of Medicine, Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, NY 10065, USA
    Ann Oncol 23:2714-9. 2012
    ....
  4. pmc Bone scan index: a quantitative treatment response biomarker for castration-resistant metastatic prostate cancer
    Elizabeth R Dennis
    Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    J Clin Oncol 30:519-24. 2012
    ..Prior studies have shown the prognostic value of a baseline BSI. This study tested whether treatment-related changes in BSI are prognostic for survival and compared BSI to prostate-specific antigen (PSA) as an outcome measure...
  5. pmc Phase I rapid dose-escalation study of AGS-1C4D4, a human anti-PSCA (prostate stem cell antigen) monoclonal antibody, in patients with castration-resistant prostate cancer: a PCCTC trial
    Emmanuel S Antonarakis
    Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, CRB1 1M59, 1650 Orleans Street, Baltimore, MD 21231, USA
    Cancer Chemother Pharmacol 69:763-71. 2012
    ..However, because of differences in antibody-dependent cellular cytotoxicity between AGS-PSCA and AGS-1C4D4, a limited Phase I trial using AGS-1C4D4 was performed evaluating safety and PK...
  6. pmc Pharmacokinetic assessment of the uptake of 16beta-18F-fluoro-5alpha-dihydrotestosterone (FDHT) in prostate tumors as measured by PET
    Bradley J Beattie
    Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    J Nucl Med 51:183-92. 2010
    ....
  7. pmc Phase 1 trial of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer
    Michael J Morris
    Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Eur Urol 56:237-44. 2009
    ..Growth of selected castration-resistant prostate cancer (CRPC) cell lines and animal models can be repressed by reexposure to androgens. Low doses of androgens, however, can stimulate tumor growth...
  8. pmc Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer
    Michael J Morris
    Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    J Clin Oncol 27:2436-42. 2009
    ..To build on this strategy and fully integrate a repetitively dosed bone-seeking radiopharmaceutical into a contemporary chemotherapy regimen, we conducted a phase I study of docetaxel and samarium-153 ((153)Sm) lexidronam...
  9. pmc Novel tracers and their development for the imaging of metastatic prostate cancer
    Andrea B Apolo
    Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
    J Nucl Med 49:2031-41. 2008
    ..Hence, although many promising agents are available for testing, such studies would benefit from closer collaboration between those in the fields of medical oncology and nuclear medicine...
  10. pmc Assessing outcomes in prostate cancer clinical trials: a twenty-first century tower of Babel
    Gretchen A Gignac
    Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Cancer 113:966-74. 2008
    ..PFS, however, is vulnerable to inter-study design variability. The authors sought to identify and quantify this variability and the resultant error in PFS across prostate cancer clinical trials...
  11. pmc Antibody mass escalation study in patients with castration-resistant prostate cancer using 111In-J591: lesion detectability and dosimetric projections for 90Y radioimmunotherapy
    Neeta Pandit-Taskar
    Nuclear Medicine Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    J Nucl Med 49:1066-74. 2008
    ..An analysis was performed to assess lesion detectability by (111)In-J591 gamma-camera imaging compared with standard imaging methods and the effect of increasing antibody mass on lesion detectability, biodistribution, and dosimetry...
  12. ncbi A phase II trial of bortezomib and prednisone for castration resistant metastatic prostate cancer
    Michael J Morris
    Department of Medicine Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    J Urol 178:2378-83; discussion 2383-4. 2007
    ..We defined the antitumor effects of bortezomib alone and in combination with prednisone in patients with progressive, castration resistant metastatic prostate cancer...
  13. ncbi Castration resistant, taxane naïve metastatic prostate cancer: current clinical approaches and future directions
    Gretchen A Gignac
    Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    J Urol 178:S30-5. 2007
    ..We focused on the current management and novel investigational strategies for the chemonaïve patient population with castration resistant metastatic disease...
  14. ncbi Phase I evaluation of J591 as a vascular targeting agent in progressive solid tumors
    Michael J Morris
    Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    Clin Cancer Res 13:2707-13. 2007
    ..This phase I trial tested the hypothesis that J591 could be used as a vascular targeting platform for patients with nonprostate solid tumors...
  15. ncbi Pilot trial of unlabeled and indium-111-labeled anti-prostate-specific membrane antigen antibody J591 for castrate metastatic prostate cancer
    Michael J Morris
    Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
    Clin Cancer Res 11:7454-61. 2005
    ..The relationship among dose, safety, pharmacokinetics, and antibody-dependent cellular cytotoxicity (ADCC) activation for unlabeled J591 has not been explored...
  16. pmc Prostate cancer clinical trial end points: "RECIST"ing a step backwards
    Howard I Scher
    Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Clin Cancer Res 11:5223-32. 2005
    ..To relate clinical issues to the clinical manifestations of prostate cancers across disease states using the eligibility and outcome criteria defined by Response Evaluation Criteria in Solid Tumors (RECIST)...
  17. ncbi Targeting osseous metastases: rationale and development of radio-immunotherapy for prostate cancer
    Michael J Morris
    Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 444, New York, NY 10021, USA
    Curr Urol Rep 6:163-70. 2005
    ..In this article, we review the rationale behind this approach, the targets being explored, the radiation sources available, and the antibodies currently under clinical development...
  18. pmc Fluorodeoxyglucose positron emission tomography as an outcome measure for castrate metastatic prostate cancer treated with antimicrotubule chemotherapy
    Michael J Morris
    Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer, New York, New York 10021, USA
    Clin Cancer Res 11:3210-6. 2005
    ..We tested the hypothesis that serial fluorodeoxyglucose positron emission tomography (FDG-PET) scans can serve as an outcome measure for patients with castrate metastatic prostate cancer treated with antimicrotubule chemotherapy...
  19. ncbi 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...