Photo by Aaron Logan
Lab mice
Existing drugs could be combined to treat double-hit lymphoma (DHL), according to preclinical research published in Science Translational Medicine.
The drugs are tigecycline, an antibiotic, and venetoclax, a BCL2 inhibitor.
Researchers observed promising activity with these drugs in combination, both in cell lines and mouse models of DHL.
The team therefore believes the drugs could be repurposed to treat DHL, which currently has a dismal prognosis.
Study author Micol Ravà, PhD, of the European Institute of Oncology in Milan, Italy, and her colleagues noted that DHL is driven by the abnormal activation of MYC and BCL2. However, selective BCL2 inhibitors like venetoclax have failed to halt disease progression in DHL patients.
Seeking a way to sensitize DHL to BCL2 inhibitors, the researchers turned to tigecycline, which interferes with mitochondria to trigger a MYC-dependent cell death pathway.
The team found that tigecycline and venetoclax demonstrated synergy in 5 DHL cell lines. The drugs were synergistic in 3 cell lines—Karpas-422, SU-DHL-6, and DOHH-2—in which neither drug alone showed significant pro-apoptotic activity.
In 2 other cell lines—SU-DHL-4 and OCI-LY8—venetoclax was active when given alone, but its activity was enhanced by the addition of tigecycline.
In mouse models of DHL (using the human cell lines SU-DHL-6, DOHH-2, and OCI-LY8), each of the drugs alone were able to slow tumor progression somewhat.
However, combination tigecycline and venetoclax exhibited “strong antitumoral activity,” according to the researchers. In fact, the combination caused full disease regression in all 8 SU-DHL-6 mice and 3 of 9 OCI-LY8 mice.
Dr Ravà and her colleagues also found the combination produced “rapid and marked tumor regression” in mice with a patient-derived xenograft.
The researchers observed no toxicity when tigecycline and venetoclax were given at low doses. However, mice receiving more aggressive treatment had some inflammation in the liver and spleen. And some mice treated with high doses of tigecycline and venetoclax died within 1 week of treatment initiation.
Finally, Dr Ravà and her colleagues found that tigecycline and venetoclax each synergized with rituximab. The team therefore concluded that tigecycline and venetoclax “have the potential to reinforce rituximab-containing therapies in the clinic.”
