Targeted therapies for renal cell carcinoma

Abstract

The management of patients with metastatic renal cell carcinoma (RCC) has changed dramatically over the past few years. Nephrectomy remains an important intervention for localized RCC but systemic therapy is the mainstay of treatment for patients who relapse after surgery or who have metastatic RCC. Before 2005, medical therapies for RCC were limited to cytokine therapies, which are very toxic and benefit only a small percentage of patients. In 2017, therapeutic agents now include kinase and immune checkpoint inhibitors. Contemporary research with these agents is now focusing on combinatorial and perioperative therapy. The field is now faced with the evolving challenge of how to select the best therapy for each patient during their natural history of disease, which has created a strong interest in modern sequencing and molecular approaches to identify biomarkers to personalize treatments. New therapeutic agents and approaches are associated with different toxicities and financial burdens, which require consideration of value by measuring clinical benefit, toxicity, and the cost of each drug with an organized framework. In this Review, we discuss the mechanisms underlying RCC and how improved molecular understanding helped the development of therapies, as well as biomarkers of response to treatment. We also discuss the value of these agents and their impact on personalization of therapy and drug development for RCC.

Vitiligo: A new side effect of everolimus therapy for metastatic renal cell carcinoma

“…[4][5][6][7] Some implicated drugs are anticonvulsants, antimalarials, antiparkinson's drugs and biological drugs such as infliximab, imiqimod and imatinib. The suggested etiopathogenesis behind drug-induced vitiligo is: (1) activation of cytotoxic T cells against melanocyte antigens (2) damage to sympathetic nerves that are connected by chemical synapses to melanocytes with a resultant functional disturbance, and (3) a direct cytotoxic nature of the drug on melanocytes (apoptosis). Most of the mechanisms suggested are hypothetical with no direct or scientific evidence to establish the exact role of the implicated drug.…”

“…Recently, new targeted drugs were proposed, including Tyrosine kinase inhibitors, checkpoint inhibitors, and combinations of these new agents that can improve outcomes for patients. 1 Among these, small-molecule multitargeted tyrosine kinase inhibitors (TKIs) such as sorafenib, sunitinib and mammalian target of rapamycin (mTOR) inhibitors such as temsirolimus and everolimus seem to be able to change the natural history of this tumor. 2 Toxicities during the early course of treatment are majorly caused from mTOR inhibitors and include hyperglycaemia, hypophosphatemia, weakness, anorexia, diarrhoea and skin reactions such as leukocytoclastic vasculitis.…”

Niclosamide Exhibits Potent Anticancer Activity and Synergizes with Sorafenib in Human Renal Cell Cancer Cells

“…While nephrectomy remains an importafnt intervention for localized RCC, systemic therapy is the mainstay of treatment for the patients with relapsed and/or metastatic RCC [1,8,9]. Despite recent advances in diagnostic imaging, surgical therapy and basic molecular understanding, many patients still experience metastatic disease, and their response rates to conventional therapies rarely exceed 25%, yet associated with serious adverse effects [1,8,10].…”

“…Despite recent advances in diagnostic imaging, surgical therapy and basic molecular understanding, many patients still experience metastatic disease, and their response rates to conventional therapies rarely exceed 25%, yet associated with serious adverse effects [1,8,10]. For the past decade, the therapeutic landscape of RCC has significantly expanded, mostly driven by targeting the dysregulated metabolic pathways involved in oxygen sensing (e.g., VHL/HIF pathway), energy sensing (e.g., HGF/MET pathway) and/or nutrient sensing cascade (e.g., AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR pathways) [8][9][10][11]. For instance, small molecule inhibitors that target VEGF receptors (Sunitinib and Sorafenib) have a favorable toxicity profile and can prolong time to progression and preserve quality of life when used in newly diagnosed or previously treated patients [8,9,12].…”

“…For the past decade, the therapeutic landscape of RCC has significantly expanded, mostly driven by targeting the dysregulated metabolic pathways involved in oxygen sensing (e.g., VHL/HIF pathway), energy sensing (e.g., HGF/MET pathway) and/or nutrient sensing cascade (e.g., AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR pathways) [8][9][10][11]. For instance, small molecule inhibitors that target VEGF receptors (Sunitinib and Sorafenib) have a favorable toxicity profile and can prolong time to progression and preserve quality of life when used in newly diagnosed or previously treated patients [8,9,12]. Temsirolimus, an MTOR inhibitor, can prolong the survival of patients with poor-risk disease [8,12].…”