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First-in-class small molecule halts breast and ovarian cancer growth in mice

2023-10-27

基因疗法临床结果

A small molecule that indirectly targets the tough-to-drug MYC gene was effective against two different types of breast cancer in mice, including an aggressive form with a high degree of MYC expression.

A small molecule that indirectly targets the tough-to-drug MYC gene appears to work against breast and ovarian cabreast cancer.MYC

In an article published Oct. 25 in the Proceedings of the NMYConal Academy of Sciences, resebreast and ovarian cancerse of Medicine presented data showing that their drug 5D4, a new class of therapy called a TopBP1 inhibitor, could stop the growth of breast and ovarian tumors in mouse models. It worked even better when combined with the PARP 1/2 inhibitor talazoparib, marketed by Pfizer as Talzenna.

“It’s very exciting to have found a TopBP1 inhibitor that really stops cancer growth in cells and in animBaylor College of Medicineg-Tsyr Lin, M.D., Ph.D., first and co-co5D4sponding author, said in a press rTopBP1.PARP 1/2 inhibitor PARP 1/2 PARP 1/2 talazoparib Pfizer Talzenna

The new findings stem from more thanTopBP1ade of research on TopBP1, a cancern that the researchers previously described as a “convergent point” of several pathways involved in cancer development. They include one that promotes the expression of MYC, the protein products of which have been found to be deregulated in more than half of cancers in humans. MYC overexpression has been linked with worse outcomes in breast, blood, lung and other types of cancer, but inhibiting it directly has proven challenging.

The Baylor team knew from earlier experiments by other researTopBP1that inhibiting TopBP1 had the effect of boosting expression of another gene, MIZ1, and that, downstream, MIZ1cancerssion limits MYC’s ability to perpetuate cancer.MYC cancers MYC cancer

“Thus, enhancement of MIZ1 activity can attenuate the [cancer-causing] activity of TopBP1d may be exploited as a therapeutic strategy,” the scienMIZ1s reasoned in their papeMIZ1iven that suppressiMYCTopBP1 frees up MIZ1, “tacancerg [TopBP1] may … result in the anti-MYC effect.”

Before they could see MIZ1her this worked in practice, cancersearchers needed to fiMYCa drug that could target exactly the right spot of the protein expressed by the TopBP1 gene. Testing thousands ofTopBP1unds throuMIZ1 type of analyTopBP1lled a molecular docking scMYCn and further optimizing the hits gave them 5D4.

After validating the small molecule’s anti-TopBP1, anti-MYC and anti-cancer activity in cell studies, the researchers moved to testing 5D4 in mice. They injected ovarTopBP1ncer and breast cancer cells into two separate groups of animals, then dosed them with either 5D4 or a control solution every three days, giving three doses total. At the end of the period, they found that the drug reduced tumor growth in both of the models compared to controls. This was also the case for a second, more aggressive model of breast cancer with a high level of MYC overexpression.

Next, based on mechanistic and cell study eTopBP1e that MYCgested a Tcancerinhibitor would have synergistic activity with PARP inhibitors, the researchers tried dovarian cancerrib tbreast cancer5D4 in two separate mouse models of breast cancer, including one that ha5D4 mutation that made it resistant to PARP inhibitors. The results showed that cancer growth was inhibited with the combination tumorgreater degree than 5D4 alone and that tumors that were resistant to talazoparib were still responsive to 5D4.breast cancer MYC

The mice didn’t develop apparent side effects to the drugs in any ofTopBP1xperiments. One limitation to the study is that PARP inhibitors PARPmouse model used was immunocompromised, sotalazoparibar how an intac5D4mmune response might affect treatbreast cancer, based on the mechanism of PARP inhibitors, there’s reason toPARP inhibitors PARPieve the combination approach might bcancer better in that instance, researchers pointed out, a possibility tha5D4hey believe warrtumorsurther study.talazoparib 5D4

The researchers plan to prepare 5D4 for use in humans, to optimize its anti-tumor effect in combination with other drugs and to reduce the potential for toxicities, Lin said in the press release.PARP inhibitors PARP