A combination of two cancer drugs could be effective against malignant peripheral nerve sheath tumors (MPNSTs). This is a conclusion based on the outcome of a recent study led by researchers at the Johns Hopkins Kimmel Cancer Center published in Science Advances[1]

The study was, in part, funded by grants from the Novartis Institutes for BioMedical Research, the NF Research Initiative, Hyundai Hope on Wheels, the Neurofibromatosis Therapeutic Acceleration Program, the Children’s Cancer Foundation and the Sidney Kimmel Cancer Center Core National Institutes of Health.

Malignant Peripheral Nerve Sheath Tumor
Malignant Peripheral Nerve Sheath Tumor, or MPNST, is a highly aggressive cancer of the cells that form the sheath that covers and protects peripheral nerves. Peripheral nerves are those outside of the central nervous system (brain and spinal cord).

MPNST is a type of sarcoma. This cancer grows in the soft tissues of the body, such as muscle, fat, tendons, ligaments, lymph and blood vessels, nerves, and other tissue that connects and supports the body. MPSNST grows quickly and can spread to other parts of the body and are stubbornly resistant to chemotherapy and radiation.

Sarcomas are a rare form of cancers, with MPNST being a rare type of sarcoma, making up 5% to 10% of all sarcoma cases.

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The disease is most common in young adults and middle-aged adults. MPNST is more common in people with a genetic condition called neurofibromatosis type 1 (NF1). About 25% to 50% of people with MPNST have NF1. And about 8% to 13% of people with NF1 will get MPNST in their lifetime.

The disease is considered aggressive, because there is up to a 65% chance of the tumor recurrence after surgery, and approximately 40% chance of metastasis, most commonly to the lung.

To date, there are limited treatment options available, and new therapeutic strategies are desperately needed to meet the unmet medical needs of patients diagnosed with MPNST.

Two drugs
In preclinical and clinical studies a combination of two drugs may show deeper and more durable anti-tumor activity in both in vivo and in vivo patient-derived models of MPNST.

Both TNO155*, a highly potent, selective, orally efficacious, first-in-class, investigational SHP2 inhibitor being developed by Novartis currently in Phase 2 studies, and ribociclib (Kisqali®; Novartis), interfere with cell growth and replication but have different mechanisms of action.  However, the initial observations support advancing this combination strategy in clinical trials with patients diagnosed with MPNST and other tumors driven by a loss of NF1.[1]

Used together, they suppressed the growth of MPNSTs in mouse models of human disease, the researchers found. 

MPNSTs grow in the soft tissue surrounding nerve cells. They are often associated with neurofibromatosis type 1, a genetic condition caused by a mutation in the tumor-suppressing gene NF1.

While rare, these tumors are aggressive and notoriously hard to treat.

“Every single clinical trial done to date has been a negative trial — there have been a lot of trials, and very limited responses,” noted Christine Pratilas, M.D., an associate professor of oncology at Johns Hopkins and the study’s senior author.

“So we’re always working for better treatments,” she added.

Pratilas and her collaborators turned to SHP2 inhibitors, an emerging class of cancer drugs. They interfere with cell growth and division in many ways, and have shown early promise in clinical trials for other types of cancers such as colorectal and gastrointestinal stromal tumors.

SHP2 is a non-receptor protein tyrosine phosphatase which is encoded by the PTPN11 gene. It is involved in cell growth and differentiation via the MAPK signaling pathway. In addition, SHP2 plays an important role in the programed cell death pathway (PD-1/PD-L1). [1]

Controlling SHP2 activity, both as an oncoprotein and a potential immunomodulator, is of high therapeutic interest, and SHP2 inhibitors offer an appealing and novel approach to inhibit receptor tyrosine kinase (RTK) signaling, which is the oncogenic driver in many tumors or is frequently feedback activated in response to targeted therapies including RTK inhibitors and MAPK inhibitors. [1][2]

Suppressing cell growth
Initial experiments in MPNST cell lines showed that knocking out the gene that makes SHP2 suppressed tumor cell growth. This suggested that SHP2 could be a promising drug target for this patient population.

Then, the researchers tested an SHP2 inhibitor drug, TNO155, in combination with ribociclib. Ribociclib belongs to a category of drugs called CDK4/6 inhibitors, which also help prevent cancer cells from dividing.

