NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target
Abstract
:1. Introduction
2. Biology of TRK Signaling
2.1. Characteristics of NTRK Genes and of TRK Signaling
2.2. The Physiological Role of NTRK Signaling and Its Role in Non-Neoplastic Diseases
3. NTRK in Tumor Development
3.1. The Oncogenic Role of NTRK: Fusions Versus Other Alterations
3.2. NTRK Alterations in Non-CNS Tumors
3.3. NTRK Fusions in Pediatric CNS Tumors
3.4. NTRK Fusions in Adult CNS Tumors
4. NTRK as a Novel Therapeutic Target
4.1. NTRK-Fusions Targeting: A Novel, Effective, Histology-Independent Anti-Neoplastic Treatment
4.2. Resistance Mechanisms to First-Generation NTRK Inhibitors
5. Testing for NTRK Fusions. Where Is Waldo?
5.1. Immunohistochemistry
5.2. Fluorescence In-Situ Hybridization
5.3. DNA and RNA Molecular Testing
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Tumor Entity | NTRK Fusions Frequency | Most Frequently Reported NTRK Fusions |
---|---|---|
Glioblastoma | 1.1% (Frattini et al.) [134] 1.1% (Shah et al.) [135] 2.6% (Zheng et al.) [124] 1.2% (Kim et al.) [136] 1.7% (Ferguson et al.) [133] | BCAN-NTRK1 NFASC-NTRK1 ARHGEF2-NTRK1 CHTOP-NTRK1 GKAP-NTRK2 KCTD8-NTRK2 TBC1D2-NTRK2 EML4-NTRK3 |
Non-brainstem high-grade glioma | 10%–40% (Wu et al.)# [121] | ETV6-NTRK3 TPM3-NTRK1 BTBD1-NTRK3 VCL-NTRK2 AGBL4-NTRK2 |
DIPG° | 4% (Wu et al.) [121] | |
Pilocytic astrocytoma | 16.6% (Ferguson et al.) [133] 3.1% (Jones et al.) [114] | BCAN-NTRK1 NACC2-NTRK2 QKI-NTRK2 |
Anaplastic astrocytoma | 2.3% (Ferguson et al.) [133] | NOS1AP-NTRK2 |
Glioma NOS | 4.1% (Ferguson et al.) [133] | SQSTM1-NTRK2 |
Low-grade glioma | 0.7% (Zhang et al.) [112] 0.43% (Stransky et al.) [72] 4.3% (Ferguson et al.) [133] | ETV6-NTRK3 AFAP1-NTRK2 VCAN-NTRK2 |
High-grade glioneuronal tumor | Case report (Kurozumi et al.) [127] | ARHGEF2-NTRK1 |
Ganglioglioma | Case report (Prabhakaran et al.) [124] | TLE4-NTRK2 |
Molecule | Population and Enrollment | Allocation and Intervention Model | Phase | Primary Outcomes | Start Date and Current Status | Identifier |
---|---|---|---|---|---|---|
Entrectinib (RXDX-101) | Adult (minimum age: 18 Years)—84 participants | Non-Randomized—Single Group Assignment | I | Dose limiting toxicity Maximum tolerated dose Recommended Phase II dose Overall response rate | 2014—Active, Not Recruiting | NCT02097810 RXDX-101-01 (STARTRK-1) |
Entrectinib (RXDX-101) | Adult (minimum age: 18 Years)—300 participants (estimated) | Non-Randomized—Parallel Assignment | II | Objective response rate | 2015—Recruiting | NCT02568267 RXDX-101-02 (STARTRK-2) |
Entrectinib (RXDX-101) | Pediatric and Adult (maximum age: 22 Years)—65 participants | Non-Randomized—Single Group Assignment | I | Maximum tolerated dose Recommended Phase II dose Objective response rate | 2016—Recruiting | NCT02650401 RXDX-101-03 (STARTRK-NG) |
Larotrectinib (LOXO-101) | Pediatric and Adult (minimum age: 18 Years)—6452 participants | Non-Randomized—Parallel Assignment | II | Proportion of patients with objective response | 2015—Recruiting | NCT02465060 EAY131 NCI-2015-00054 |
Larotrectinib (LOXO-101) | Pediatric and Adult (minimum age: 12 Years)—320 participants | Non-Randomized—Parallel Assignment | II | Best overall response rate | 2015—Recruiting | NCT02576431 LOXO-TRK-15002 (NAVIGATE) |
