Chromophobe renal cell carcinoma (chRCC) diagnostics and therapeutics development services strive to provide a holistic understanding of the disease and formulate effective therapeutic strategies. Protheragen provides fully integrated services for the development of diagnostics and therapeutics aimed at chRCC. We also provide genetic and genomic profiling, immunohistochemistry, metabolomic profiling, and the design of targeted therapies and immunotherapies.
Overview of Chromophobe Renal Cell Carcinoma (chRCC)
Chromophobe renal cell carcinoma (chRCC) is a specific subtype of renal cell carcinoma (RCC) which makes up about 5% of all RCC cases. It is distinguished from other subtypes of RCC, such as clear cell RCC (ccRCC), through its specific genetic, genomic, and pathological attributes. Patients diagnosed with chRCC tend to be diagnosed and treated earlier in the disease course and are less aggressive in their clinical course relative to ccRCC. In contrast, metastatic or advanced chRCC is known to have a worse prognosis with a median overall survival of approximately 2 years for those with advanced disease. Histologically, chRCC is characterized by large, polygonal cells that have a pale, abundant cytoplasm with prominent cell borders and is thought to originate from the intercalated cells of the distal nephron.
Fig.1 Genomic architecture, cell of origin, and pathogenesis of chromophobe RCC. (Garje R.,
et al., 2021)
Pathogenesis of Chromophobe Renal Cell Carcinoma (chRCC)
The development of chRCC cancer is genetic and multifactorial in nature, which includes genomic and metabolic alterations. One of the hallmark features of chRCC is chromosomal aneuploidy. The most frequently lost entire chromosomes comprise 1, 2, 6, 10, 13, 17, and 21. Although it is not definitively understood why these chromosomes are lost, this form of instability is an integral aspect of chRCC. Moreover, chRCC is characterized by having a low mutational burden, with TP53 and PTEN being the most frequently mutated genes. Furthermore, there is an abundance of mitochondrial DNA genetic aberrations, in particular with the electron transport chain complex 1, which results in heightened oxidative stress. The development and progression of chRCC is attributed to a combination of the above genetic and metabolic alterations.
Diagnostics Development for Chromophobe Renal Cell Carcinoma (chRCC)
Genetic Profiling for chRCC Diagnosis
Understanding the molecular mechanisms of chRCC, as well as diagnosing it, has become much easier with the genetic profiling tools available today. This also involves the detection of somatic mutations in critical genes and chromosomal losses. In chRCC, chromosomal losses of 1, 2, 6, 10, and 17 are often observed and are identifiable using FISH techniques. These chromosomal losses are fundamental in differentiating chRCC from the other subtypes of RCC.
Immunohistochemistry (IHC) and Biomarker Detection
The use of immunohistochemistry is essential in diagnosing chRCC and is particularly helpful in distinguishing it from renal oncocytomas and other kidney tumors. Diagnostic challenges owing to histological resemblance are often resolved owing to the positive expression of CK7 and CD117 (C-Kit) markers in chRCCs. Moreover, IHC markers like RB1 and PDL1 have been used to further elucidate the tumor's biology and anticipate the patient's response to targeted therapeutics.
Therapeutics Development for Chromophobe Renal Cell Carcinoma (chRCC)
Developing targeted therapies is one of the most promising avenues in chRCC therapeutics development. In many preclinical models, small molecule inhibitors focus on the PTEN, TSC1, and TP53 genes because of their numerous mutations. Some chRCC tumors, especially those with hyperactive mTORC1 signaling, respond to mTOR inhibitor Everolimus, which is used in other tumors. Managing advanced metastatic chRCC is partially successful with the TKIs Sunitinib and Pazopanib that target VEGFR.
Table 1. Ongoing clinical trials in chRCC. (Henske E. P., et al., 2023)
| Study |
Design |
N |
Cohort/Drug |
Histology |
Endpoints |
| NCT03635892, CA209-9KU |
Phase II, open-label, single-arm |
15 |
Cabozantinib and nivolumab |
Metastatic nccRCC with chRCC cohort |
ORR per RECIST v1.1 |
| NCT03685448, UNICAB |
Phase II, Multicenter, single-arm |
48 |
Cabozantinib |
Metastatic nccRCC with chRCC cohort |
ORR per RECIST v1.1 |
| NCT03541902, CABOSUN II |
Phase II, single institution, randomized |
84 |
Cabozantinib vs. sunitinib |
Metastatic nccRCC with chRCC cohort |
PFS, ORR, and OS |
| NCT03866382 |
Phase II, single-arm, open-label |
186 |
cabozantinib combined with nivolumab and ipilimumab |
Multiple rare genitourinary malignancies with chRCC cohort |
ORR |
| NCT04071223, RadiCal |
Phase II, randomized, open-label |
210 |
Radium 223 + cabozantinib vs cabozantinib alone |
ccRCC and nccRCC with chRCC cohort |
Symptomatic skeletal event (SSE)-free survival |
| NCT04267120, LENKYN trial |
Phase II, single-arm |
34 |
Lenvatinib 20 mg/day and pembrolizumab 200 mg IV every 3 weeks |
Metastatic nccRCC with chRCC cohort |
ORR |
| NCT03177239, ANZUP1602/UNISoN |
Phase II, single-arm, sequential |
85 |
Single-agent Nivolumab and, upon progression, combination ipilimumab and nivolumab |
Metastatic nccRCC with chRCC cohort |
ORR per RECIST v1.1 |
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 offers comprehensive services for the development of diagnostics and therapeutics for chromophobe renal cell carcinoma (chRCC). Our services include advanced imaging techniques, histopathological and immunohistochemical analyses, and state-of-the-art genetic and molecular profiling. We specialize in the development of targeted therapies, including mTOR inhibitors, tyrosine kinase inhibitors, and novel ferroptosis inducers.
Disease Models
- FLCN Gene Knock-Out Models
- TFEB Overexpression Models
- VhlΔ/ΔTrp53Δ/ΔRb1Δ/Δ Models
- Patient-Derived Xenograft (PDX) Models
Protheragen's preclinical research services include in vitro and in vivo model development, drug screening, and efficacy testing. We leverage cutting-edge technologies and a deep understanding of chRCC biology to identify novel therapeutic targets and evaluate the efficacy of potential drugs. If you are interested in our services, please feel free to contact us.
References
- Garje, Rohan, et al. "Comprehensive review of chromophobe renal cell carcinoma." Critical reviews in oncology/hematology 160 (2021): 103287.
- Henske, Elizabeth P., et al. "Chromophobe renal cell carcinoma." Cancer Cell 41.8 (2023): 1383-1388.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
