Mantle cell lymphoma (MCL) is an aggressive non-Hodgkins B-cell lymphoma with a characteristic t(I1:14)(g13;g32) translocation causing overexpression of cyclin D1. While various chemotherapeutic regimens are available to treat MCL, patients ultimately relapse due to residual tumor cells. Therefore, new treatment regimens are needed to target therapy-resistant residual MCL, thus offering greater survival benefits to patients.

To address this issue, therapy-resistant tumor cells were isolated from kidneys, livers, and lungs of NOD-SCID mice inoculated with Cranta-519 human MCL (GP), and cultured to produce stable cell lines. Preliminary studies confirmed these cells to have resistance to vincristine, increased proliferative capacities in several lines, and to display unique transcript- level expression patterns in the Sonic Hedgehog (Shh) and PI3K/Akt/survivin pathways.

Targeting the Shh signaling pathway in vivo using a multi-pronged treatment strategy incorporating a Shh signaling inhibitor (Cur-691—Genentech Corporation), adoptive T cell immunotherapy, and chemotherapy significantly increased survival of mice inoculated with GP. Additionally, in vitro analysis utilizing the protease inhibitor ritonavir to target the PI3K/Akt/survivin pathway led to reduced proliferation, induction of apoptosis, and downregulation of target transcripts of the PI3K/Akt/survivin pathway in GP and the GRLI liver-isolated therapy-resistant line. While ritonavir treatment as a single agent was not sufficient to significantly increase survival in vivo, studies are warranted and ongoing to test the effects of ritonavir in a multi-pronged treatment approach against MCL.

In conclusion, through the development and characterization of these therapy-resistant mantle cell lymphoma lines, the unique biology underlying relapsing MCL may be divulged. In so doing, novel therapies may be designed that effectively target residual MCL tumors, thus prolonging tumor-free survival. These novel treatment strategies could translate to clinical trials, offering patients efficacious treatment to eliminate tumor burden and give long-term, tumor-free survival from MCL.