Micrograph showing DLBCL
Preclinical research suggests the dual PI3K/mTOR inhibitor PQR309 has activity against several types of lymphoma and works well in combination with other agents.
PQR309 exhibited anti-lymphoma activity as a single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab.
PQR309 demonstrated greater activity against B-cell lymphoma than T-cell lymphoma, and the inhibitor was able to overcome both primary and acquired resistance to idelalisib.
Francesco Bertoni, MD, of the Institute of Oncology Research in Bellinzona, Switzerland, and his colleagues conducted this research and reported the results in Clinical Cancer Research.
The work was funded by PIQUR Therapeutics AG, the company developing PQR309, and some study authors are PIQUR employees.
The researchers tested PQR309 in 49 human lymphoma cell lines—7 activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), 18 germinal center B-cell (GCB) DLBCL, 10 mantle cell lymphoma (MCL), 3 splenic marginal zone lymphoma (SMZL), 2 chronic lymphocytic leukemia (CLL), 4 Hodgkin lymphoma, and 5 anaplastic large-cell lymphoma (ALCL).
In most cell lines, PQR309 halted proliferation, mainly due to cell-cycle arrest with a block in G1. However, PQR309 induced apoptosis in 2 cell lines tested—SU-DHL-4 and TMD8.
The researchers noted that PQR309 was significantly more active in the B-cell lymphoma cell lines (DLBCL, MCL, CLL, and SMZL) than in the T-cell lymphoma cell line ALCL (P=0.028).
PQR309 exhibited similar activity in ABC and GCB DLBCL cell lines, de novo DLBCL, and DLBCL derived from transformed follicular lymphoma. TP53, MYC, and BCL2 status also had no significant effect on PQR309 activity.
The researchers compared cell lines that were very sensitive to PQR309 to those with low sensitivity to the drug and identified differences.
The team said that transcripts preferentially expressed in PQR309-sensitive cell lines were significantly enriched of genes involved in BCR pathway/signaling and BLIMP1 targets. Transcripts associated with less sensitive cell lines were enriched of members of proteasome pathway, response to unfolded proteins, MYC targets, XBP1 targets, genes downregulated by mTOR inhibitors, and genes involved in oxidative phosphorylation.
PQR309 demonstrated synergistic effects when combined with the BTK inhibitor ibrutinib, the immunomodulatory drug lenalidomide, the anti-CD20 monoclonal antibody rituximab, and the proteasome inhibitor marizomib.
PQR309 demonstrated synergistic or additive effects when combined with the BCL2 inhibitor venetoclax, the HDAC inhibitor panobinostat, and the PROTAC BET inhibitor ARV-825.
In addition, PQR309 was active in lymphoma cell lines with primary and secondary resistance to the PI3K inhibitor idelalisib.
The researchers believe the results of this study, together with ongoing clinical studies of PQR309, can lead to better treatments for lymphoma patients and better understanding of the mechanisms of anti-lymphoma agents.
