Collecting duct carcinoma (CDC) is an uncommon and highly aggressive form of cancer that originates from the distal convoluted tubule. At Protheragen, we are focused on responding to the particular challenges associated with the CDC by developing novel and comprehensive approaches to diagnostics and therapeutics.
Overview of Collecting Duct Carcinoma (CDC)
Collecting duct carcinoma (CDC) is a very aggressive and rare subtype of renal cell carcinoma (RCC) that arises from the principal cells of the renal collecting ducts of Bellini. The extracting duct distinguishing features that contribute to its incredibly ominous prognosis include an advanced stage at diagnosis, a strong proclivity towards, and propensity for regional spread of malignancy. The 2016 WHO Classification of Tumors of the Urinary System has defined criteria for CDC tumors, which include predominant tubular morphology, infiltrative growth patterns, and desmoplastic stromal reactions. Regardless of these criteria, the diagnosis remains elusive due to the formative features with other high-grade renal carcinomas, which are often encountered in practice.
Fig.1 Pathological analysis of collecting duct carcinoma. (Wenzel M.,
et al., 2021)
Pathogenesis of Collecting Duct Carcinoma (CDC)
The pathogenesis of collecting duct carcinoma is characterized by specific genetic and molecular changes; however, the interplay of these factors remains largely unexplored. Recent research employing next-generation sequencing (NGS) techniques has demonstrated that mutations in NF2, SETD2, SMARCB1, and CDKN2A genes are common. These abnormalities have identifiable therapeutic implications. For example, there seems to be therapeutic potential for mTOR inhibitors in cases of NF2 mutations, which occur in roughly 29% of CDC cases. Furthermore, the CDC also involves seamless diverse alterations in PIK3CA, PIK3R2, FBXW7, BAP1, DNMT3A, VHL, and HRAS, which underscore its complex molecular heterogeneity.
Diagnostics Development for Collecting Duct Carcinoma (CDC)
Histopathological Examination
The diagnosis of collecting duct carcinoma (CDC) is supported primarily by histopathological examination, which remains critical to the integrative multi-modality biopsies. Important diagnostic criteria include high-grade tubular type CDC and infiltrative stromal desmoplasia. IHC is fundamental in establishing the diagnosis and separating CDC from most other renal neoplasms. Some studies indicate PAX8 is always positive in CDC, while 34be12 shows variable positivity during its application for differential diagnoses, which demonstrates important corroborative value. Other markers such as CK7, GATA3, and p63/p40 may rule out urothelial carcinoma involvement.
Molecular Diagnostics
The adoption of advanced technologies such as molecular diagnostics and further next-generation sequencing (NGS) has transformed the diagnosis of CDC. With NGS, it's possible to detect certain genetic changes like NF2, SETD2, or SMARCB1 mutations. These changes at the molecular level facilitate not only a more precise diagnosis but also enable tailored therapeutic approaches. For instance, mTOR inhibitors may be suitable in therapy after confirming NF2 mutations; similarly, ERBB2 amplifications could indicate responses to HER2-targeted therapies.
Therapeutics Development for Collecting Duct Carcinoma (CDC)
- Targeted Therapies
The targeted therapies are promising in the therapeutic of CDC. The use of some mTOR inhibitors, such as everolimus, has shown efficacy, especially for cases with NF2 mutations. Other agents, such as VEGF and CDK4/6, are being studied as well. For example, ERBB2 amplification identified in some cases of CDC indicates possible applicability of HER2-targeted therapies.
- Immunotherapy
Immunotherapy is a new possible approach to treating CDC. For example, nivolumab and ipilimumab have been used as checkpoint inhibitors and exhibited some partial responses. Atezolizumab combined with bevacizumab also showed promise in clinical trials. Tumors arising from CDCs are known to overexpress PD-L1; therefore, there is a rationale for the use of immunotherapy in this cancer type.
Table 1. Summary of ongoing clinical trials in patients with variant histology renal cell carcinoma and collecting duct carcinoma. (Suarez C., et al., 2022)
| Name |
ClinicalTrials.gov Identifier |
Phase |
Intervention arm |
Prior Therapy Allowed |
Primary Endpoint |
Accruing |
| CaNI |
NCT04413123 |
II |
Cabozantinib plus Nivolumab and Ipilimumab |
Yes * |
ORR |
Yes |
| ICONIC |
NCT03866382 |
II |
Cabozantinib plus Nivolumab and Ipilimumab |
Yes ¢ |
ORR |
Yes |
| CA209-9KU |
NCT03635892 |
II |
Cabozantinib plus Nivolumab |
Yes * |
ORR |
Yes |
| ANZUPI602 |
NCT03177239 |
II |
Nivolumab followed by Nivolumab plus Ipilimumab |
Yes & |
ORR |
Yes |
| SUNNIFORECAST |
NCT03075423 |
II |
Nivolumab plus Ipilimumab versus Standard of Care (sunitinib) |
No |
OS |
Yes |
| ALTER-UC-001 |
NCT05124431 |
II |
Anlotinib plus Everolimus |
No |
ORR |
Yes |
| NCT04385654 |
II |
Toripalimab plus Axitinib |
No |
PRR |
Yes |
| RadiCAL |
NCT04071223 |
II |
Radium-223 plus Cabozantinib |
Yes # |
SSE |
Yes |
ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PRR, pathologic response rate; SSR, symptomatic skeletal event-free survival.
*No prior immunotherapy or cabozantinib.
&No prior immunotherapy.
#No prior cabozantinib.
¢No prior cabozantinib. Also, patients who have received both prior MET and VEGF and prior PD-1/PD-L1/CTLA-4 (sequentially or in combination) are also not allowed.
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 is a leading provider of preclinical research services dedicated to advancing therapy development for rare cancers, such as collecting duct cancer. Our specialized services span the entire preclinical development pipeline, offering unparalleled expertise to pharmaceutical and biotechnology companies.
Disease Models
- VHL/Trp53 Double-Knockout Mice in the Renal Collecting Duct Lineage
- N-nitrosodimethylamine (NDMA)-Induced Renal Collecting Duct Tumor Models
- PDX Models
Recognizing the unique complexities of Collecting Duct Carcinoma, Protheragen offers highly customized services tailored to the specific needs of each research program. Our flexible approach allows clients to choose from a diverse range of preclinical activities, from focused target validation studies to integrated drug discovery programs. If you are interested in our services, please feel free to
contact us.
References
- Cabanillas, Gerardo, et al. "Collecting duct carcinoma of the kidney: diagnosis and implications for management." Urologic Oncology: Seminars and Original Investigations. Vol. 40. No. 12. Elsevier, 2022.
- Suarez, Cristina, et al. "Update in collecting duct carcinoma: Current aspects of the clinical and molecular characterization of an orphan disease." Frontiers in oncology 12 (2022): 970199.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
