Targeted Intervention of Breast Oncogenic Pathways

Summary

Principal Investigator: Said M Sebti
Abstract: DESCRIPTION (provided by applicant): The overall goal of this proposal is to understand how the serine/threonine protein kinase Akt cooperates with other oncogenic/tumor survival pathways to cause breast cancer, and to develop preclinically and clinically novel combination therapies for more effective breast cancer treatment. Overexpression of receptor tyrosine kinases such as ErbB2, which leads to persistent hyperactivation of a large number of oncogenic/tumor survival proteins such as Ras, Rho, Ral, Akt, MEK and STAT3, is associated with poor prognosis, resistance to chemotherapy and shortened survival time of breast cancer patients. This prompted the development of novel agents such as the ErbB2 antibody Herceptin and small molecule inhibitors of the activation of Akt (Triciribine (TCN/TCN-P)), MEK (CI-1040), Ras and other farnesylated proteins (Tipifarnib) and Rho and other geranylgeranylated proteins (GGTI-2417). A large body of evidence implicates Akt in cancer development and maintenance, but interfering with Akt alone does not appear to be sufficient, suggesting that blocking other pathways in combination with Akt inactivation is critical to thwarting breast cancer. For example, inactivation of Akt with TCN in combination with either Tipifarnib or GGTI-2417 is synergistic, suggesting that Akt cooperates with farnesylated and geranylgeranylated (prenylated) proteins yet to be identified, to cause breast cancer. In this application we propose to use high throughput screens based on RNA interference to identify these prenylated proteins and to develop novel combination therapies for breast cancer. The hypothesis to be tested is that hyperactivated Akt cooperates with prenylated proteins to contribute to breast oncogenesis and tumor resistance, and that targeted intervention of Akt in combination with other anti-signaling and cytotoxic agents suppresses tumor growth and induces apoptosis in breast tumors. The specific aims are: 1) To identify prenylated proteins whose knockdown sensitizes breast cancer cells to inactivation of Akt by TCN, 2) To identify specific prenylated proteins whose knockdown sensitizes breast cancer cells to the knock down of the three Akt isoforms, Akt1, Akt2 or Akt3, 3) To determine if inactivation of Akt by TCN sensitizes human breast tumors to cytotoxic and anti-signaling agents relevant to breast cancer treatment and, 4) To conduct hypothesis-driven phase I/II clinical trials of pre-operative TCN-P plus weekly paclitaxel and Tipifarnib followed by AC plus Tipifarnib in patients with locally advanced and metastatic breast cancer. Results from these studies will lead to the identification of oncogenic/tumor survival prenylated proteins that cooperate with Akt to cause breast cancer as well as to the design of novel combination therapies that will improve breast cancer survival by increasing the cure rate in patients with locally advanced breast cancer. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to develop combination therapies to improve breast cancer survival by increasing the cure rate in patients with locally advanced breast cancer. This will be done by: i) identifying novel proteins that cooperate with the protein Akt to cause breast cancer and ii) developing inhibitors of such proteins. Clinical trials will be performed to evaluate the efficacy of the drug combinations.
Funding Period: 2003-06-13 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Targeted inhibition of farnesyltransferase in locally advanced breast cancer: a phase I and II trial of tipifarnib plus dose-dense doxorubicin and cyclophosphamide
    Joseph A Sparano
    New York Phase II Consortium, Albert Einstein Cancer Center, Montefiore Medical Center Weiler Division, Department of Oncology, 2 S, Room 47 48, 1825 Eastchester Rd, Bronx, NY 10461, USA
    J Clin Oncol 24:3013-8. 2006
  2. pmc Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis
    Norbert Berndt
    Drug Discovery Department and Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center, Tampa, FL, USA
    Cell Cycle 12:2024-32. 2013
  3. pmc Identification of novel ROCK inhibitors with anti-migratory and anti-invasive activities
    R A Patel
    Drug Discovery Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
    Oncogene 33:550-5. 2014
  4. pmc Vitamin E δ-tocotrienol induces p27(Kip1)-dependent cell-cycle arrest in pancreatic cancer cells via an E2F-1-dependent mechanism
    Pamela J Hodul
    Department of Gastrointestinal Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America
    PLoS ONE 8:e52526. 2013
  5. pmc Measurement of protein farnesylation and geranylgeranylation in vitro, in cultured cells and in biopsies, and the effects of prenyl transferase inhibitors
    Norbert Berndt
    Department of Drug Discovery, Moffitt Cancer Center, Tampa, Florida, USA
    Nat Protoc 6:1775-91. 2011
  6. pmc Targeting protein prenylation for cancer therapy
    Norbert Berndt
    Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA
    Nat Rev Cancer 11:775-91. 2011
  7. pmc Combination of farnesyltransferase and Akt inhibitors is synergistic in breast cancer cells and causes significant breast tumor regression in ErbB2 transgenic mice
    Maria E Balasis
    Drug Discovery Department, H Lee Moffitt Cancer Center and Research Institut, Yale University, New Haven, Connecticut, USA
    Clin Cancer Res 17:2852-62. 2011
  8. pmc The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane
    N Berndt
    Drug Discovery Department, Moffitt Cancer Center, Tampa, FL 33612, USA
    Cell Death Differ 17:1795-804. 2010
  9. pmc Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer
    Joseph A Sparano
    New York Cancer Consortium, including the Montefiore Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10461, USA
    Clin Cancer Res 15:2942-8. 2009
  10. pmc Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy
    Aslamuzzaman Kazi
    Drug Discovery Program, Moffitt Cancer Center, Tampa, FL 33612, USA
    Mol Cell Biol 29:2254-63. 2009

