Summary of treatment options for renal cell carcinoma: what is the current situation and what is the future?

Renal cell carcinoma (RCC) is the most common and deadly tumor of the urinary system, accounting for 5% of all cancer diagnoses worldwide, and it mostly affects men
.

In the next few years, RCC morbidity and mortality are expected to rise, and it is estimated that more than 300,000 people will die by 2040
.

RCC has different molecular and histological subtypes (Table 1)
.

Clear cell RCC (ccRCC), papillary RCC (pRCC) and chromophobe RCC (crRCC) are the most common RCC subtypes (≥5%), while the remaining subtypes account for ≤1%
.

Importantly, each subtype exhibits specificity in terms of prognosis and treatment
.

Table 1.
Different histological subtypes and characteristics of RCC.
Current treatment options for RCC treatment.
RCC treatment methods include partial or radical nephrectomy, ablation (radiation, cryo or microwave ablation) and active monitoring
.

Surgical resection can cure patients with early RCC, but many patients will relapse or may have metastatic disease at the time of diagnosis and require additional systemic treatment
.

Another treatment option for RCC is radiation therapy, although RCC is inherently resistant to radiation
.

Early immunotherapy using immunostimulants and cytotoxic chemotherapeutics has limited results, with a remission rate of about 10%
.

Over the years, many new therapies that have the potential to treat mRCC have emerged, including targeted therapies for mammalian target of rapamycin (mTOR) and receptor tyrosine kinase (RTK) signals
.

Although the outcome of treatment is good, targeted therapy is prone to drug resistance
.

Recently, new strategies based on immunotherapy have been developed to target the interaction between cancer immune cells (immune checkpoint inhibitors) and have achieved certain success in RCC therapy
.

1.
Anti-angiogenic drugs Although many RCCs are formed spontaneously, the hereditary form of ccRCC shows changes in chromosome 3, resulting in the loss or silencing of the von-Hippel-Lindau (VHL) gene
.

This leads to the activation of HIF-1α, leading to the up-regulation of pro-angiogenic factors such as VEGF
.

Targeted RTK, including VEGFR and its ligand VEGF (angiogenic factor), is considered to be the main therapeutic intervention for patients with advanced RCC
.

Bevacizumab (VEGF-a inhibitor) is the first anti-angiogenic drug available for RCC patients
.

Later, several VEGFR inhibitors were approved, including sorafenib, sunitinib, pazopanib, cabotinib, and axitinib (Figure 1, Figure 2a)
.

Figure 1.
Current interventions for the treatment of patients with advanced renal cell carcinoma (RCC).
Figure 2.
Different drug structures for the treatment of RCC.
Bevacizumab (Figure 1) was approved in 2004.
It is a monoclonal antibody that can bind to Neutralize circulating VEGF-a protein (VEGFR1/2 ligand)
.

The combination therapy of bevacizumab-interferon-α (IFN-α) almost doubled the progression-free survival (PFS) of mRCC patients (5.
4 months to 10.
2 months), compared with those who underwent complete or partial nephrectomy.
Compared with patients (13%), they showed a higher objective response rate (31%)
.

RTK signal activates several downstream signal transduction cascade proteins (Figure 1), which contribute to tumor growth and metastasis
.

TK inhibitor (TKI) binds outside the active site of RTK, inhibits protein substrate or ATP binding and destroys TK signal
.

Sorafenib (Figure 1, Figure 2a) was approved by the U.
S.
Food and Drug Administration (FDA) in 2005 and was approved by the European Medicines Agency (EMA) for the treatment of advanced renal cancer in 2006
.

Sorafenib shows active activity in blocking VEGFR-2, PDGFR-α and RAF kinases
.

The rapid approval of sorafenib prompted the acceptance of other emerging RTK inhibitors, such as sunitinib, which targets VEGFR-1 and -2, PDGFR-β and -α, c-KIT, and FLT3 and RET kinases
.

Sunitinib is used in the first-line treatment of ccRCC
.

Pazopanib was approved in 2011 (Figure 1, Figure 2a) is a potent and selective multi-target RTK inhibitor that can block VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit and c- Fms
.

Studies have shown that pazopanib and sunitinib are equally effective in PFS and overall survival (OS)
.

However, pazopanib has lower cytotoxicity and higher objective remission rate
.

Axitinib (Figure 1, Figure 2a) was approved for RCC therapy in 2012 and showed activity on VEGFR1, VEGFR2, VEGFR3, PDGFR-β and c-Kit
.

