Christine Pratilas, MD, in the lab. Credit: Frederick W. Dubs, Johns Hopkins Pathology Photography & Graphics
A combination of two cancer drugs may be effective against malignant peripheral nerve sheath tumors (MPNST) – soft tissue tumors stubbornly resistant to chemotherapy and radiation therapy – according to a laboratory study led by Johns Hopkins researchers Kimmel Cancer Center.
Both drugs interfere with cell growth and replication but have different mechanisms of action. Used together, they suppressed the growth of MPNSTs in mouse models of human disease, the researchers found. The results were published on November 24, 2023 in the journal Scientists progress.
MPNSTs develop in the soft tissues surrounding nerve cells. They are often associated with neurofibromatosis type 1, a genetic disease caused by a mutation in the NF1 tumor suppressor gene. Although rare, these tumors are aggressive and notoriously difficult to treat.
“Every clinical trial done so far has been negative. There have been many trials and very limited responses,” says Christine Pratilas, MD, associate professor of oncology at Johns Hopkins and senior author of the study. . “So we are always working towards better treatments.”
Pratilas and colleagues turned to SHP2 inhibitors, an emerging class of cancer drugs. They interfere with cell growth and division in several ways and have shown great promise in clinical trials for other types of cancers such as colorectal and gastrointestinal stromal tumors.
Initial experiments on MPNST cell lines showed that inactivation of the gene responsible for SHP2 suppressed tumor cell growth. This suggests that SHP2 could be a promising drug target for this patient population.
Next, the researchers tested an SHP2 inhibitor drug, TNO155, in combination with ribociclib. Ribociclib belongs to a class of drugs called CDK4/6 inhibitors, which also help prevent cancer cells from dividing.
Pratilas and his colleagues tested the drugs in six different patient-derived xenografts, models in which human tumors are transplanted into mice. This approach allowed researchers to see how the same treatment could apply to diverse patients with different tumor genetics.
The SHP2 inhibitor worked well alone in half of the mouse models tested. The addition of ribociclib enhanced the tumor suppressive effects in the other models.
The combination of drugs produced a response that held up better over time. Four weeks into the trial, TNO155 alone appeared to be as effective as the two drugs combined in some mice. But by 10 weeks, tumors in mice treated only with TNO155 had begun to grow, while the combined strategy still effectively kept tumors at bay.
Used together, the drugs disrupted tumor cell replication and triggered cell death, the study found.
These two drugs are currently being tested together in an independent clinical trial for different types of cancer. “So we knew that if we found that this drug combination was active in preclinical testing, there would be a translation pathway,” says Pratilas.
Other cancers, such as melanomas and lung cancers, can also result from NF1 mutations, so the drug combination could be just as effective in other types of tumors.
“Clinical trials of SHP2 inhibitors in humans are relatively new, so it is not yet clear where they will lead to successful clinical applications,” says Pratilas. “Our data support SHP2 as a target for tumors driven by loss of NF1.”
Co-authors of the study included Jiawan Wang, Ana Calizo, Lindy Zhang, Kai Pollard and Nicolas Llosa of Johns Hopkins. Other authors were from the Pacific Northwest National Laboratory in Seattle, the Siteman Cancer Center at Washington University in St. Louis, the Masonic Cancer Center and Department of Biomedical Engineering at the University of Minnesota, and the Novartis Institutes for BioMedical Research in Cambridge, Massachusetts.
More information:
Jiawan Wang et al, CDK4/6 inhibition enhances SHP2 inhibitor efficacy and depends on RB function in malignant peripheral nerve sheath tumors, Scientists progress (2023). DOI: 10.1126/sciadv.adg8876
Provided by Johns Hopkins University School of Medicine
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