Dual Targeting of Tumor-Initiating Cells in Small Cell Lung Cancer
Technical Report,01 Sep 2018,31 Aug 2019
Cleveland Clinic Cleveland United States
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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. Chemotherapy preferentially targets non-TICs, which comprise the bulk of tumors, but spares self-renewing TICs, providing the rationale for our second approach using CBL and RT together to synergize with the standard-of-care chemotherapeutic agent cisplatin, as a novel overall treatment strategy for SCLC.
- Medicine and Medical Research