Pratilas and her colleagues tested the drugs in six different patient-derived xenografts — models in which human tumors are transplanted into mice. This approach allowed the researchers to see how the same treatment might play out for a variety of patients with different tumor genetics.

The SHP2 inhibitor worked well alone in half of the mouse models tested. Adding in ribociclib enhanced the tumor-suppressing effects in the other models.

Combining the drugs produced a response that held up better over time. Four weeks into the trial, TNO155 alone seemed about as effective as the two drugs combined in some of the mice. But by 10 weeks, the tumors in mice treated with just TNO155 had started to grow, while the combination strategy was still effectively holding tumors at bay.

Used together, the drugs disrupted tumor cell replication and triggered cell death, the study showed.

These two drugs are currently being tested together in an unrelated clinical trial for different kinds of cancer, so “we knew if we found this drug combination was active in pre-clinical tests, there would be a pathway to translation,” Pratilas says.

Other cancers, such as melanomas and lung cancers, also can arise from mutations in NF1, so the drug combination could be similarly effective in other types of tumors.

“SHP2 inhibitor clinical trials in humans are relatively new, so where they’ll achieve successful clinical applications is relatively unknown,” says Pratilas.

“Our data support SHP2 as a target for tumors driven by the loss of NF1,” Pratillas concluded.


Study co-authors 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 Novartis Institutes for BioMedical Research in Cambridge, Massachusetts.

Note: * The structure of TNO155 is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

Clinical trials
Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors – ClinicalTrials.gov ID NCT03114319
Phase Ib Study of TNO155 in Combination With Spartalizumab or Ribociclib in Selected Malignancies – ClinicalTrials.gov ID NCT04000529

Highlights of Prescribing Information
Ribociclib (Kisqali®; Novartis)[Prescribing Information]

[1] Wang J, Calizo A, Zhang L, Pino JC, Lyu Y, Pollard K, Zhang X, Larsson AT, Conniff E, Llosa NJ, Wood DK, Largaespada DA, Moody SE, Gosline SJ, Hirbe AC, Pratilas CA. CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors. Sci Adv. 2023 Nov 24;9(47):eadg8876. doi: 10.1126/sciadv.adg8876. Epub 2023 Nov 24. PMID: 38000020; PMCID: PMC10672174.
[2] LaMarche MJ, Acker M, Argintaru A, Bauer D, Boisclair J, Chan H, Chen CH, Chen YN, Chen Z, Deng Z, Dore M, Dunstan D, Fan J, Fekkes P, Firestone B, Fodor M, Garcia-Fortanet J, Fortin PD, Fridrich C, Giraldes J, Glick M, Grunenfelder D, Hao HX, Hentemann M, Ho S, Jouk A, Kang ZB, Karki R, Kato M, Keen N, Koenig R, LaBonte LR, Larrow J, Liu G, Liu S, Majumdar D, Mathieu S, Meyer MJ, Mohseni M, Ntaganda R, Palermo M, Perez L, Pu M, Ramsey T, Reilly J, Sarver P, Sellers WR, Sendzik M, Shultz MD, Slisz J, Slocum K, Smith T, Spence S, Stams T, Straub C, Tamez V Jr, Toure BB, Towler C, Wang P, Wang H, Williams SL, Yang F, Yu B, Zhang JH, Zhu S. Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer. J Med Chem. 2020 Nov 25;63(22):13578-13594. doi: 10.1021/acs.jmedchem.0c01170. Epub 2020 Sep 24. PMID: 32910655.
[3 ] Liu C, Lu H, Wang H, Loo A, Zhang X, Yang G, Kowal C, Delach S, Wang Y, Goldoni S, Hastings WD, Wong K, Gao H, Meyer MJ, Moody SE, LaMarche MJ, Engelman JA, Williams JA, Hammerman PS, Abrams TJ, Mohseni M, Caponigro G, Hao HX. Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling. Clin Cancer Res. 2021 Jan 1;27(1):342-354. doi: 10.1158/1078-0432.CCR-20-2718. Epub 2020 Oct 12. PMID: 33046519.

Featured image: Christine Pratilas, M.D., in the lab. Photo courtesy: © 2016 – 2024: Frederick W. Dubs, Johns Hopkins Pathology Photography & Graphics. Used with permission.

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