Larotrectinib (LOXO-101) | Pediatric and Adult (maximum age: 21 Years) —174 participants | Non-Randomized—Parallel Assignment | I/II | Number and severity of adverse events (Phase I) Overall response rate (Phase II) | 2015—Recruiting | NCT02637687 LOXO-TRK-15003 (SCOUT) |
Larotrectinib (LOXO-101) | Pediatric and Adult (from 12 Months to 21 Years)—1000 participants (estimated) | Non-Randomized—Parallel Assignment | II | Objective response rate | 2017—Recruiting | NCT03155620 APEC1621SC NCI-2017-01251 |
Larotrectinib (LOXO-101) | Pediatric and Adult (from 12 Months to 21 Years)—49 participants | Non-Randomized—Single Group Assignment | II | Objective response rate | 2017—Recruiting | NCT03213704 APEC1621A NCI-2017-01264 |
Larotrectinib (LOXO-101) | Pediatric and Adult (maximum age: 30 Years)—70 participants | Non-Randomized—Single Group Assignment | II | Objective response rate | 2019—Recruiting | NCT03834961 ADVL1823 NCI-2019-00015 |
Repotrectinib (TPX-0005) | Pediatric and Adult (12 Years and older)—450 (estimated) | Non-Randomized—Single Group Assignment | I/II | Dose limiting toxicities Recommended Phase II dose Overall response rate | 2019—Recruiting | NCT03093116 TPX-0005-01 (TRIDENT-1) |
Repotrectinib (TPX-0005) | Pediatric (4 Years to 12 Years)—12 participants | Non-Randomized—Single Group Assignment | I | Dose limiting toxicities Pediatric recommended Phase II dose | 2019—Recruiting | NCT04094610 TPX-0005-07 |
Selitrectinib (LOXO-195) | Pediatric and Adult (minimum age: 1 Month) | Expanded Access (Individual Patients) | NA | NA | 2017—Available (Expanded Access) | NCT03206931 |
Selitrectinib (LOXO-195) | Pediatric and Adult (minimum age: 1 Month)—93 participants | Non-Randomized—Sequential Assignment | I/II | Maximum tolerated dose Recommended dose Overall response rate | 2017—Recruiting | NCT03215511 LOXO-EXT-17005 |
Assay Type | Advantages | Limitations | Turnaround Time | Main Role in Potential Diagnostic Algorithms |
---|---|---|---|---|
IHC |
|
| 1–2 days | Screening |
FISH |
|
| 3–5 days | Confirmatory |
RT-PCR |
|
| 5–7 days | Confirmatory |
Real time-PCR |
|
| 5–7 days | Screening/Confirmatory* |
RNA-NGS |
|
| 1–3 weeks | Screening/Confirmatory* |
DNA-NGS |
|
| 1–3 weeks | Screening/Confirmatory* |
DNA/RNA-NGS |
|
| 1–3 weeks | Screening/Confirmatory* |
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Gambella, A.; Senetta, R.; Collemi, G.; Vallero, S.G.; Monticelli, M.; Cofano, F.; Zeppa, P.; Garbossa, D.; Pellerino, A.; Rudà, R.; et al. NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target. Int. J. Mol. Sci. 2020, 21, 753. https://doi.org/10.3390/ijms21030753
Gambella A, Senetta R, Collemi G, Vallero SG, Monticelli M, Cofano F, Zeppa P, Garbossa D, Pellerino A, Rudà R, et al. NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target. International Journal of Molecular Sciences. 2020; 21(3):753. https://doi.org/10.3390/ijms21030753
Chicago/Turabian StyleGambella, Alessandro, Rebecca Senetta, Giammarco Collemi, Stefano Gabriele Vallero, Matteo Monticelli, Fabio Cofano, Pietro Zeppa, Diego Garbossa, Alessia Pellerino, Roberta Rudà, and et al. 2020. "NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target" International Journal of Molecular Sciences 21, no. 3: 753. https://doi.org/10.3390/ijms21030753