Renal cell carcinoma (RCC) is the most common malignant tumor of the adult kidney, accounting for more than 85% of renal malignancies with a high degree of malignancy. The incidence rate is about 3% of adult malignant tumors, and the rate of incidence is increasing by 2% every year, the high incidence age is 50-70 years old, and the ratio of male to female is 2:1. The current treatment is mainly surgery plus radiotherapy and chemotherapy. Renal cell carcinoma is less sensitive to radiotherapy and chemotherapy, and for patients with advanced stage, metastasis or recurrence, it is even more powerless. Restricted renal cell carcinoma (RCC) can be cured by local surgical resection, but it is prone to recurrence. There is no effective treatment to stop recurrence after surgery. In addition, because many tumors are asymptomatic in early stages, they are detected at intermediate or advanced stages. The prognosis of recurrent and metastatic renal cell carcinoma is poor, with a median survival of 12 months.
Renal cell carcinoma can cause an immune response that leads to spontaneous shrinkage of the tumor itself, so many immunotherapeutic measures, such as interleukin-2 (IL-2), have been used more often in recent years. In the United States, high-dose IL-2 is the only drug approved for metastatic renal cell carcinoma in appropriately selected patients. Low-dose IL-2 and interferon (IFNa) are used in patients in good general condition with no postoperative liver or bone metastases. After failure of cytokine-based therapy, there is no definitive second-line treatment option. In this case, it is not helpful to hope for IL-2 and interferon (IFNa), other experimental drugs thalidomide, new cytokines such as IL-4, IL-6, IL-12, etc., vaccine-based therapy and cytotoxic chemotherapy only result in a small percentage of tumor shrinkage.
Promising therapeutic measures for metastatic renal cell carcinoma stem from the increased understanding of the role of hypoxia-inducible factor (HIF)-related proteins (vascular endothelial growth factor) [VEGF], platelet-derived growth factor (PDGF), transforming growth factor a (TGFa) and their receptors on endothelial, pericytes and tumor cells in the pathogenesis and progression of renal cell carcinoma. These approaches are molecularly targeted therapies.
I. Molecular pathogenesis and inhibition of angiogenesis
Approximately 65-75% of all renal epithelial tumors are clear cell carcinomas, while others include papillary, suspicious cell, collecting duct cell, medullary, and eosinophilic granulosa cell carcinomas. The subtypes of renal cell carcinoma are distinguished by genetic abnormalities and the expression patterns of the associated genes. These genetic abnormalities are first identified by studying the patient’s cancer syndrome. As an example, von Hippel-Lindau disease is an autosomal dominant syndrome caused by mutations in the VHL gene (located at 3p25) and involves multiple systemic lesions, including renal carcinoma, angiogenic cell tumors of the central nervous system and retina, adrenal pheochromocytoma, renal, pancreatic and epididymal cysts, etc. Genetic analysis of VHL-associated tumors. Seventy-five to 80% of disseminated clear cell carcinomas exhibit loss of heterozygotes. These findings suggest the pathogenesis of VHL gene mutations in hereditary and sporadic renal cell carcinomas.
VHL accelerates the degradation of several proteins associated with growth and solid tumor angiogenesis, such as hypoxia-induced transcription factor 1 (HIF1), and under normal oxygen content, VHL binds to HIF to ubiquitinate it as a target for proteasome action. Under hypoxic conditions, HIF1 accumulates and stimulates the synthesis of various HIF-induced proteins, including VEGF, PDGFβ, transforming growth factor-β1 (TGF-β1), and erythropoietin (EPO). In the absence of VHL, even in the presence of normal oxygen content, HIF1-induced protein overexpression contributes to the malignant phenotype of renal clear cell carcinoma.
Tumor growth and metastasis are dependent on neovascularization and the provision of oxygen and nutrients to tumor cells. Vascular endothelial growth factor (VEGF) is the most important growth factor in tumor angiogenesis and it plays a key role in the growth and progression of human cancers, including renal cancer. Renal cell carcinoma is a better model to study the inhibition of angiogenesis as a therapeutic measure, such as the frequency of loss of the second allele of the VHL gene and the associated dysregulation of the HIF1-inducible gene, the angiogenic factors VEGF and PDGF, and the high-density characteristics of these tumor vessels. In fact, most of the new therapeutic approaches for renal cell carcinoma focus mainly on anti-angiogenic therapy targeting VEGF or its receptors.
II. Targeted therapeutic agents
1. Vascular endothelial growth factor-targeted therapeutic measures – including monoclonal antibodies and signal transduction inhibitors.
(1) Anti-vascular endothelial growth factor (VEGF) antibody – Phase I clinical trial for advanced renal cell carcinoma demonstrated the recombinant human-derived anti-vascular endothelial growth factor (VEGF) monoclonal antibody – bevacizumab (Avastin, bevacizumab) A phase II clinical trial involving 116 patients with kidney cancer who were not sensitive to cytokine therapy treated with bevacizumab 3 mg/kg, 10 mg/kg and placebo, repeated every two weeks, showed that the time to disease progression was significantly higher in the bevacizumab high-dose group than in the placebo group (4,8 vs. 2,5 months) and that a higher proportion of patients had no disease progression within 8 months ( 30% vs. 5%). There were four cases of partial remission in the high-dose group. Although these data show promise, Phase III clinical trials are still needed to validate the benefit of bevacizumab in advanced renal cell carcinoma. The US FDA has approved bevacizumab for advanced colorectal cancer at a dose of 5 mg/m2, the
Rini, BI et al. explored whether bevacizumab (bevacizumab) + erlotinib (erlotinib) (epidermal growth factor receptor inhibitor) for advanced renal cancer could achieve synergistic effects on the action of the two molecular pathways. In an initial report of a phase II clinical trial, 15 of 63 metastatic kidney cancers were objectively effective (14 PR, 1 CR). The median survival and progression-free survival within 18 months were 11 months and 26%, respectively. Whether these results are better than single-agent bevacizumab needs to be confirmed by other trials.
