Dual Targeting of Tumor-Initiating Cells in Small Cell Lung Cancer
Abstract
Small cell lung cancer (SCLC) has a dismal prognosis despite aggressive therapeutic approaches, and there is a clear need to develop more effective interventions. The role of tumor-initiating cells (TICs) in SCLC is largely unknown, although it is widely believed to be an important mechanism driving chemo-resistance in other cancers. Among cancers, SCLC is recognized for its rapid response to chemotherapy and equally rapid relapse. Thus, it is an ideal cancer in which to study TIC targeting, and drugs that selectively eradicate TICs offer great promise for treatment in this disease. Moreover, combinations of drugs will have more beneficial effects than a single agent.Here we seek to develop an innovative and novel therapeutic regimen for SCLC by identifying synergistic combination therapies using two drugs, Rovalpituzumab tesirine (ROVA-T) and CBL0137 (CBL), both of which target SCLC TICs. ROVA-T (RT), a potent anti-cancer humanized antibody-drug conjugate, selectively targets delta-like protein 3 (DLL3), which is highly expressed in SCLC TICs. The experimental drug CBL has potent anticancer activity. CBL inhibits the histone chaperone Facilitates Chromatin Transcription (FACT), which is required for the expression of transcription factors that are essential for TIC maintenance. Thus, the TIC-targeting mechanisms of CBL and RT are entirely different, targeting two different proteins, FACT and DLL3 that are highly expressed in SCLC TICs and each is thought to control the tumor-initiating properties through different pathways. Furthermore, combination of TIC-targeting drugs with traditional chemotherapy may be especially effective in overcoming resistance.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2020
- Accession Number
- AD1129193
Entities
People
- Sarmishtha De