CDK inhibitor for the treatment of HER breast cancer

Approximately of breast cancers overexpress oncogenic tyrosine kinase receptor HER NEU Patients with metastatic HER cancer typically receive HER targeting monoclonal antibodies trastuzumab and pertuzumab often combined with a taxane a small molecule HER inhibitor lapatinib or a HER specific antibody drug conjugate T DM are used in later arms of treatment Despite the transformative effect of HER targeting drugs in the adjuvant setting nearly of patients with metastatic HER breast cancer have intrinsic resistance and nearly all become resistant to HER targeting therapy after initial response There is a clear need for an agent that when combined with HER targeting drugs would overcome or prevent resistance to such drugs We have developed highly selective and non toxic inhibitors of cyclin dependent kinase CDK and its paralog CDK which unlike better known members of the CDK family regulate transcription but not cell cycle progression Higher CDK expression is associated with a shorter relapse free and distant metastasis free survival in HER patients We have found that Senexin B CDK inhibitor drug candidate has a strong synergistic effect with different classes of HER targeting agents in all the tested HER breast cancer cell lines and overcomes both inherent and acquired resistance to such drugs Furthermore combining Senexin B with HER 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 CDK and HER targeting drugs We now propose to develop a therapeutic strategy combining CDK and HER targeting drugs for the treatment of metastatic HER breast cancer In Aim we will investigate whether Senexin B potentiates the effect of the trastuzumab pertuzumab T P combination the current first line standard of care for HER breast cancers in vitro and in vivo and whether Senexin B prevents the development of resistance to T P In Aim we will test if cells selected for acquired T P resistance and T P treated tumors overexpress CDK 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 HER and CDK 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 HER targeting therapies We hope that the use of CDK inhibitors will have a transformative effect on the long term survival of patients with metastatic HER breast cancer Approximately of breast cancers are characterized as HER positive and patients with such cancers are treated with HER targeting drugs such as Herceptin Although HER targeting drugs given after surgery drastically decrease tumor recurrence nearly of patients with metastatic HER positive breast cancer do not respond to HER targeting therapy and almost all of the initially responsive cancers eventually become resistant We have found that a non toxic drug acting on proteins called CDK overcomes resistance to HER targeting drugs and prevents such resistance from developing we now propose a program of studies that will lead to combining this drug with HER targeting therapies in the treatment of patients with metastatic HER positive breast cancer