Drug Discovery Opinion

Around 85% of non-Hodgkin’s lymphomas in the United States are B-cell lymphomas and, of these, diffuse large B-cell lymphoma (DLBCL) account for about one in three cases. DLBCL is a fast growing lymphoma and only about half of people with this type of lymphoma are cured by current treatments, which include radiation therapy, chemotherapy and monoclonal antibodies.

Researchers, including scientists from Weill Cornell Medical College, have now discovered that the heat shock protein inhibitor, PU-H71, selectively kills DLBCLs that depend on the B-cell lymphoma 6 protein (BCL-6) transcriptional repressor. BCL-6 is involved in the pathogenesis of around 70% of cases of DLBCL. BCL-6 and heat shock protein (Hsp90) were almost invariantly co-expressed in the nuclei of primary DLBCL cells and a complex of Hsp90 and BCL-6 was found to stabilise BCL-6 mRNA and protein. Hsp90 inhibitors allowed transcription of genes normally repressed by BCL-6 and a stable mutant of BCL-6 was found to rescue DLBCL cells from Hsp90 inhibitor–induced apoptosis. In mouse xenograft models, PU-H71 was shown to preferentially accumulate in lymphomas compared to normal tissues, and led to almost complete tumour regression by allowing reactivation of key BCL-6 target genes and inducing apoptosis. PU-H71 shows very low toxicity in animal models and the researchers hope that the compound will be similarly well tolerated and efficacious in human patients.

The study is published in Nature Medicine.

PU-H71 has previously been shown to induce complete responses in triple-negative breast cancer models. Triple-negative breast cancers are defined by a lack of expression of estrogen, progesterone or HER2 receptors and are currently treated with conventional chemotherapy which is effective only in some patients, leaving others with high rates of early relapse.

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