Late-stage RCC clinical trials have proved that axitinib is more effective than sorafenib (PFS of sorafenib is 6.
7 months and 4.
7 months)
.

Toxicity-related discontinuations in the axitinib group were also less common (4% vs 8%)
.

Levatinib (Figure 1, Figure 2a) was approved in 2016 in combination with everolimus (see below) for the treatment of metastatic RCC
.

Lovatinib can target a variety of RTKs, namely VEGFR1-3, FGFR1-4, PDGFR-α, RET and KIT
.

Compared with the administration of everolimus alone, the combined administration significantly improved OS within 9 months and increased PFS
.

Cabozantinib (Figure 1, Figure 2a) was approved in 2016 for the treatment of patients with advanced RCC who had previously received anti-angiogenic drug therapy
.

Cabozantinib targets MET, VEGFR2, and other receptor tyrosine kinases, including RET, KIT, AXL, and FLT3
.

In RCC treatment, this is the first drug to show a significant increase in all three clinical efficacy endpoints: overall response rate (ORR), PFS, and OS
.

2.
The mammalian target of rapamycin inhibitor mTOR is a highly conserved serine/threonine kinase from the PI3K-related kinase family, and it plays an important role in the regulation of cell growth, proliferation and metabolism
.

Rapamycin (Figure 2b), also known as sirolimus, is a natural compound isolated from Streptomyces hygroscopicus and was approved in 1999
.

Initially developed as an immunosuppressant to prevent rejection of solid organ transplantation, it has a complex immunomodulatory effect in cancer and binds to FKBP12
.

The rapamycin-FKBP12 complex targets and inactivates mTORC1
.

Rapalogs (analogs of rapamycin), everolimus and temsirolimus are the most common mTOR inhibitors and have been shown to have potent anticancer activity against several tumor types including RCC (Figure 2b)
.

Tamirolimus is the first mTOR inhibitor and was approved in 2007 for the treatment of patients with advanced RCC
.

In this trial, the use of tamsulolimus resulted in prolonged OS in high-risk RCC patients (10.
9 months compared to 8.
9 months in the IFN-α group)
.

Compared with IFN-α treatment (1.
9 months), PFS also extended to 3.
8 months
.

Everolimus (Figure 3) is different from temsirolimus because it is not metabolized to rapamycin in the body
.

It inhibits mTORC1 and interferes with cell cycle regulation and cell response to hypoxia
.

Everolimus was approved by the FDA as a second-line treatment for RCC patients who failed Sorafenib and/or Sunitinib
.

These molecules have a common chemical core, and the only change occurs in the C1 of the 2-methoxycyclohexane unit
.

In rapamycin, this unit binds a hydroxyl group in C1, and everolimus displays a hydroxyl group at the end of the carbon chain; temsirolimus has a substituted acetate group at this position
.

Figure 3.
The first-line treatment of renal cell carcinoma (RCC).
The activity of mTOR is controlled by mTORC1 and mTORC2.
The first is sensitive to rapamycin, and the second is considered resistant to rapamycin
.

This phenomenon has led to the development of ATP-competitive mTOR inhibitors, which are a class of second-generation mTOR inhibitors
.

Sapanisertib (Figure 2b), also known as INK128 or TAK-228, is an experimental mTORC1/2 dual kinase inhibitor
.

This drug has yet to be approved, but is being studied for advanced solid tumors (including RCC), blood and inflammatory diseases
.

Vistusertib (Figure 2B), AZD2014, is a newly developed mTORC1/2 kinase inhibitor that shows a higher efficacy than rapamycin
.

A clinical trial of mRCC is investigating its ability to delay cancer regeneration for a long time compared to everolimus
.

AZD8055 (Figure 2b) is an experimental anticancer drug taht can also inhibit the activity of mTORC1/2
.

Reduce cell cycle progression, induce cell cycle arrest and apoptosis
.

3.
Immunotherapy approved in 1986, IFN-α activates natural killer (NK) cells, enhances the activity of macrophages, induces differentiation of dendritic cells, and promotes anti-tumor immunity
.

Although IFN-α does not significantly improve the prognosis of patients, it is better tolerated and less severely toxic than high-dose IL-2
.

Aldesleukin is a form of recombinant IL-2, which was approved for RCC treatment in 1992
.

It stimulates the proliferation and maturation of T cells and is used for RCC therapy
.

High-dose IL-2 is only slightly better than cytotoxic chemotherapy and radiotherapy
.

