by ecancer reporter Janet Fricker

A high-throughput screening platform capable of testing compounds in ‘pair-wise’ matrix blocks for synergistic, additive properties has revealed multiple possibilities for combinations of drugs with ibrutinib in Bruton’s tyrosine kinase (BTK).

Such combinations, say the US authors, can now be prioritized in clinical trials.

For cancer treatment many drug regimens are comprised of five or more agents identified as a result of protracted, empirical clinical trial-and-error.

Take the example of R-CHOP, which consists of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, and is commonly used for treatment of diffuse large B-cell lymphoma (DLBCL).

In 2013 the US Food and Drug Administration indicated their willingness to consider combinations of novel therapies at an earlier stage of clinical development, highlighting the need for innovative technologies to accelerate the discovery of novel drug combinations.

The BTK inhibitor ibrutinib is felt to be particularly appropriate for this approach since its optimal clinical development depends upon pairing with other agents to increase response rates and durability, as well as to circumvent potential resistance mechanisms.

In the current study Lesley Mathews Griner and colleagues, from the National Institutes of Health, Bethesda, MD, undertook a large, high-throughput combination screen of the Bruton’s tyrosine kinase inhibitor ibrutinib versus a library of 459 agents using 6 x 6 dose-response (matrix) blocks.

A key feature of their approach was that the high-throughput screening platform enabled the discovery of the different dose ranges in which drugs synergize.

Results showed a striking number of cooperative interactions between ibrutinib and inhibitors of the PI3K signalling pathway including CAL-101 (idelalisib), BKM-120, and the dual PI3K/ mammalian target of rapamycin (mTOR) inhibitors BEZ-235 and GDC-0980 (38–41), the allosteric AKT inhibitor MK-2206 and the clinically approved mTORC1 inhibitor everolimus.

“Based on the test case of ibrutinib, we are excited by the prospect of matrix drug screening to uncover actionable drug combinations in cancer and for other diseases. The high-throughput nature of the platform allows a scale and reproducibility of experimentation that cannot be achieved by conventional methods,” write the authors.

Given the synergy between ibrutinib and multiple agents uncovered, they add, it may eventually become possible to combine three or more agents to overcome the aggressive nature of ABC DLBCL.

Reference

L Mathews Griner, R Guha, P Shinn, et al. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. PNAS. doi/10.1073/pnas.1311846111.