Renal Medullary Carcinoma (RMC) is a significant concern within oncology due to its aggressive characteristics and strikingly aloof predilection for the young population, especially those with sickle cell trait. Protheragen understands the growing demand in relation to the problem posed by RMC. With our experience in oncology along with drug development, Protheragen is able to provide integrated diagnostics and therapeutics development services.
Overview of Renal Medullary Carcinoma (RMC)
Renal Medullary Carcinoma (RMC) is a rare and highly aggressive cancer that more often than not impacts young individuals of African descent, particularly those with sickle cell trait or disease. RMC was first described by Davis et al in 1995; it emerges from the collecting duct epithelium of the kidney and has detrimental patient outcomes, with a median overall survival of approximately 13 months. Most patients have advanced-stage disease at the time of presentation, frequently with metastatic spread to regional lymph nodes as well as the liver, lungs, and bones. There is typically rapid tumor progression along with high resistance to conventional chemotherapeutic drugs.
Fig.1 Timeline of RMC research over the past two decades. (Su, Y.,
et al., 2022)
Pathogenesis of Renal Medullary Carcinoma (RMC)
The RMC is characterized by the multifactorial pathogenesis involving deletion of the SMARCB1 (INI1) cancer-prone gene, which acts as a key initiator. This deletion tends to result from hemizygous deletions and balanced translocations, causing excessive cell cycle advancement and tumor formation. The existence of either sickle cell trait or disease comes as a major health concern because the hypoxic conditions within the renal medulla sustain severe oxygen deficiency, causing extensive damage and repair processes that can trigger SMARCB1 deletion. In addition, chronic medullary hypoxia may over activate the hypoxia-inducible factor pathway secondary to a lack of oxygen, which leads to HIF-1 production that could aid in neovascularization and progression of tumors.
Diagnostics Development for Renal Medullary Carcinoma (RMC)
Imaging Techniques
For the first evaluation of RMC, imaging studies like CT scans and MRIs are essential. They assist in evaluating the tumor's size and area as well as metastatic involvement. CT scans often show a renal medullary mass that has poorly defined borders with concomitant necrosis and hemorrhage. MRI gives detailed information about the tumor's relationship with neighboring structures, which aids in the detection of small satellite nodules within the renal cortex.
Fine-Needle Aspiration Cytology
Fine-needle aspiration (FNA) biopsy of a primary renal tumor or its metastases can yield significant diagnostic information. Cytological examination usually shows high-grade carcinoma containing loosely adherent cell clusters as well as single, dispersed cells. The neoplastic cells frequently display abnormal nuclei that are nucleolated and granular with a lacy chromatin pattern alongside cytoplasmic vacuoles.
Immunohistochemistry
The confirmation of RMC diagnosis is aided considerably by the use of immunohistochemical staining. Positive results are often obtained with low-molecular-weight cytokeratin (CAM 5.2), pancytokeratin (AE1/AE3), vementin, PAX-8, EMA, HIF, and VEGF. A distinctive feature of RMC, which differentiates it from other renal tumors, is the lack of INI1/SMARCB1 nuclear staining, which hypermarks non-RMC renal tumors. Supporting diagnosis may also be performed using OCT3/4 and SALL4.
Molecular Techniques
In recent years, linked-read genome sequencing and PCR-based microsatellite analysis have emerged as advanced molecular techniques for detecting genetic changes in RMC. These techniques are capable of identifying hemizygous deletions, balanced translocations, and loss of heterozygosity (LOH) involving the SMARCB1 gene. In addition to RNA sequencing, array comparative genomic hybridization (array CGH) contributes to reconstructing the molecular profile of RMC, which further helps in discovering possible targets for therapeutics.
Therapeutics Development for Renal Medullary Carcinoma (RMC)
- Targeted Therapies
Inhibitors of EZH2 and the ubiquitin-proteasome system (UPS), among other targeted therapies, are currently being investigated for their potential use in the therapeutic of renal medullary carcinoma (RMC). Preclinical studies indicate that there is an apoptotic response and cell cycle arrest in RMC cells when UPS is inhibited. Also, EZH2 inhibitors appear to be effective since the loss of SMARCB1 results in overactivation of PRC2, making these regions therapeutically targetable.
- Immunotherapies
Immunotherapies, in particular the inhibitors of PD-1, are actively being investigated for RMC. There are case reports describing some responses to nivolumab therapy, but the relationship between PD-L1 expression and response to nivolumab remains ambiguous. Some combination therapies, including antiangiogenic drugs like bevacizumab, have also been recorded to enhance survival in some cases.
Table 1. Therapeutics of Renal Medullary Carcinoma (RMC).
| Therapeutics |
Drug Name |
Target |
Description |
Stage |
| Chemotherapy |
Carboplatin/Paclitaxel |
/ |
Combination chemotherapy regimen used in RMC, often in conjunction with bevacizumab. |
Approved |
| Chemotherapy |
Gemcitabine/Cisplatin |
/ |
Another commonly used chemotherapy regimen for RMC. |
Approved |
| Targeted Therapy |
Bevacizumab |
VEGF |
Monoclonal antibody targeting VEGF, often used in combination with chemotherapy. |
Approved |
| Targeted Therapy |
Sunitinib |
VEGF |
Tyrosine kinase inhibitor targeting VEGF, used in some RMC cases. |
Approved |
| Targeted Therapy |
Everolimus |
mTOR |
mTOR inhibitor used in some RMC cases, though results have been mixed. |
Approved |
| Immunotherapy |
Nivolumab |
PD-1 |
PD-1 inhibitor showing variable responses in RMC, with some cases showing a temporary response. |
Phase II |
| Proteasome Inhibitors |
Bortezomib |
Chymotrypsin-like Subunit |
First-generation proteasome inhibitor used in combination with chemotherapy, showing prolonged time to progression in some cases. |
Phase II |
| Proteasome Inhibitors |
Ixazomib |
Chymotrypsin-like Subunit |
Second-generation proteasome inhibitor being tested in combination with chemotherapy. |
Phase II |
| EZH2 Inhibitors |
Tazemetostat |
EZH2 |
Inhibitor targeting EZH2, currently in phase II clinical trials for SMARCB1-negative tumors, including RMC. |
Phase II |
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 extends complete services in the creation of diagnostics and therapeutics for renal medullary carcinoma (RMC). We are able to offer comprehensive services ranging from molecular characterization to preclinical testing because of our modern facilities and expert workforce. We particularly focus on developing targeted immunotherapies. Advanced genomic profiling and functional genomics are performed to identify possible therapeutic targets.
- UOK353 and UOK360 Renal Medullary Carcinoma Cell Lines
- Genetically Engineered Mouse Models (GEMMs)
- Caki-2 Xenograft Models
- Streptozotocine-induced Models
- Formic Acid FNT-induced Models
At Protheragen, we are dedicated to advancing the field of renal medullary carcinoma (RMC) research and development. Our comprehensive suite of services includes diagnostics and therapeutics development, preclinical research, and customized solutions tailored to meet the unique needs of each project. If you are interested in our services, please feel free to contact us.
References
- Su, Yongdong, and Andrew L. Hong. "Recent advances in renal medullary carcinoma." International Journal of Molecular Sciences 23.13 (2022): 7097.
- Shah, Amishi Y., et al. "Management and outcomes of patients with renal medullary carcinoma: a multicentre collaborative study." BJU international 120.6 (2017): 782-792.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
