NEW YORK – After seeing the surprising preclinical efficacy of a SHP2 inhibitor in RAS-wild-type, NF1-mutant pediatric neuroblastoma, researchers at the Massey Cancer Center at Virginia Commonwealth University are working with the National Cancer Institute to explore how to bring SHP099 into the clinic.
Researchers evaluated SHP099 in a study involving more than 900 cell lines from 28 tumor types. In a paper published in Cell Reports in July, they reported that neuroblastoma was the second most sensitive subset of cancer to SHP099, after leukemia. Because neuroblastoma has few targeted therapy options, investigators, led by Anthony Faber, co-lead of the developmental therapeutics program at Massey Cancer Center, dove further into the predictors of response and resistance to SHP099 in neuroblastoma.
Faber and colleagues noted that SHP099 is similar to a SHP2 inhibitor being developed by Novartis, TNO155, which is in a Phase I clinical trial in advanced solid tumors. TNO155 showed some activity in solid tumors in a Phase I trial, data from which the company presented earlier this year. In that trial, TNO155 monotherapy was given to patients with colorectal, gastrointestinal stromal, non-small cell lung, and head and neck cancers, and 20 percent of patients achieved stable disease as their best response. Novartis is also studying TNO155 in several combination trials, including with EGFR, KRAS G12C, CDK4/6, and checkpoint inhibitors.
Faber noted that Novartis also conducted a high-throughput screening analysis to determine which tumor types were sensitive to TNO155, but did not include cancers that occur in pediatric patients, such as neuroblastoma. Meanwhile, Faber's team analyzed a wider range of cancers and some pediatric tumors.
The sensitivity to SHP2 in neuroblastoma was unexpected because these tumors have a low rate of RAS and RAF mutations, which, like SHP2, occur in the MAPK pathway. "Most of the cancers that are sensitive to SHP2 inhibitors are active through the MAPK pathway or through receptor tyrosine kinases like EGFR or HER2," Faber said. "The MAPK pathway is indeed important in neuroblastoma, but it's mostly not activated through receptor tyrosine kinases. In that sense, it was surprising that it was so sensitive to SHP2 inhibitors."
Faber and colleagues hypothesized that the high somatic mutation burden in these neuroblastoma tumors could be making them sensitive to SHP2 inhibition. The mutations driving these tumors, such as NF1 loss, HRAS Q61K mutations, and ALK activating mutations, often result in the activation of the MEK/ERK pathway, which also interacts with the MAPK pathway.
Despite the frequent activation of MEK and ERK, previous preclinical studies have found that MEK inhibitors are often not effective in neuroblastomas. Faber and colleagues suggested that SHP2 inhibitors may be favored over MEK inhibitors based on their findings because most of the common mutations they saw in high-risk neuroblastoma, such as ALK mutations and NF1 loss, were SHP2 dependent.
In their study, neuroblastoma models with low expression of NF1 responded the best to SHP099. This, again, suggested that SHP2 inhibition could be effective for patients with relapsed high-risk neuroblastoma, which often has NF1 loss. While this subset of high-risk neuroblastomas is rare, Faber noted it is among the deadliest, with about half of pediatric patients dying from this cancer.
They also found that RAS- and RAF-mutant neuroblastoma models were resistant to SHP099. However, this resistance could be addressed with the combination of a SHP2 inhibitor and RAS inhibitors or MEK inhibitors, such as Novartis' Mekinist (trametinib), Faber said.
"These [SHP2] drugs are very ineffective as single-agent inhibitors against RAS-mutant cancers. In fact, they were the least sensitive cancers in our screen and in the Novartis screen," Faber said. "Because of feedback when you inhibit mutant RAS, several authors have demonstrated that combining the SHP2 inhibitor with either a RAS inhibitor or another MAPK pathway inhibitor like trametinib actually works together very nicely to block that feedback activation and further inhibit tumor growth."
With these results in hand, Faber and colleagues are beginning to explore how to bring SHP099 into clinical studies for certain neuroblastoma patients. They are exploring where SHP099 could fit in the current treatment paradigm for high-risk neuroblastoma patients.
These patients often receive several rounds of treatment. First, they get induction chemotherapy, followed by surgery, then maintenance therapy with retinoic acid-based treatments and United Therapeutics Oncology's immunotherapy Unituxin (dinutuximab).
Faber noted that moving the drug into pediatric clinical trials will be challenging, but that his team is working with collaborators at the National Cancer Institute to bring the drug into the clinic.
"We think the maintenance period is probably the most appropriate time to introduce the SHP2 inhibitor. We're starting to look at SHP2 inhibitors in combination with dinutuximab and retinoic acids to see if there is additive activity," Faber said. "It would be wonderful if we saw something greater than that, like synergistic activity. If they work well together, that's where this is headed, towards introducing the SHP2 combination into patients."