MiT Family Translocation Renal Cell Carcinomas (tRCC) constitute an atypical and much more sophisticated type of renal cell carcinoma. As a research service provider, we focus on the complex biology of tRCC as well as Protheragen's commitment to tRCC complexities, employing novel research and service solutions, fueled by years of experience in developing preclinical therapeutics and diagnostics.
Overview of MiT Family Translocation Renal Cell Carcinomas (tRCC)
The MiT family translocation renal cell carcinoma (tRCC) is a rare type of non-clear cell renal cell carcinoma (nccRCC) defined by chromosomal translocations of the TFE3 and TFEB genes. The interstitial deletions that cause MiT: TFE fusions overexpress the corresponding transcription factors, which are critically involved in tumor pathogenesis and progression. It constitutes 1%-5% of adult cases but is more common in children, where it accounts for nearly 20% of pediatric renal carcinomas. The clinical presentation greatly varies: some patients may have indolent disease, while others face rapidly progressive metastatic disease.
Fig.1 Molecular profiling of MiT family tRCC. (Qu, Y.,
et al., 2022)
Pathogenesis of MiT Family Translocation Renal Cell Carcinomas (tRCC)
Pathogenesis of tRCC is mainly associated with genetic fusions of TFE3 and TFEB genes. These transcription factors are known to regulate important cellular activities such as proliferation, differentiation, and survival at the cellular level, and their respective genes are transcribed due to overexpression from the fusions. Different clinical presentations or responses to therapy may result from varying specific partner genes associated with these fusions. In tRCC, for example, fusions with SFPQ, ASPSCR1, NONO, PRCC, RBM10 have been reported. It is well established that excessive expression of TFE3 and TFEB triggers downstream signaling pathways like PI3K/AKT/mTOR, which aid in tumorigenesis along with tumor progression.
Diagnostics Development for MiT Family Translocation Renal Cell Carcinomas (tRCC)
Immunohistochemistry (IHC)
Immunohistochemistry is essential for the diagnosis of tRCC and involves the use of antibodies to identify specific proteins associated with tumor cell constituents. Cathepsin K is a marker that is expressed in about 60% of Xp11 tRCCs and in nearly all t (6;11) tRCCs. Other supporting diagnostic markers include HMB45 and Melan-A. PAX8 also serves as a useful marker due to its high expression in the tumors from tRCCs. The combination of these markers assists in distinguishing tRCC from other renal cell neoplasms.
Fluorescence In Situ Hybridization (FISH)
FISH remains the most reliable method for diagnosing tRCC with TFE3 or TFEB gene rearrangements. Chromosomal translocations may be identified through FISH, where specific probes are attached to a fluorescent dye; therefore, it can determine Xp11 gene rearrangements. The tRCC diagnosis and classification accuracy are dependent on FISH analysis, particularly with distinct morphologies that overlap with other renal cell carcinomas.
Therapeutics Development for MiT Family Translocation Renal Cell Carcinomas (tRCC)
- Immune Checkpoint Therapy (ICT)
Dual ICT combinations, like nivolumab plus ipilimumab, demonstrating low objective response rates (ORR) and short progression-free survival (PFS) window, indicate limited responsiveness in the context of tRCC. Combining ICT with Vascular Endothelial Growth Factor (VEGF) Targeted therapy (TT), but other therapeutic regimens demonstrated more promising outcomes regarding ORR and PFS. Some studies reported better clinical outcomes with the combination of avelumab plus axitinib and nivolumab plus cabozantinib.
- Targeted Therapy
Targeted interventions like cabozantinib have proven to be effective in tRCC. As a tyrosine kinase inhibitor, Cabozantinib targets VEGF, MET, and AXL. In certain studies, it has achieved objective response rates of up to 36% with some reporting a median progression-free survival of 5.4 months. Other sunitinib-type targeted agents have also been tried with mixed success. Work continues in developing targeted therapies with an emphasis on discovering predictive biomarkers as well as optimizing therapeutic sequences.
Table 1. Therapeutics of MiT Family Translocation Renal Cell Carcinomas (tRCC).
| Therapeutics |
Drug Name |
Mechanism |
Description |
Stage |
| Targeted Therapy |
Sunitinib |
VEGF |
Showed an objective response rate (ORR) of 10%-15% and progression-free survival (PFS) of 7-8 months in tRCC. |
Retrospective studies |
| Targeted Therapy |
Cabozantinib |
VEGF, MET, AXL |
Demonstrated activity with an ORR of 16.6% and a median PFS of 8.4 months in tRCC. Also evaluated in Phase II trials for nccRCC, including some tRCC patients. |
Retrospective studies |
| Targeted Therapy |
Axitinib |
VEGF |
Used in combination with ICT (Avelumab or Pembrolizumab) for tRCC. |
Retrospective studies |
| Targeted Therapy |
Bevacizumab |
VEGF |
Used in combination with Atezolizumab (ICT) for tRCC. |
Retrospective studies |
| Immune Checkpoint Therapy |
Nivolumab |
PD-1 |
Used as a single agent in tRCC, showed an ORR of 16.6% and median PFS of 2.5 months. |
Retrospective studies |
| Immune Checkpoint Therapy |
Ipilimumab |
CTLA-4 |
Used as a single agent or in combination (e.g., with Nivolumab) in tRCC. |
Retrospective studies |
| Immune Checkpoint Therapy |
Avelumab |
PD-L1 |
Used in combination with Axitinib (VEGF TT) for tRCC. |
Retrospective studies |
| Immune Checkpoint Therapy |
Pembrolizumab |
PD-1 |
Used in combination with Axitinib (VEGF TT) for tRCC. |
Retrospective studies |
| Immune Checkpoint Therapy |
Atezolizumab |
PD-L1 |
Used in combination with Bevacizumab (VEGF TT) for tRCC. Evaluated in Phase II trials for nccRCC, including some tRCC patients. |
Retrospective studies |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen specializes in offering all-inclusive solutions towards the development of diagnostic and therapeutic MiT family translocation renal cell carcinomas (tRCC). Providing advanced immunohistochemistry, as well as fluorescence in situ hybridization for diagnostic accuracy, is among our offered services. We also offer preclinical research services such as assessing immune checkpoint inhibitors and other targeted therapy agents. Our tailored offerings are aimed at providing comprehensive support for our clients' demands in order to facilitate efficient and groundbreaking therapeutic developments for tRCC.
Disease Models
- Sglt2-Cre; ASPSCR1-TFE3LSL/+ Models
- Pax8-Cre; ASPSCR1-TFE3LSL/+ Models
- ASPSCR1-TFE3 Tumor Graft Models
- PRCC-TFE3 Tumor Graft Models
- SFPQ-TFE3 Tumor Graft Models
- RBM10-TFE3 Tumor Graft Models
- MALAT1-TFEB Tumor Graft Models
Protheragen offers customized services for the development of diagnostics and therapeutics for tRCC. Our services are designed to meet the specific needs of our clients, ensuring the development of effective and innovative therapeutics. If you are interested in our services, please feel free to contact us.
References
- Qu, Yuanyuan, et al. "Proteogenomic characterization of MiT family translocation renal cell carcinoma." Nature Communications 13.1 (2022): 7494.
- Alhalabi, Omar, et al. "Immune checkpoint therapy combinations in adult advanced MiT family translocation renal cell carcinomas." The Oncologist 28.5 (2023): 433-439.
- Caliò, Anna, et al. "Comprehensive analysis of 34 MiT family translocation renal cell carcinomas and review of the literature: investigating prognostic markers and therapy targets." Pathology 52.3 (2020): 297-309.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
