CDK8/19 inhibitor for the treatment of HER2+ breast cancer

Information

  • Research Project
  • 9408874
  • ApplicationId
    9408874
  • Core Project Number
    R43CA221485
  • Full Project Number
    1R43CA221485-01
  • Serial Number
    221485
  • FOA Number
    PA-16-302
  • Sub Project Id
  • Project Start Date
    7/1/2017 - 7 years ago
  • Project End Date
    6/30/2018 - 6 years ago
  • Program Officer Name
    EVANS, GREGORY
  • Budget Start Date
    7/1/2017 - 7 years ago
  • Budget End Date
    6/30/2018 - 6 years ago
  • Fiscal Year
    2017
  • Support Year
    01
  • Suffix
  • Award Notice Date
    6/28/2017 - 7 years ago
Organizations

CDK8/19 inhibitor for the treatment of HER2+ breast cancer

Approximately 20% of breast cancers overexpress oncogenic tyrosine kinase receptor HER2/NEU. Patients with metastatic HER2+ cancer typically receive HER2-targeting monoclonal antibodies, trastuzumab and pertuzumab (often combined with a taxane); a small-molecule HER2 inhibitor lapatinib or a HER2-specific antibody-drug conjugate T-DM1 are used in later arms of treatment. Despite the transformative effect of HER2- targeting drugs in the adjuvant setting, nearly 70% of patients with metastatic HER2+ breast cancer have intrinsic resistance and nearly all become resistant to HER2-targeting therapy after initial response. There is a clear need for an agent that, when combined with HER2-targeting drugs, would overcome or prevent resistance to such drugs. We have developed highly selective and non-toxic inhibitors of cyclin-dependent kinase 8 (CDK8) and its paralog CDK19, which, unlike better-known members of the CDK family, regulate transcription but not cell cycle progression. Higher CDK8 expression is associated with a shorter relapse-free and distant metastasis-free survival in HER2+ patients. We have found that Senexin B, CDK8/19 inhibitor drug candidate, has a strong synergistic effect with different classes of HER2-targeting agents in all the tested HER2+ breast cancer cell lines and overcomes both inherent and acquired resistance to such drugs. Furthermore, combining Senexin B with HER2-targeting drugs suppressed the development of drug resistance. Synergistic inhibition of phosphorylation of two transcription factors implicated in breast cancer has been identified as a putative mechanism of synergy between CDK8- and HER2-targeting drugs. We now propose to develop a therapeutic strategy combining CDK8/19- and HER2- targeting drugs for the treatment of metastatic HER2+ breast cancer. In Aim 1, we will investigate whether Senexin B potentiates the effect of the trastuzumab/pertuzumab (T+P) combination, the current first line standard-of-care for HER2+ breast cancers, in vitro and in vivo, and whether Senexin B prevents the development of resistance to T+P. In Aim 2, we will test if cells selected for acquired T+P resistance and T+P treated tumors overexpress CDK8, as a possible patient selection criterion for the initial clinical development. We will also determine if treatment with T+P combined with Senexin B, in vitro and in vivo, decreases the phosphorylation of HER2- and CDK8-regulated transcription factors, as potential markers of treatment response. The anticipated Phase II SBIR program will include preclinical dose regimen optimization, extension of synergy studies to other drug combinations, optimization of the marker assays, and initiation of a Phase I clinical trial of a combination of Senexin B with HER2-targeting therapies. We hope that the use of CDK8/19 inhibitors will have a transformative effect on the long-term survival of patients with metastatic HER2+ breast cancer.

IC Name
NATIONAL CANCER INSTITUTE
  • Activity
    R43
  • Administering IC
    CA
  • Application Type
    1
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    299993
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    395
  • Ed Inst. Type
  • Funding ICs
    NCI:299993\
  • Funding Mechanism
    SBIR-STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    SENEX BIOTECHNOLOGY, INC.
  • Organization Department
  • Organization DUNS
    170943240
  • Organization City
    COLUMBIA
  • Organization State
    SC
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    292083402
  • Organization District
    UNITED STATES