Author of

• 17556

  +

  P2.03a - Poster Session with Presenters Present (ID 464)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 17604

    +

    P2.03a-048 - The CDK4/6 Inhibitor G1T28 Protects Immune Cells from Cisplatin-Induced Toxicity in vivo and Inhibits SCLC Tumor Growth (ID 6225)

    14:30 - 14:30  |  Author(s): A. Poteete
    • Abstract

    Background:
    Small cell lung cancer (SCLC) is an aggressive form of lung cancer characterized by loss of the tumor suppressor Rb. Chemotherapy remains the standard of care for SCLC patients but produces severe myelosuppression that compromises patient outcomes. G1T28 is a potent and selective CDK4/6 inhibitor in development to reduce chemotherapy-induced myelosuppression and preserve immune system function in SCLC patients. Cyclin dependent kinases 4 and 6 (CDK4/6) phosphorylate Rb protein promoting proliferation of specific cell types such hematopoietic stem progenitor cells (HSPCs) by allowing cells to progress through G1 to S phase. HSPCs are exquisitely dependent upon CDK4/6 for proliferation and become arrested in the G1 phase of the cell cycle upon exposure to G1T28. We hypothesize that G1T28-mediated CDK4/6 inhibition may selectively protect immune cells (Rb intact) from chemotherapy without antagonizing the antitumor efficacy in Rb deficient tumors, such as SCLC. G1T28 preservation of adaptive immunity from cisplatin-induced cytotoxicity may enhance the efficacy of chemotherapy in SCLC tumors by allowing a more robust host-immune response.
    
    Methods:
    Syngeneic mouse models were established by flank injection of KP1 and TKOTmG murine cells derived from TP53 and RB1 or TP53, RB1 and P130 mutant mice respectively. When tumors reached 150mm[3], mice were randomized and treated with G1T28, cisplatin and combination of both. Tumor volumes were measured and immune populations from tumor, spleen and peripheral blood were analyzed by flow cytometry.
    
    Results:
    CDK4/6 inhibition by G1T28 protects peripheral white blood cells (lymphocytes, monocytes and eosinophils) from cisplatin-induced cytotoxicity in the syngeneic SCLC KP1 mouse model. Additionally, treatment with G1T28 prior to cisplatin inhibited tumor growth to a greater extent than cisplatin alone (46% versus 12%, respectively) in the syngeneic SCLC TKOTmG mouse model.
    
    Conclusion:
    G1T28-mediated CDK4/6 inhibition protects immune cells from chemotherapy and potentiates the reduction of tumor volume when combined with cisplatin in a syngeneic Rb deficient SCLC mouse model. Studies are ongoing to determine if the immune protection by G1T28 is enhancing the anti-tumor activity of cisplatin in this model, as well as to evaluate other potential mechanisms. Additionally, clinical trials testing the combination of G1T28 with chemotherapy in patients with extensive stage SCLC are currently in progress (1[st] line, carboplatin-etoposide, NCT02499770; 2[nd] line, topotecan, NCT02514447).