Abstract
Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma, often arising in patients with neurofibromatosis type I (NF1), and has a poor prognosis with a 5-year survival rate of only 8–13%. Current treatments are largely ineffective, underscoring the need for new therapeutic targets. Dysregulation of the cell cycle is a key contributor to cancer development, making cyclin-dependent kinases (CDKs) promising targets for cancer therapy. However, single-agent therapies often face rapid resistance, suggesting that combinatorial approaches may offer greater therapeutic efficacy. Notably, TSPO deficiency modulates the cell cycle in MPNSTs via CDK1, presenting a potential molecular target for both prognosis and treatment.
Commentary
MPNSTs are aggressive Schwann cell-derived sarcomas, frequently associated with NF1 mutations. Traditional treatments, including surgery and chemotherapy, are largely ineffective, highlighting the urgent need for novel therapeutic strategies. NF1 loss leads to RAS pathway activation, which in turn activates multiple signaling cascades, including RAF-MEK-ERK1/2, PI3K-AKT, and RalGDS pathways. Inhibition of these pathways has been explored, with MEK inhibitors, such as selumetinib, showing some promise in clinical trials (NCT03433183). However, combinatorial approaches targeting additional pathways, like SHP2 [1], may offer better outcomes, particularly in cases of acquired resistance to MEK inhibitors.
Immune therapy is currently a new method for treating various cancers, helping more and more patients achieve long-lasting and safe clinical responses. MPNST is filled with a large number of immune cells, such as macrophages, fibroblasts, mast cell, B cell and T cell infiltration, which provides multiple options for immunotherapy of MPNST. Immune checkpoint blockade is the signification method in immunotherapy. PD-1 is an immunosuppressive receptor that exists on immune cells such as T cells. When PD-1 binds to its ligand PD-L1, an inhibitory signal is generated, which suppresses the function of T cells and prevents the immune system from attacking the tumor. In MPNST, scholars have studied the effectiveness of CD274/PD-L1 amplification in anti-PD-1 therapy, demonstrating that anti-PD-1 therapy has a certain positive effect on MPNST [2].
Targeting tumor-associated macrophages is also an important method because macrophages are the predominant immune cells found in the tumor microenvironment across MPNST [3]. MPNSTs mainly use colony stimulating factor 1 (CSF1) to target macrophages for treatment, which is a small molecule tyrosine kinase inhibitor for receptor signaling, also known as pexidartinib [4]. When using pexidartinib to treat MPNST xenograft mice, it was found to significantly inhibit tumor growth, and it effectively reduced the TAM population by inhibiting the CSF1R, c-KIT, and PDGFRb signaling pathways [5]. Sirolimus is a PI3K/Akt pathway inhibitor for tumor growth and survival. Studies have shown that the combination of pexidartinib and sirolimus can enhance macrophage depletion and reduce tumor volume [6].
Translocator protein (TSPO) is located on the outer mitochondrial membrane and participates in various biological activities, such as metabolism, steroid formation, and inflammation/immune regulation [7]. In previous studies, TSPO was considered a marker of microglial cell activation [8]. The authors listed the expression and function with TSPO in some common cancers. But interestingly, TSPO has both procancer [9] and anticancer effects on gliomas [10]. The ligands of TSPO are divided into endogenous ligands and exogenous ligands, as well as agonists and antagonists of TSPO. In another review [11], the roles of various ligands in inflammation and immunity are elaborated, and TSPO ligands also play important roles in other biological processes.
The TSPO specific ligand vinpocetine exerts neuroprotective effects by inhibiting microglial inflammation. Vinpocetine inhibited nitrite oxides and inflammatory factors such as interleukin-1 in BV-2 microglia β (IL-1β) IL-6 and tumor necrosis factor-α (TNF-α). In vivo experiments, the treatment of hypoxia mice with vinpocetine also inhibited inflammatory molecules, showed that vinpocetine may be effective for the treatment of neuroinflammatory diseases [12]. In another study, midazolam inhibited the upregulation of CD80 and the release of IL-6 and NO in LPS induced THP-1 cells and PMDM, primarily inhibiting NF-κB/AP-1 in THP-1 cells and the activation of MAPK pathway [13].
