Credit: Rhoda Baer
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A new drug can safely target the NF-κB pathway in multiple myeloma (MM), according to research published in Cancer Cell.
The investigators identified an interaction between the NF-κB-regulated antiapoptotic factor GADD45β and the JNK kinase MKK7 as a therapeutic target in MM.
They then developed a drug known as DTP3, which disrupts the GADD45β/MKK7 complex, thereby killing MM cells in vitro and in vivo, without harming normal cells.
“Lab studies suggest that DTP3 could have therapeutic benefit for patients with multiple myeloma and potentially several other types of cancer, but we will need to confirm this in our clinical trials, the first of which will start next year,” said study author Guido Franzoso, MD, PhD, of Imperial College London in the UK.
Dr Franzoso and his colleagues knew that NF-κB is overactive in MM and other malignancies, but targeting NF-κB can have detrimental effects on healthy cells. So they looked for target genes downstream of NF-kB that might be responsible for its role in cancers.
By studying cells from MM patients, the investigators identified the protein complex GADD45β/MKK7, which appeared to play a critical role in allowing MM cells to survive.
Searching for a safe way to target the NF-kB pathway, the team screened more than 20,000 molecules and found 2 that disrupted GADD45β/MKK7. Further refinements led to the development of DTP3.
In human MM cells, DTP3 had a similar anticancer potency to that of bortezomib, but with a more than 100-fold higher cancer-cell specificity. DTP3 also retained full therapeutic efficacy in cell lines that were resistant to standard MM treatments.
In mice, DTP3 eradicated MM, with no apparent side effects at the effective doses.
In an orthotopic xenograft model of MM, control mice had a median overall survival of 26 days. But mice treated with DTP3 had a median overall survival that extended past the experimental endpoint on day 161.
“We had known for many years that NF-kB is very important for cancer cells, but because it is also needed by healthy cells, we did not know how to block it specifically,” Dr Franzoso said.
“The discovery that blocking the GADD45β/MKK7 segment of the NF-kB pathway with our DTP3 peptide therapeutic selectively kills myeloma cells could offer a completely new approach to treating patients with certain cancers, such as multiple myeloma.”
A spinout company, Kesios Therapeutics, was formed to commercialize DTP3 and other drug candidates based on Dr Franzoso’s research, with support from Imperial Innovations, a technology commercialization company focused on developing academic research in the UK.
