Oncolytic Viruses in Renal Cell Carcinoma Treatment
Renal cell carcinoma (RCC) is the most common malignant tumor in the kidney, causing tens of thousands of deaths worldwide each year. RCC originates from the renal cortex and can be classified according to histology. The vast majority of cases originate from clear cell RCC (ccRCC). Local RCC can be treated by surgical resection, but there are a large number of cases with metastatic disease (more than 15%) or subsequent metastatic recurrence. At present, various treatment methods have very limited therapeutic effects on this metastatic RCC (mRCC). However, based on the known response of mRCC to immunotherapy and the characteristic molecular aberrations of the disease, oncolytic virus (OV) therapy will be the first choice for future treatment, because these drugs can tamper with common cancer-causing signaling pathways and produce anti-tumor immune responses.
Immune Characteristics of RCC
Like most cancers, RCC is characterized by abnormal expression of several oncogenes, and these abnormalities have proven to be crucial in allowing OV replication. The association between the loss of the tumor suppressor gene von Hipper Lindau (VHL) and the development of familial and sporadic ccRCC is the most widely studied aberration in RCC molecular biology because almost all familial ccRCC cases and more than 70% of sporadic ccRCC cases involve inactivation of the VHL locus. VHL gene product protein VHL (pVHL) plays an indispensable role in the cell's response to hypoxia. It can combine the cell's oxygen state with gene transcription by acting as a substrate recognition unit for the E3 ligase complex. The complex is ubiquitinated and targets members of the proteosome-degraded hypoxia-inducible factor (HIF) transcription factor family. Due to this effect, loss of pVHL through inactivation will result in reduced proteasome degradation of HIFs, thereby accumulating in the nucleus and driving the expression of genes encoding hypoxic response elements (HRE) in its promoter region. In addition, oncogenic signal transduction (i.e., PI3K / Akt / mTOR), tumor hypoxia and constitutive activation (i.e., the loss of tuberous sclerosis complex 2) also contribute to the upregulation of HIF in RCC.
Fig.1 Biological pathways and the resulting therapeutic targets in renal cell carcinoma. (Rini, 2009)
RCC has other genetic abnormalities including c-MET, Wnt/b-catenin and E-cadherin pathways. This extensive abnormal signaling not only contributes to the selective replication of OV in cancer cells, but also contributes to the design of genetically engineered viruses, which can be used as effective tumor killers through transcription and/or translation targeting. With the development and popularization of high-throughput biological methods and systems biology, more and more proteins related to the occurrence and development of RCC have been identified. Their functions involve cytoskeletal remodeling, mitochondrial dysfunction and lipid metabolism. Besides, large-scale exon sequencing studies on RCC cell lines and tissues have also identified abnormalities in histone modification pathways that can regulate gene transcription.
The Potential of OV for RCC Treatment
- Adenovirus. Adenovirus is a non-enveloped dsDNA virus that has been shown to have oncolytic activity against a variety of malignant tumors, and its genetic modification is relatively easy, allowing the insertion of therapeutic transgenes despite the increasing evidence that adenovirus is preclinical against the efficacy of RCC at the level, but so far no clinical trials have been initiated.
- Vaccinia virus (VV). VV belongs to the poxvirus family, is an enveloped dsDNA virus, used as a vector for gene therapy, and has direct oncolytic properties. Studies have demonstrated the efficacy of VV in the treatment of RCC. Intraviral and intravenous administration of RCC xenograft mouse models can lead to a significant reduction in tumor volume.
- Herpes simplex virus (HSV). HSV belongs to the herpes virus family and is a large enveloped dsDNA virus. HSV exhibits selective replication in mutant cells, which is the result of mutations in genes required for PKR response in mutant hosts and viral replication. HSV is currently the most commonly used OVs for RCC treatment. Although there is a large amount of preclinical evidence supporting the use of oncolytic HSV against RCC, there are no ongoing clinical trials to evaluate the efficacy of these drugs against the disease.
Reference
- Rini, B. I.; et al. Renal cell carcinoma. The Lancet. 2009, 373.9669: 1119-1132.