Succinate Dehydrogenase Deficient Renal Cell Carcinoma (SDH-deficient RCC) is an important focus area in oncology that requires complex pioneering techniques for its diagnosis and therapeutic. Protheragen offers a robust suite of services tailored to advance both diagnostics and therapeutics for SDH-deficient RCC.
Overview of Succinate Dehydrogenase Deficient Renal Cell Carcinoma
Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare subtype of RCC noted for bi-allelic mutations resulting in one of four subunits of the SDH complex (SDHA, B, C, and D), which leads to functional loss of the SDH enzyme. This subtype was first recognized as a provisional entity by the 2013 International Society of Urological Pathology (ISUP) Vancouver Classification, and its prevalence is estimated to be between 0.05% and 0.2%of all RCCs. The SDH-deficient form of RCC typically arises in younger adults around the age of 38 to 40 years, associated with rather distinct histological features such as solid or nested, or tubular patterns with gradations containing cyst formation; their cells also have eosinophilic cytoplasm accompanied by flocculent intracytoplasmic inclusions.
Fig.1 Pathology of succinate dehydrogenase deficient renal cell carcinoma. (Liu W.,
et al., 2023)
Pathogenesis of Succinate Dehydrogenase Deficient Renal Cell Carcinoma
The pathogenesis of SDH-deficient RCC revolves around the loss of the SDH enzyme function through biallelic mutation in SDH subunits. This cellular disturbance causes succinate to accumulate in the cytosol, which, in turn, stabilizes hypoxia-inducible factor (HIF) by inhibiting HIF prolyl hydroxylase. The now-stabilized HIF triggers transcription of various pro-angiogenic factors such as VEGF and energy metabolism molecules along with genes responsible for cell survival and proliferation, which together foster a tumor-friendly pseudohypoxia microenvironment that promotes neoplasm development. Moreover, the accumulation of succinate inhibits TET enzymes, leading to extensive genome-wide hypermethylation changes, further fueling potential cancerous alterations.
Diagnostics Development for Succinate Dehydrogenase Deficient Renal Cell Carcinoma
Genetic Testing
Genetic testing forms the backbone in the detection of SDH-deficient RCC. Biallelic mutations within the SDH subunits can be detected through comprehensive genomic profiling. As an example, next-generation sequencing (NGS) has the capability to identify particular alterations within genes SDHA, SDHB, SDHC, and SDHD which is essential for formulating a precise diagnosis and tailoring therapeutic strategies.
Immunohistochemistry
Immunohistochemical staining for SDHB is critical in detecting SDH-deficient RCC. The absence of SDHB expression correlates with SDH deficiency since the loss of any SDH subunit leads to complex instability and degradation. This type of staining is commonly done on formalin-fixed, paraffin-embedded (FFPE) tissue sections.
Histological Examination
Studies conducted on the histology of tumors showcases particular defining traits pertaining to SDH-deficient RCC, which includes solid or nested structures and tubules with varying cystic components. The tumor cells are usually characterized by an eosinophilic cytoplasm coupled with flocculent, intracytoplasmic inclusions. Furthermore, examination via electron microscopy reveals pathologically swollen mitochondria featuring increased amounts of mitochondrial matrix and few degenerate or compressed cristae.
Therapeutics Development for Succinate Dehydrogenase Deficient Renal Cell Carcinoma
- Targeted Therapies: Therapies aimed at treating SDH-deficient RCC are centered around the pseudohypoxia pathway and angiogenesis. The VEGF receptors are targeted by TKIs like sunitinib, pazopanib, axitinib, and sorafenib due to their role in SDH-deficient tumorigenesis. These therapeutics have demonstrated some success; however, response rates remain variable even among patients experiencing what is considered a partial clinical response.
- Combination Therapies: Research is ongoing into enhancing the outcomes of SDH-deficient RCC by aimed combination therapies that target multiple pathways. For instance, the use of TKIs in conjunction with immunotherapies or metabolic modulators may produce synergistic effects.
- Metabolic Modulators: In light of the therapeutic potential of metabolic modulators aimed at addressing the SDH deficiency, further investigation is warranted, given the associated vulnerabilities. The focus of these agents seeks to exploit SDH-deficient tumors' metabolic dependencies, like the reliance on glycolysis for energy capture.
Table 1. Therapeutics of Succinate Dehydrogenase Deficient Renal Cell Carcinoma.
| Therapeutics |
Drug Name |
Target |
Description |
| Immunotherapy |
PD-1 inhibitor |
PD-1 |
Administered for 10 weeks; the tumor was unresponsive. |
| Tyrosine Kinase Inhibitor |
Sunitinib |
VEGF, multi-kinase |
Administered; partial clinical response observed, but severe skin rash led to withdrawal after 16 days. |
| Tyrosine Kinase Inhibitor |
Pazopanib |
VEGF, multi-kinase |
Administered; partial clinical response observed, but acute drug hepatotoxicity necessitated intermittent therapeutic and eventual withdrawal after 10 weeks. |
| Tyrosine Kinase Inhibitor |
Axitinib |
VEGF receptors |
Administered for 3 months with limited response. |
| Tyrosine Kinase Inhibitor |
Sorafenib |
RAF kinase, VEGF receptors, multi-kinase |
Maintained stable disease with modest side effects for 7 months. |
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
For SDH-deficient RCC, Protheragen offers complete diagnostic and therapeutic development services. We carry out genetic tests, immunohistochemistry, and histology examinations for precise diagnosis. In addition, we focus on the creation of specific therapeutic, combinatorial therapies, as well as metabolic modulators to remedy the complex nature of SDH deficient RCC.
Disease Models
- Sdhb Knockout Mouse Models
- Sdha Knockout Mouse Models
- Human SDH-deficient RCC Xenograft Models
- Rat SDH-deficient Pheochromocytoma Xenograft Models
At Protheragen, our preclinical research services for SDH-deficient RCC are designed to accelerate the discovery and development of novel interventions. This includes establishing and characterizing relevant in vitro and in vivo models that faithfully recapitulate the genetic and pathological features of SDH-deficient tumors. If you are interested in our services, please feel free to contact us.
References
- Liu, Wenqin, et al. "Imaging findings of succinate dehydrogenase-deficient renal cell carcinoma." Clinical Case Reports 11.8 (2023): e7799.
- Tsai, Tsung-Heng, and Wen-Ying Lee. "Succinate dehydrogenase–deficient renal cell carcinoma." Archives of pathology & laboratory medicine 143.5 (2019): 643-647.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
