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Raczka et al. Cancer Drug Resist 2019;2:356-64 I http://dx.doi.org/10.20517/cdr.2018.004 Page 357
[1-3]
over 100,000 deaths annually . Surgery can be performed for early stage localized tumors, however 30%
[4]
of patients present with metastases at the time of diagnosis . Of those who present with non-metastatic
RCC, many will develop tumors at distant sites, such as brain, lungs, lymph nodes, liver and bone. At this
[5]
stage, the 5-year survival rate is 0%-20% . Drug resistance to currently available therapies is a significant
[6]
issue in the treatment of RCC and can be attributed to very high intra-tumoral heterogeneity (ITH) . It is
estimated that 25%-30% of patients presenting with advanced RCC do not respond to antiangiogenic drug
therapy from the beginning, which results in a poor prognosis. Of those who initially respond, most develop
resistance within 6-15 months after the start of treatment . Current efforts aiming at overcoming these
[7-9]
issues involve combination therapies with already approved targeted therapies and checkpoint inhibitors, as
well as therapies targeting altered tumor metabolism.

CURRENT STATE OF AVAILABLE THERAPIES
Monotherapies
From the early 1990s until 2006, RCC was treated with interferon-α or interleukin-2 (IL-2). These treatments
had low rates of efficacy (5%-20%), high morbidity and mortality and are rarely used today. A multi-target
receptor tyrosine kinase (RTK) inhibitor, sunitinib, was approved by the FDA in 2006 and started the era
of targeted therapy for RCC [10,11] . Until 2009, when the FDA approved everolimus as a second-line therapy,
no drugs were available for patients whose disease progressed after initial treatment [12,13] . Other approved
RTK inhibitors include bevacizumab, axitinib and lenvatinib, all inhibiting vascular endothelial growth
factor receptors (VEGFR). Pazopanib is another approved small molecule, which works as a multityrosine
kinase inhibitor. Additionally, cabozantinib inhibits AXL, RET, MET, KIT, FLT3, ROS1, TYRO3 and
TRKB, as well as VEGFR . Mammalian target of rapamycin (mTOR) is a serine/threonine-specific protein
[12]
[14]
kinase frequently mutated in RCC. Examples of mTOR inhibitors include everolimus and temsirolimus .
Ipilimumab is designed to target Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4), a protein receptor
which downregulates the immune system by inhibiting T cell proliferation and IL-2 production. Inhibition
of CTLA-4 leads to reprogramming of T cell metabolism, thus activating these cells. Several programmed
death-1 (PD-1) receptor inhibitors, such as nivolumab, pembrolizumab and ateozumab, work to increase T
cell metabolism [12,15] . Despite significant progress in the field, drug resistance remains a significant health
[12]
burden .
Combination therapies
Combination therapy is a treatment approach where two or more therapeutics are used together to treat a
disease. It was first applied to treat cancer in 1965, when Emil Frei, James F. Holland and Emil J. Freirich
noticed that the treatment of acute leukemia in children using methotrexate, 6-mercaptopurine plus
[16]
vincristine had an additive effect on disease remission . Since then, combination therapies with drugs that
target different biochemical pathways have been of great focus in cancer research. The objective of these
studies is to find combinations which have synergistic or additive effects. More recently, efforts have been
made to develop restrictive combinations, which spare healthy cells but specifically target tumor cells. This
approach takes advantage of differences between healthy and malignant cells, such as the absence of a drug
target. This is exemplified by the absence of functional p53 in some tumor cells, where growth of normal
cells is arrested by one drug in order to protect them from the effect of another drug, which only targets
actively dividing cells . Drug repurposing is another approach where drugs already approved for use in
[17]
[18]
treatment of different diseases could be employed in the cancer setting .
Development of combination therapies is on the increase and could one day become a new standard of care. Its
superiority over monotherapy presents in a potential decrease in drug resistance with concurrent therapeutic
benefit, such as reduced tumor growth and prevention of metastases. The first FDA-approved combination
for advanced RCC was lenvatinib plus everolimus as second-line therapy. The approval was based on a better
[19]
outcome over therapy with a single agent and acceptable toxicity . Similarly, following Phase II clinical trials,