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Background: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and is notorious for its resistance to both chemotherapy and small-molecule inhibitor targeted therapies. Subcellular targeted cancer therapy may thwart the resistance to produce a substantial effect., Methods: We tested whether the resistance can be circumvented by subcellular targeted cancer therapy with DZ-CIS, which is a chemical conjugate of the tumor-cell specific heptamethine carbocyanine dye (HMCD) with cisplatin (CIS), a chemotherapeutic drug with limited use in ccRCC treatment because of frequent renal toxicity., Results: DZ-CIS displayed cytocidal effects on Caki-1, 786-O, ACHN, and SN12C human ccRCC cell lines and mouse Renca cells in a dose-dependent manner and inhibited ACHN and Renca tumor formation in experimental mouse models. Noticeably, in tumor-bearing mice, repeated DZ-CIS use did not cause renal toxicity, in contrast to the CIS-treated control animals. In ccRCC tumors, DZ-CIS treatment inhibited proliferation markers but induced cell death marker levels. In addition, DZ-CIS at half maximal inhibitory concentration (IC50) sensitized Caki-1 cells to small-molecule mTOR inhibitors. Mechanistically, DZ-CIS selectively accumulated in ccRCC cells' subcellular organelles, where it damages the structure and function of mitochondria, leading to cytochrome C release, caspase activation, and apoptotic cancer cell death., Conclusions: Results from this study strongly suggest DZ-CIS be tested as a safe and effective subcellular targeted cancer therapy., (© 2023. The Author(s).)

Renal-cell carcinoma remains one of the elusive cancers that lacks a biomarker. It is the eighth most commonly diagnosed malignancy in the United States, and the incidence has slowly trended upward. In addition to the increase in newly diagnosed cases, the prevalence and overall survival of individuals with kidney cancer also has increased substantially. This formal review synopsizes the literature regarding the current treatment landscape, the utility of biomarkers in renal-cell carcinoma, and future directions regarding next-generation sequencing of circulating tumor DNA., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Renal cell carcinoma (RCC) is among the most commonly diagnosed solid malignancies, but until recently there were few systemic treatment options for advanced disease. Since 2005, the treatment landscape has been transformed by the development of several novel systemic therapies. In particular, tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor (VEGF) pathway have been instrumental in improving outcomes in patients with metastatic disease. Areas covered: The armamentarium of TKIs available for the treatment of RCC has expanded in recent years. The most active area of research at this time is the development of treatment regimens combining newer-generation TKIs and immune checkpoint inhibitors. Emerging data point to a role for combination therapy in the frontline management of advanced RCC. Other ongoing areas of research include the use of TKIs in the adjuvant setting and the role of cytoreductive nephrectomy within a changing treatment landscape. Expert opinion: Although TKIs and immune checkpoint inhibitors have incrementally improved outcomes for patients with advanced RCC, long-term survival remains poor. The development of regimens combining these agents represents the next step in the evolution of the field. For the clinician, this will offer exciting possibilities and novel challenges.

Background: TRC105 is an IgG1 endoglin monoclonal antibody that potentiates VEGF inhibitors in preclinical models. We assessed safety, pharmacokinetics, and antitumor activity of TRC105 in combination with axitinib in patients with metastatic renal cell carcinoma (mRCC)., Subjects, Materials, and Methods: Heavily pretreated mRCC patients were treated with TRC105 weekly (8 mg/kg and then 10 mg/kg) in combination with axitinib (initially at 5 mg b.i.d. and then escalated per patient tolerance to a maximum of 10 mg b.i.d.) until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design., Results: Eighteen patients (median number of prior therapies = 3) were treated. TRC105 dose escalation proceeded to 10 mg/kg weekly without dose-limiting toxicity. Adverse event characteristics of each drug were not increased in frequency or severity when the two drugs were administered concurrently. TRC105 and axitinib demonstrated preliminary evidence of activity, including partial responses (PR) by RECIST in 29% of patients, and median progression-free survival (11.3 months). None of the patients with PR had PR to prior first-line treatment. Lower baseline levels of osteopontin and higher baseline levels of TGF-β receptor 3 correlated with overall response rate., Conclusion: TRC105 at 8 and 10 mg/kg weekly was well tolerated in combination with axitinib, with encouraging evidence of activity in patients with mRCC. A multicenter, randomized phase II trial of TRC105 and axitinib has recently completed enrollment (NCT01806064)., Implications for Practice: TRC105 is a monoclonal antibody to endoglin (CD105), a receptor densely expressed on proliferating endothelial cells and also on renal cancer stem cells that is implicated as a mediator of resistance to inhibitors of the VEGF pathway. In this Phase I trial, TRC105 combined safely with axitinib at the recommended single agent doses of each drug in patients with renal cell carcinoma. The combination demonstrated durable activity in a VEGF inhibitor-refractory population and modulated several angiogenic biomarkers. A randomized Phase II trial testing TRC105 in combination with axitinib in clear cell renal cell carcinoma has completed accrual., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

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.