TSPO ligands XBD173 and GLX35322 were used in a mouse model of glioblastoma. The result had proved TSPO deletion causes ROS and angiogenesis via NOX4 signal pathway, and the treatment was effective [14]. In hepatocellular carcinoma, TSPO ligands PK11195 combined with anti PD-1 antibodies showed that it can inhibit ferroptosis and anti-tumor immunity (Table 1) [15,16].
|
Disease Model |
Treatment |
Effect |
Ligand Treatment |
Outcome |
Reference |
|
Glioma U118MG in the CAM model |
TSPO-KO |
VEGF-α, IL-8, MMP2 ?? |
- |
- |
[17] |
|
Glioma U118MG in vitro |
TSPO-KO |
HIF-1α ?? |
- |
Hypoxia, angiogenesis, glycolysis |
[10] |
|
Mouse model of glioblastoma |
Conditional deletion of TSPO |
ROS ?? NOX4 signal activation |
XBD173 GLX35322 |
TSPO deletion induces ROS production and angiogenesis via the NOX4 signaling pathway |
[14] |
|
C20 microglial cell line |
TSPO knockout |
Inflammation ?? |
- |
- |
[18] |
|
Septic mice |
TSPO knockout |
Improve the survival rate Inhibit M1 cells and promote M2 cells Reduce inflammation |
Koumine |
Regulate M1/M2 polarization Reduce the inflammatory response |
[19] |
|
M2 microglia |
-
IL-4 |
Decrease TSPO
PPAR-γ activation |
PK11195
FGIN-1-27/ overexpressed TSPO |
PPAR-r CD206/Arg-1/YM-1/FIZZ-1??
PPAR-r CD206/Arg-1/YM-1/FIZZ-1?? |
[20] |
|
Th1 type immune response |
TSPO ligand treatment |
Inhibit the Th1 cell response |
FGIN-1-27 Ro5-4846 |
IFN-r ??; T-bet ?? Inhibit nonmemory CD4+ T-cell differentiation to Th1 cells |
[21] |
|
GBM BTICs cocultured with T cells |
-
Silencing of TSPO |
TNF-α, IFN-γ induce TSPO upregulation Sensitized BTICs against T-cell-mediated cytotoxicity Protected BTICs against TRAIL-induced apoptosis |
- |
- |
[22] |
|
GBM |
- |
- |
D-DPA |
Target mitochondria in TAMs to inhibit tumors |
[23] |
|
Xenograft produced by MDA-MB-231 and MCF-7 breast cancer cell lines |
[18-F]DPA-714 |
TSPO high expression colocalized with F4/80-positive macrophages |
- |
- |
[24] |
|
Breast cancer |
Target TSPO for PDT |
MDA-MB-231 cell apoptosis No effect on MCF-7 cells |
IRT700DX-6T |
Inhibit the growth of MDA-MB-231 cells |
[25] |
|
Colorectal cancer |
Target TSPO for PDT |
Apoptosis ICD activation |
IRT700DX-6T |
CD8+ T-cell ?? Treg ?? |
[26] |
|
Pancreatic cancer |
Target TSPO for PDT |
Inhibit cell proliferation |
IRT700DX-6T |
CD8+ T-cell ?? CD?? Treg ?? |
[27] |
|
Hepatocellular carcinoma |
TSPO overexpression |
P62 accumulation Nrf2-dependent antioxidant defense system inhibits ferroptosis PD-L1 increased |
PK11195 Anti PD-1 antibodies |
Inhibit ferroptosis Antitumor immunity |
[15, 16] |
In the cell proliferation process, the cell cycle is strictly regulated by certain mechanisms [28]. Cyclin dependent protein kinases(CDKs) are a group of serine/threonine protein kinases. CDKs drive the cell cycle through chemical reactions with serine/threonine proteins and work synergistically with cyclin, making them important factors in cell cycle regulation. The binding of small inhibitor protein CDK inhibitors (CKIs) negatively regulates CDK activity [29,30]. In RNA sequencing (RNA Seq) data of the transcriptome of PNF/ANNUBP and MPNSTs, it was found that the transcription levels of FOXM1 mRNA and key transcription targets (such as AURKB, BIRC5, CENPA, CCNB1, CDK1) [31,32] were significantly increased in MPNSTs [33].