In the past few years, new immunotherapy strategies for the treatment of mRCC patients have been explored
.

Some new immunotherapy drugs, such as programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) checkpoint inhibitors, It has become an integral part of the management of advanced or mRCC treatment
.

New preclinical compounds for RCC therapy Although the survival rate and outcome of mRCC patients receiving targeted therapy have improved, genetic and/or epigenetic modifications that lead to downstream activation of signaling pathways can eventually lead to cancer resistance
.

In order to find new treatment options for these unmet needs, the pharmaceutical chemistry community has been isolating natural compounds and synthesizing new derivatives to test the anti-RCC anti-cancer properties in vitro and in vivo
.

The picture below shows the chemical drug molecule under research, and we will illustrate it with an example
.

 Figure 4.
The diversity of natural and synthetic molecules and their activity on renal cell carcinoma (RCC) Zang et al.
synthesized a series of novel 4-aniline-thieno[2,3-d]pyrimidine derivatives (compound 1, figure) 4a), used as a potential inhibitor of mitogen-activated protein kinase (MAPK) interacting serine/threonine kinase 1 (MNK1)
.

Deng and colleagues studied the anticancer properties of compound 4 (Figure 4a) on ACHN cells
.

After 24 hours of treatment, when the concentration was 9 mM, cell viability decreased
.

The researchers also observed the ability of sinomenine to induce apoptosis in a dose-dependent manner, accompanied by a decrease in the expression of autophagy-related proteins p62, Beclin1, and LC3-II/LC3-I
.

In addition, sinomenine can inactivate the PI3K/AKT/mTOR pathway and affect the nuclear translocation of AKT
.

Y.
Naro and colleagues identified oxadiazole-based compounds (compound 5, Figure 4a) as miR-21 inhibitors
.

Further research revealed its ability to sensitize A498 cells to the chemotherapeutic drug Topotecan by significantly increasing the expression of tumor suppressor PDCD4 and PTEN, thereby silencing miR-21
.

The effect of topotecan increased cell viability and colony formation test by 10 times
.

Co-administration of the lead compound and 10 μM topotecan resulted in A498 sensitization, resulting in an IC50 value of 74 nM
.

A recent study focused on the application of berberine (compound 10, Figure 4b) in photodynamic therapy (PDT).
Berberine is a naturally occurring isoquinoline alkaloid with photosensitive properties
.

The compound increases cytotoxicity in RCC cell lines in a concentration and time dependent manner and is effectively internalized
.

Due to the increased phototoxicity, the combination of this natural compound with PDT results in a more potent anti-cancer effect
.

Studies on the mechanism of action have proved that berberine induces cell death in ACHN and 786-O cell lines through autophagy and apoptosis (caspase-3 activity)
.

In addition, after treating 786-O cells with PDT-related berberine, the three target genes of anticancer drugs expressed differently (VEGF-D and human telomerase reverse transcriptase were down-regulated, and polo-like kinase 3 was overexpressed).
Triggers changes in metabolites that inhibit cell proliferation and migration, as well as angiogenesis
.

The editor concludes that targeted therapy brings new hope to RCC patients, and it is expected to improve efficiency and safety compared with conventional therapy
.

VEGFR signaling and mTOR are important targets, and several approved drugs have significantly improved the survival rate of RCC patients
.

However, long-term remission is still relatively rare, and the development of drug resistance has become a problem with these treatments
.

Whether used alone or in combination with targeted therapies, new immunotherapies (ICIs) that target the interaction between cancer and immune cells have been revolutionizing the treatment of cancer and have shown promising results in RCC
.

However, the long-lasting response rate of ICI is limited to certain patients
.

Given the limitations of RCC treatment, many researchers are looking for new drug candidates for this specific cancer type
.

Therefore, several new structures, natural and synthetic, have been tested for their anti-RCC activity, revealing promising results and safety profiles
.

Although the targets of some drugs are known, many drugs are only characterized by their ability to interfere with the aggressiveness of different cancers
.

Future research on these new molecules and their molecular targets can arouse more interest and lead to new RCC therapies
.

Most research is still in the preclinical stage, and clinical research is urgently needed for the most promising drug candidates
.

References 1.
References: Renal cell carcinoma therapy: current and new drug candidates The copyright statement welcomes personal comments and sharing
.

Any other media or website that needs to reprint or quote the copyrighted content of this website must be authorized and see "Reposted from: Aogu" in a prominent position
.