(2) Small molecule vascular endothelial growth factor receptor (VEGFR) inhibitors – Another approach to inhibit the VEGF signaling pathway is small molecule VEGF receptor inhibitors. This targeted therapy blocks the intracellular receptor adenosine triphosphate at the receptor binding site, and in some cases, other tyrosine kinases. These drugs have some effectiveness and include vatalanib, sunitinib, sorafenib and AG 13736, all of which are effective oral inhibitors of VEGFR-1, 2, 3 and other kinases.
vatalanib – The initial phase I clinical trial was done specifically in patients with metastatic renal cell carcinoma. Forty-five patients were treated at five dose levels in the dose range of 300-1500 mg/d, with no maximum tolerated dose determined. vatalanib was effective in 7 of 37 patients with evaluable efficacy (1 PR, 6 MR). Subsequent treatment of 10 patients with the recommended phase II trial dose resulted in progression-free disease within 2 months of initiation of therapy and a median progression-free survival time of 6 months.
Sunitinib (Sutent, SU11248) – mostly translated as sunitinib in China – is a novel class of drugs that selectively targets multiple receptor tyrosine kinases and blocks four signaling pathways involved in angiogenesis, VEGF, PDGF, KIT and FLT3. 2005 In a phase II clinical trial of sunitinib in patients with advanced renal cancer after failure of cytokine therapy reported at the ASCO meeting in 2005, the preliminary study reported 63 patients in the clinical trial, of whom 25 (40%) achieved PR (evaluated by RECIST criteria), 21 (33%) achieved SD, and 17 (27%) had progressive disease (PD).
The patients tolerated the drug well and most of the side effects manifested mildly, mainly fatigue, while other rare side effects were diarrhea, nausea, vomiting, tongue pain, neutropenia, and thrombocytopenia.
AG-013736 – Another effective multi-targeted tyrosine kinase inhibitor administered orally, experimentally proven to be effective in patients with advanced renal cancer who have failed cytokine therapy. In a phase II study, 52 patients with advanced kidney cancer were treated with 10 mg/d AG-013736 for 4 weeks. The initial study reported efficacy of PR in 21 cases (40%), and a median 12-month follow-up found no disease progression in 36 cases (69%). The study found that AG-013736 was well tolerated orally despite transient hypertension in 17 patients.
Sorafenib (BAY 43-9006) – mostly translated as sorafenib by domestic scholars – is not the first orally administered multikinase inhibitor and is a potent small-molecule vascular endothelial growth factor receptor 2 (VEGFR-2), FLT3, platelet-derived growth factor receptor (PDGFR), fibroblast Growth factor receptor 1 (FGFR1) tyrosine kinase inhibitor. Sorafenib has dual anti-tumor effects: it inhibits tumor cell proliferation directly by blocking the RAF/MEK/ERK-mediated cell signaling pathway, and it also inhibits tumor growth by acting on VEGFR, inhibiting neovascularization and cutting off nutrient supply to tumor cells. The purpose is to inhibit tumor growth by acting on VEGFR, inhibiting neovascularization and cutting off nutrient supply to tumor cells.
The results of a phase II clinical study reported at the 2004 ASCO annual meeting showed that treatment with BAY 43-9006 in patients with advanced kidney cancer resulted in significant and sustained therapeutic effects in 106 patients treated, 37 of whom had at least 25% tumor shrinkage 12 weeks after the initial start of treatment. BAY 43-9006 was approved by the FDA in December 2005 for the treatment of advanced renal cell carcinoma.
Sorafenib is well tolerated. The most common drug-related side effects are rash, hand-foot syndrome and fatigue, occasionally transient hypertension, and also hair loss, nausea, vomiting and loss of appetite.
2. mTOR kinase inhibitors – The mTOR signaling pathway has the function of regulating cell cycle, cell growth, division, and neoangiogenesis. Blocking these signaling pathways has become another new target for the treatment of renal cell carcinoma.
Temsirolimus (CCI-779) – a rapamycin analogue and competitive mTOR kinase inhibitor – is effective in advanced renal cell carcinoma. In a randomized phase II clinical study, 3 dose levels were tested in 111 patients with advanced renal cancer, with 1 CR and 7 PRs, for an overall effectiveness rate of 7%. Although the effective rate was low, 26% of patients achieved MR, 17% of patients had stable disease for 6 months or more, with relatively long time to disease progression (5 or 8 months) and median survival of 15 months, which demonstrated the significant anti-tumor activity of the drug.
3. Anti-EGFR therapy – Although renal cell carcinoma highly expresses EGFR, the loss of the VHL gene leads to an increase in transforming growth factor a (TGFa) levels. Epidermal growth factor antagonists such as cetuximab, gefitinib, and panitumumab (ABX-EGF) are not effective in the treatment of renal cell carcinoma.
III. Summary and recommendations
Several drugs targeting the hypoxia-inducible factor-vascular endothelial growth factor (HIF-VEGF) signaling pathway have shown high effectiveness in the treatment of advanced renal cell carcinoma. These drugs resulted in tumor shrinkage in more than 50% of patients compared to controls and also prolonged disease-free survival.
However, the objective effectiveness of these agents is at best partial remission, with most patients progressing after 9-12 months. Therefore, the benefit of these drugs alone is limited. Future efforts are directed at studying the principles of action of the various drugs, mechanisms of resistance, and the combination and selection of the appropriate drug for the patient. This research is ongoing and will hopefully provide us with useful information soon.