Previous studies have found that CDK4/6 inhibitor monotherapy has excellent anti-tumor effects on newly developed MPNSTs in mice, but drug resistance occurs rapidly [34]. In recent studies, the use of MEK inhibitors alone has been ineffective against MPNST. The low-dose combination of MEK inhibitor (mirdametinib) and CDK4/6 inhibitor (palbociclib) can cause significant tumor regression and improve survival rate in immunocompetent mice carrying MPNSTs [35]. The inhibition of cell cycle CDKs (CDK1, CDK2, CDK4, and CDK6) by Flavopiridol/Avocidib promotes G1 and G2 cell cycle arrest [36]. According to preliminary data, seliciclib is a relatively specific inhibitor of CDK1, CDK2, and CDK5. However, subsequent data showed that CDK7 and CDK9 were also inhibited, leading to transcriptional repression [37,38]. Dinaciclib [39], AT7519 and a flavonoid compound produced from digitalis bulbs can stimulate cell apoptosis, G0/G1 phase arrest, and the flavonoid compound produced from thistle bulbs also inhibit cancer cell angiogenesis by limiting CDK1 and CDK6 [40].
MEK inhibitors, such as trametinib, block the MAPK/ERK pathway, which is crucial for cell growth and survival in many cancers, including MPNST [41]. This pathway is often dysregulated in MPNST due to mutations in the NF1 gene. MEK inhibitors are a targeted therapy, specifically targeting the MAPK pathway, which plays a significant role in MPNST progression. Clinical trials have shown progression-free survival (PFS) benefits in certain patients with MPNST. MEK inhibitors primarily target the tumor cells and may not significantly impact the tumor microenvironment or enhance immune responses, which may be a limitation for some tumors, including MPNST [42]. Immune checkpoint inhibitors (PD-1/PD-L1 inhibitors) like pembrolizumab and nivolumab work by blocking the PD-1/PD-L1 interaction, thereby stimulating T cells to attack tumor cells. Immune checkpoint inhibitors have demonstrated significant efficacy in cancer [43].
Overall, the author detected new resources to the MPNST field and extend our understanding of cell cycle mechanisms to targeted therapies. But inadequately, they did not provide a timely pre-clinical study to treat MPNST. According to previous literature, the author team may direct new combination strategies to optimize CDK1 inhibitor and TSPO ligands treatments for NF1-deficient MPNST patients [44].
References
2. Özdemir BC, Bohanes P, Bisig B, Missiaglia E, Tsantoulis P, Coukos G, et al. Deep Response to Anti-PD-1 Therapy of Metastatic Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumor With CD274/PD-L1 Amplification. JCO Precis Oncol. 2019;3:1-6.
3. Dancsok AR, Gao D, Lee AF, Steigen SE, Blay JY, Thomas DM, et al. Tumor-associated macrophages and macrophage-related immune checkpoint expression in sarcomas. Oncoimmunology. 2020;9(1):1747340.
4. Benner B, Good L, Quiroga D, Schultz TE, Kassem M, Carson WE, et al. Pexidartinib, a Novel Small Molecule CSF-1R Inhibitor in Use for Tenosynovial Giant Cell Tumor: A Systematic Review of Pre-Clinical and Clinical Development. Drug Des Devel Ther. 2020;14:1693-704.
5. Patwardhan PP, Surriga O, Beckman MJ, de Stanchina E, Dematteo RP, Tap WD, et al. Sustained inhibition of receptor tyrosine kinases and macrophage depletion by PLX3397 and rapamycin as a potential new approach for the treatment of MPNSTs. Clin Cancer Res. 2014;20(12):3146-58.
6. Zheng Y, Jiang Y. mTOR Inhibitors at a Glance. Mol Cell Pharmacol. 2015;7(2):15-20.
7. Weinberg SE, Sena LA, Chandel NS. Mitochondria in the regulation of innate and adaptive immunity. Immunity. 2015;42(3):406-17.
8. Yasin N, Veenman L, Singh S, Azrad M, Bode J, Vainshtein A, et al. Classical and Novel TSPO Ligands for the Mitochondrial TSPO Can Modulate Nuclear Gene Expression: Implications for Mitochondrial Retrograde Signaling. Int J Mol Sci. 2017;18(4):786.