Research Grants

  1. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013

Detail Information

Publications12

  1. ncbi Targeted inhibition of farnesyltransferase in locally advanced breast cancer: a phase I and II trial of tipifarnib plus dose-dense doxorubicin and cyclophosphamide
    Joseph A Sparano
    New York Phase II Consortium, Albert Einstein Cancer Center, Montefiore Medical Center Weiler Division, Department of Oncology, 2 S, Room 47 48, 1825 Eastchester Rd, Bronx, NY 10461, USA
    J Clin Oncol 24:3013-8. 2006
    ....
  2. pmc Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis
    Norbert Berndt
    Drug Discovery Department and Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center, Tampa, FL, USA
    Cell Cycle 12:2024-32. 2013
    ..Taken together, the results suggest that these two enzymes cooperate to induce malignant transformation and warrant further preclinical studies to evaluate the potential of combining inhibitors of Akt and ASAH1 to treat cancer. ..
  3. pmc Identification of novel ROCK inhibitors with anti-migratory and anti-invasive activities
    R A Patel
    Drug Discovery Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
    Oncogene 33:550-5. 2014
    ..The potential of this class of RKIs as anti-tumor agents warrants further advanced preclinical studies. ..
  4. pmc Vitamin E δ-tocotrienol induces p27(Kip1)-dependent cell-cycle arrest in pancreatic cancer cells via an E2F-1-dependent mechanism
    Pamela J Hodul
    Department of Gastrointestinal Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America
    PLoS ONE 8:e52526. 2013
    ....
  5. pmc Measurement of protein farnesylation and geranylgeranylation in vitro, in cultured cells and in biopsies, and the effects of prenyl transferase inhibitors
    Norbert Berndt
    Department of Drug Discovery, Moffitt Cancer Center, Tampa, Florida, USA
    Nat Protoc 6:1775-91. 2011
    ..These protocols require from 1 d (enzyme assays) to up to 3 months (autoradiography of [(3)H]-labeled proteins)...
  6. pmc Targeting protein prenylation for cancer therapy
    Norbert Berndt
    Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA
    Nat Rev Cancer 11:775-91. 2011
    ..One GGTI has recently entered the clinic, and the safety and efficacy of GGTIs await results from clinical trials...
  7. pmc Combination of farnesyltransferase and Akt inhibitors is synergistic in breast cancer cells and causes significant breast tumor regression in ErbB2 transgenic mice
    Maria E Balasis
    Drug Discovery Department, H Lee Moffitt Cancer Center and Research Institut, Yale University, New Haven, Connecticut, USA
    Clin Cancer Res 17:2852-62. 2011
    ..Our findings warrant further investigation of the combination of farnesyltransferase and Akt inhibitors...
  8. pmc The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane
    N Berndt
    Drug Discovery Department, Moffitt Cancer Center, Tampa, FL 33612, USA
    Cell Death Differ 17:1795-804. 2010
    ....
  9. pmc Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer
    Joseph A Sparano
    New York Cancer Consortium, including the Montefiore Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10461, USA
    Clin Cancer Res 15:2942-8. 2009
    ....
  10. pmc Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy
    Aslamuzzaman Kazi
    Drug Discovery Program, Moffitt Cancer Center, Tampa, FL 33612, USA
    Mol Cell Biol 29:2254-63. 2009
    ..Thus, GGTI treatment might improve the poor prognosis of breast cancer patients with low nuclear p27(Kip1) levels...
  11. pmc Vitamin E delta-tocotrienol levels in tumor and pancreatic tissue of mice after oral administration
    Kazim Husain
    Department of Gastrointestinal Oncology and Drug Discovery, Moffitt Cancer Center, Department of Oncological Sciences University of South Florida, Tampa, FL 33612, USA
    Pharmacology 83:157-63. 2009
    ..Our data suggest that bioactive levels of delta-tocotrienol can be achieved in the pancreas following oral administration and supports its clinical investigation in pancreatic cancer...
  12. pmc Phase I-II study of the farnesyl transferase inhibitor tipifarnib plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in HER2/neu-negative inflammatory carcinoma and non-inflammatory estrogen receptor-positive breast carcinoma
    Eleni Andreopoulou
    Department of Oncology, Montefiore Medical Center Weiler Division Albert Einstein College of Medicine, 2 South, 1825 Eastchester Road, Bronx, 10461, NY, USA
    Breast Cancer Res Treat 141:429-35. 2013
    ....

Research Grants30

  1. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
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