Vrije Universiteit Brussel

 

Publications on Multiple Myeloma

A novel therapeutic combination using PD 0332991 and bortezomib: study in the 5T33MM myeloma model
  • A novel therapeutic combination using PD 0332991 and bortezomib: study in the 5T33MM myeloma model.

    Menu E, Garcia J, Huang X, Di Liberto M, Toogood PL, Chen I, Vanderkerken K, Chen-Kiang S.

    Cancer Res 68 (14), 5519-23, 2008.

    Abstract:
    Multiple myeloma (MM) remains incurable partly because no effective cell cycle-based therapy has been available to both control tumor cell proliferation and synergize with cytotoxic killing. PD 0332991 is an orally active small molecule that potently and specifically inhibits Cdk4 and Cdk6. It has been shown to induce rapid G1 cell cycle arrest in primary human myeloma cells and suppress tumor growth in xenograft models. To improve therapeutic targeting of myeloma progression, we combined tumor suppression by PD 0332991 with cytotoxic killing by bortezomib, a proteasome inhibitor widely used in myeloma treatment, in the immunocompetent 5T33MM myeloma model. We show that 5T33MM tumor cells proliferate aggressively in vivo due to expression of cyclin D2, elevation of Cdk4, and impaired p27Kip1 expression, despite inhibition of Cdk4/6 by p18INK4c and the maintenance of a normal plasma cell transcription program. PD 0332991 potently inhibits Cdk4/6-specific phosphorylation of Rb and cell cycle progression through G1 in aggressively proliferating primary 5T33MM cells, in vivo and ex vivo. This leads to tumor suppression and a significant improvement in survival. Moreover, induction of G1 arrest by PD 0332991 sensitizes 5T33MM tumor cells to killing by bortezomib. Inhibition of Cdk4/6 by PD 0332991, therefore, effectively controls myeloma tumor expansion and sensitizes tumor cells to bortezomib killing in the presence of an intact immune system, thereby representing a novel and promising cell cycle-based combination therapy.

 

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