9. Troike KM, Acanda de la Rocha AM, Alban TJ, Grabowski MM, Otvos B, Cioffi G, et al. The Translocator Protein (TSPO) Genetic Polymorphism A147T Is Associated with Worse Survival in Male Glioblastoma Patients. Cancers (Basel). 2021;13(18):4525.
10. Fu Y, Wang D, Wang H, Cai M, Li C, Zhang X, et al. TSPO deficiency induces mitochondrial dysfunction, leading to hypoxia, angiogenesis, and a growth-promoting metabolic shift toward glycolysis in glioblastoma. Neuro Oncol. 2020;22(2):240-52.
11. Betlazar C, Middleton RJ, Banati R, Liu GJ. The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes. Cells. 2020;9(2):512.
12. Zhao YY, Yu JZ, Li QY, Ma CG, Lu CZ, Xiao BG. TSPO-specific ligand vinpocetine exerts a neuroprotective effect by suppressing microglial inflammation. Neuron Glia Biol. 2011;7(2-4):187-97.
13. Horiguchi Y, Ohta N, Yamamoto S, Koide M, Fujino Y. Midazolam suppresses the lipopolysaccharide-stimulated immune responses of human macrophages via translocator protein signaling. Int Immunopharmacol. 2019;66:373-82.
14. Jiang H, Li F, Cai L, Chen Q. Role of the TSPO-NOX4 axis in angiogenesis in glioblastoma. Front Pharmacol. 2022;13:1001588.
15. Zhang D, Man D, Lu J, Jiang Y, Ding B, Su R, et al. Mitochondrial TSPO Promotes Hepatocellular Carcinoma Progression through Ferroptosis Inhibition and Immune Evasion. Adv Sci (Weinh). 2023:e2206669.
16. Zheng Q, Yang Q, Zhou J, Gu X, Zhou H, Dong X, et al. Immune signature-based hepatocellular carcinoma subtypes may provide novel insights into therapy and prognosis predictions. Cancer Cell Int. 2021;21(1):330.
17. Bode J, Veenman L, Caballero B, Lakomek M, Kugler W, Gavish M. The 18 kDa translocator protein influences angiogenesis, as well as aggressiveness, adhesion, migration, and proliferation of glioblastoma cells. Pharmacogenet Genomics. 2012;22(7):538-50.
18. Bader S, Würfel T, Jahner T, Nothdurfter C, Rupprecht R, Milenkovic VM, et al. Impact of Translocator Protein 18 kDa (TSPO) Deficiency on Mitochondrial Function and the Inflammatory State of Human C20 Microglia Cells. Cells. 2023;12(6):954.
19. Jin GL, Liu HP, Huang YX, Zeng QQ, Chen JX, Lan XB, et al. Koumine regulates macrophage M1/M2 polarization via TSPO, alleviating sepsis-associated liver injury in mice. Phytomedicine. 2022;107:154484.
20. Zhou D, Ji L, Chen Y. TSPO Modulates IL-4-Induced Microglia/Macrophage M2 Polarization via PPAR-γ Pathway. J Mol Neurosci. 2020;70(4):542-9.
21. Zhang Y, Yu S, Li X, Yang B, Wu C. The ligands of translocator protein inhibit human Th1 responses and the rejection of murine skin allografts. Clin Sci (Lond). 2017;131(4):297-308.
22. Menevse AN, Ammer LM, Vollmann-Zwerenz A, Kupczyk M, Lorenz J, Weidner L, et al. TSPO acts as an immune resistance gene involved in the T cell mediated immune control of glioblastoma. Acta Neuropathol Commun. 2023;11(1):75.
23. Sharma A, Liaw K, Sharma R, Thomas AG, Slusher BS, Kannan S, et al. Targeting Mitochondria in Tumor-Associated Macrophages using a Dendrimer-Conjugated TSPO Ligand that Stimulates Antitumor Signaling in Glioblastoma. Biomacromolecules. 2020;21(9):3909-22.
24. Hardwick M, Fertikh D, Culty M, Li H, Vidic B, Papadopoulos V. Peripheral-type benzodiazepine receptor (PBR) in human breast cancer: correlation of breast cancer cell aggressive phenotype with PBR expression, nuclear localization, and PBR-mediated cell proliferation and nuclear transport of cholesterol. Cancer Res. 1999;59(4):831-42.
