BRUSSELS—Malignant peripheral nerve tumors are rare but aggressive, and successfully treating them is quite difficult. However, researchers in the U.S. have now shown that a combination of two types of anti-cancer drugs, MEK and SHP2 inhibitors, can effectively target the mechanism that drives the cancer’s growth.
Although research has only been carried out in cells and mice thus far, the researchers’ discovery may be able to improve treatment and outcomes for patients with this cancer, according to Dr. Jiawan Wang, who is a postdoctoral research fellow at the Department of Oncology/Pediatric Oncology at Johns Hopkins University School of Medicine in Baltimore.
Wang will present the findings at the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, which is taking place online on October 24-25.
“This research is an innovative biology-based and mechanistic approach to tackling the problems of tumors that are driven by RAS activation and are resistant to current treatments,” said Professor Emiliano Calvo, co-chair of the EORTC-NCI-AACR Symposium on behalf of the EORTC; director of START Madrid Group; and Director of Clinical Research at the START Madrid-Centro Integral Oncológico Clara Campal hospital. “We look forward to the early phase trials of this combination in patients with great interest and excitement. New and better ways of treating these patients are urgently needed.”
Malignant peripheral nerve sheath tumors (MPNST) are cancers of the connective tissue surrounding nerves, and are classified as sarcomas. MPNST account for 5-10 percent of soft tissue sarcomas. They are treated with surgery, chemotherapy and sometimes radiotherapy, but overall prognosis is poor.
“There is an urgent, unmet need for new treatments for this disease. Our findings have immediate translational implications and may inform future clinical trials for patients with MPNST,” added Wang.
Wang and her colleagues — led by Dr. Christine Pratilas, also at Johns Hopkins — knew that in the majority of these tumors, growth is driven by the loss of a protein called neurofibromin 1 (NF1). NF1 regulates a cell signaling pathway called RAS/MEK/ERK.
Neurofibromatosis is a genetic condition in which tumors, which are normally benign, grow in the nervous system. But these benign tumors can change into malignant tumors, and people with neurofibromatosis type 1 are at high risk of developing MPNST. And anti-cancer drugs designed to inhibit MEK have had limited effect against MPNST, when tested in cells and mice in the lab.
Researchers learned how MPNST adapts its response to anti-cancer drugs that disrupt the signals that drive the cancer’s growth. Cell surface receptors called receptor tyrosine kinases (RTKs) interacted with the RAS protein to limit cancer cells’ sensitivity to drugs that inhibit MEK.
“As there are no drugs available that inhibit RAS, we thought that an alternate strategy would be to use a drug against a protein called SHP2, which plays a role in the activation of RAS when RTKs are active, to regulate cell survival and proliferation,” she added.
The team investigated the activity of an existing SHP2 inhibitor, named SHP099, on MPNST cells in the lab. It produced a modest response, but the combination of the SHP2 inhibitor with an MEK inhibitor worked even better.
“We found that this combination was effective in MPNST that were resistant to MEK inhibition, and it also showed efficacy in plexiform neurofibroma, which is an abnormal yet benign tumor that occurs commonly in patients with neurofibromatosis type 1,” stated Wang. “We then confirmed the efficacy of the combination in MPNST in mice.”
“The MEK inhibitor that we tested is trametinib, which is an FDA-approved drug for melanoma, lung and thyroid cancers; and the SHP2 inhibitor, SHP099, is a compound related to another drug, TNO155, which is currently in clinical development as single agent or in combination with other drugs for several cancer types,” she continued. “The low dose combination of trametinib and SHP099 was well tolerated in mice we tested.”
There are concerns related to treating patients with a combination of SHP2 and MEK inhibitors, because of the potential for adverse side-effects. Studies in patients are needed to evaluate the safety of the combination. Wang believes that side effects expected at high doses of the drugs could be minimized, if lower doses of both drugs are used.
“In our work, we used a low-dose treatment schedule of 0.3 mg/kg trametinib and/or 50 mg/kg SHP099 once daily, five days on and two days off, and we did not observe obvious weight loss, despite some hair loss indicating possible skin toxicity in some mice receiving a combination of the two drugs,” Wang noted.
Next, the researchers plan to test the drug combination in a wide range of patient-derived MPNST that have been grafted into mice. If results are successful, the combination could move forward into clinical trials in human patients.