Drug developed for lymphoma could provide hope for lung cancer patients
A novel drug being developed for blood cancers may also provide hope for lung cancer patients.
In findings presented April 19 at the Annual Meeting of the American Association for Cancer Research (AACR), 
the lab of Leandro Cerchietti, M.D., revealed early evidence that a BCL6 inhibitor initially studied as a potential B-cell lymphoma treatment might also be effective against hard-to-treat, chemo-resistant non-small cell lung cancers.
BCL6 is the most frequently involved oncogene in diffuse large B-cell lymphoma (DLBCL) and, as a transcriptional repressor, allows cells to proliferate in spite of replication stress. Cerchietti identified BCL6 as a potential therapeutic target in DLBCL several years ago while working under the mentorship of Ari Melnick, M.D. They teamed up with Alexander MacKerell, Ph.D., and Fengtian Xue, Ph.D., from the University of Maryland School of Pharmacy, to develop FX-1, a small molecule inhibitor of BCL6 for treatment of B-cell lymphoma.
Mariano Cardenas, Ph.D., a post-doc in Melnick’s lab, led a team that characterized the anti-lymphoma activity of FX-1 cell death in vitro and in vivo. Similar to an early version of the compound, FX-1 inhibits BCL6 activity by preventing the binding of BCL6 co-repressors to its BTB-domain. Since the drug inhibits only a specific subset of BCL6 functions, it is highly specific and can be safely administered in vivo.
Cerchietti’s postdoctoral fellow, Rossella Marullo, M.D., Ph.D., wondered if the drug could also work for other cancers. In non-small cell lung cancers (NSCLC), the gene is amplified in about 40 percent of squamous cell carcinomas and 2.2 percent of adenocarcinomas, according to The Cancer Genome Atlas (TCGA).
Marullo measured the expression of BCL6 in a panel of 20 lung cancer cell lines, and also engineered her own cell lines to express different levels of the protein. She then performed various tests to elucidate the role of BCL6 in DNA damage response, cell-cycle arrest, cell doubling time and colony formation.
“The results suggested that a major role of BCL6 in lung cancer could be to establish a DNA damage tolerant phenotype,” Marullo said. “Under these premises, BCL6 inhibition should preferentially affect the proliferation of cells with elevated genomic instability.”
She tested this theory by exposing the cell lines to Xue’s drug
“FX-1 inhibits the proliferation of about 40 percent (6 of 15) of the NSCLC cell lines tested, at doses similar to those required to kill DLBCL cells,” Marullo said.
Inhibiting BCL6 may be even more effective as a supplement to the chemotherapy drugs currently in use, by reducing the cancer’s tolerance to DNA damage.
Marullo has already started to explore this possibility through additional tests in cell cultures and in mice.
“Combination of FX-1 and cisplatin, which is commonly used as a first-line treatment in lung cancer, achieved a higher tumor growth control than either drug alone, without significant increase in toxicity,” she said.
She is also testing an extended panel of cell lines to identify which subsets of NSCLC are more likely to respond to treatment. Ultimately, the scientists hope to transfer these discoveries to the clinic, experimenting with different drug combinations and treatment scenarios.