25. Zhang S, Yang L, Ling X, Shao P, Wang X, Edwards WB, et al. Tumor mitochondria-targeted photodynamic therapy with a translocator protein (TSPO)-specific photosensitizer. Acta Biomater. 2015;28:160-70.
26. Xie Q, Li Z, Liu Y, Zhang D, Su M, Niitsu H, et al. Translocator protein-targeted photodynamic therapy for direct and abscopal immunogenic cell death in colorectal cancer. Acta Biomater. 2021;134:716-29.
27. Zhang D, Xie Q, Liu Y, Li Z, Li H, Li S, et al. Photosensitizer IR700DX-6T- and IR700DX-mbc94-mediated photodynamic therapy markedly elicits anticancer immune responses during treatment of pancreatic cancer. Pharmacol Res. 2021;172:105811.
28. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9(3):153-66.
29. Barnum KJ, O'Connell MJ. Cell cycle regulation by checkpoints. Methods Mol Biol. 2014;1170:29-40.
30. Lim S, Kaldis P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development. 2013;140(15):3079-93.
31. Song BN, Chu IS. A gene expression signature of FOXM1 predicts the prognosis of hepatocellular carcinoma. Exp Mol Med. 2018;50(1):e418.
32. Kim SK, Roh YG, Park K, Kang TH, Kim WJ, Lee JS, et al. Expression signature defined by FOXM1-CCNB1 activation predicts disease recurrence in non-muscle-invasive bladder cancer. Clin Cancer Res. 2014;20(12):3233-43.
33. Kohlmeyer JL, Kaemmer CA, Lingo JJ, Voigt E, Leidinger MR, McGivney GR, et al. Oncogenic RABL6A promotes NF1-associated MPNST progression in vivo. Neurooncol Adv. 2022;4(1):vdac047.
34. Kohlmeyer JL, Kaemmer CA, Pulliam C, Maharjan CK, Samayoa AM, Major HJ, et al. RABL6A Is an Essential Driver of MPNSTs that Negatively Regulates the RB1 Pathway and Sensitizes Tumor Cells to CDK4/6 Inhibitors. Clin Cancer Res. 2020;26(12):2997-3011.
35. Kohlmeyer JL, Lingo JJ, Kaemmer CA, Scherer A, Warrier A, Voigt E, et al. CDK4/6-MEK Inhibition in MPNSTs Causes Plasma Cell Infiltration, Sensitization to PD-L1 Blockade, and Tumor Regression. Clin Cancer Res. 2023;29(17):3484-97.
36. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015;14(2):130-46.
37. Le Tourneau C, Faivre S, Laurence V, Delbaldo C, Vera K, Girre V, et al. Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur J Cancer. 2010;46(18):3243-50.
38. Benson C, White J, De Bono J, O'Donnell A, Raynaud F, Cruickshank C, et al. A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. Br J Cancer. 2007;96(1):29-37.
39. Parry D, Guzi T, Shanahan F, Davis N, Prabhavalkar D, Wiswell D, et al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 2010;9(8):2344-53.
40. Toogood PL, Harvey PJ, Repine JT, Sheehan DJ, VanderWel SN, Zhou H, et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem. 2005;48(7):2388-406.
41. Wang J, Pollard K, Allen AN, Tomar T, Pijnenburg D, Yao Z, et al. Combined inhibition of SHP2 and MEK is effective in models of NF1-deficient malignant peripheral nerve sheath tumors. Cancer Res. 2020;80(23):5367-79.
42. Borcherding DC, Amin NV, He K, Zhang X, Lyu Y, Dehner C, et al. MEK Inhibition Synergizes with TYK2 Inhibitors in NF1-Associated Malignant Peripheral Nerve Sheath Tumors. Clin Cancer Res. 2023;29(8):1592-604.
43. Davis LE, Nicholls LA, Babiker HM, Liau J, Mahadevan D. PD-1 Inhibition Achieves a Complete Metabolic Response in a Patient with Malignant Peripheral Nerve Sheath Tumor. Cancer Immunol Res. 2019;7(9):1396-400.
44. Zhang X, Hu C, Sun S, Guo C, Bu Y, Wang Z, et al. TSPO deficiency promotes the progression of malignant peripheral sheath tumors by regulating the G2/M phase of the cell cycle via CDK1. Sci Rep. 2024;14(1):26235.