Renal cell carcinoma (RCC) historically has had limited treatment options in the metastatic setting but in the last decade, a significant arsenal of new therapies has emerged. Specifically, targeted anti-angiogenic therapies through vascular endothelial growth factor (VEGF) inhibition and immunotherapy through PD-1 inhibition have become the foundation of metastatic RCC treatment increasing not only progression-free survival but also an improved overall survival with improved toxicity profiles compared with older therapies such as IL-2 and interferon. With the development of these newer medications, the optimal sequence and pairing of treatments is not yet well understood but important studies are ongoing as this information will allow for more effective and safe treatment of patients.

Use of clinically active agents, such as kinase inhibitors, before nephrectomy is safe and feasible and can decrease the size of primary tumours, enabling optimization of the surgical approach. However, the overall clinical benefit of the neoadjuvant use of toxic drugs, such as axitinib, has not yet been demonstrated.

Introduction: Understanding the molecular pathogenesis of renal cell carcinomas (RCC) has identified targets for therapeutic intervention. The recognition of the importance of hypoxia-inducible factor-1α (HIF-1α) signaling in the pathogenesis of clear-cell RCC has led to widespread study of angiogenesis inhibitors. While the major component of the angiogenic process in RCC is VEGF, targeting of the mTOR pathway is important because activation of the upstream PI3K/Akt/mTOR signaling pathways is one method by which constitutive HIF-1α activation or upregulation occurs., Areas Covered: Current FDA-approved anti-angiogenic agents as first- and second-line treatment for RCC, as well as agents in development will be reviewed., Expert Opinion: Novel agents targeting non-VEGFR signals in kidney cancer will be met with new successes and new challenges in therapeutic development. While several of these agents will likely show activity, they may accentuate toxicity. Careful triage of these agents paired with biomarker studies will facilitate development of these agents and identification of those patients most likely to benefit from these emerging therapies.

The 21st century has seen an explosion in the development of agents for renal-cell carcinoma (RCC), a malignancy previously considered refractory to systemic therapy beyond cytokine therapy. At this time, there are six US Food and Drug Administration (FDA)-approved agents available. In addition, there was a recent favorable review by the FDA's Oncologic Drugs Advisory Committee of a next-generation vascular endothelial growth factor receptor (VEGFR) inhibitor, axitinib (Inlyta); other agents are in advanced testing. Moreover, while VEGF- and mammalian target of rapamycin (mTOR)-targeted therapies have become the mainstay of RCC treatment, other new molecular targets and therapeutic approaches are being developed. The availability of active agents also brings opportunities for additional clinical maneuvers, such as neoadjuvant and adjuvant therapy, as well as a need for decisions on combinatorial therapeutics in the advanced disease setting. Together, these developments and the issues they raise pose important challenges for oncologists and cancer biologists, given the limited number of patients and resources available for studies and the urgent clinical needs of the patients and families affected by RCC.

Purpose: This study assessed the efficacy and safety of linifanib in patients with advanced renal cell carcinoma (RCC) who were previously treated with sunitinib., Materials and Methods: This open-label, multicentre, phase 2 trial of oral linifanib 0.25 mg/kg/day enrolled patients who had prior nephrectomy and adequate organ function. The primary end-point was objective response rate (ORR) per response evaluation criteria in solid tumors (RECIST) by central imaging. Secondary end-points were progression-free survival (PFS), overall survival (OS) and time to progression (TTP). Safety was also assessed., Results: Fifty-three patients, median age 61 years (range 40-80) were enrolled (August 2007 to October 2008) across 12 North-American centres. Median number of prior therapies was 2 (range 1-4); 43 patients (81%) had clear-cell histology. ORR was 13.2%, median PFS was 5.4 months (95% Confidence Interval (CI): 3.6, 6.0) and TTP was the same; median OS was 14.5 months (95% CI: 10.8, 24.1). The most common treatment-related adverse events (AEs) were diarrhoea (74%), fatigue (74%) and hypertension (66%), and the most common treatment-related Grade 3/4 AE was hypertension (40%)., Conclusions: Linifanib demonstrated clinically meaningful activity in patients with advanced RCC after sunitinib failure. At 0.25 mg/kg/day, significant dose modifications were required. An alternative, fixed-dosing strategy is being evaluated in other trials., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objectives: Renal cancer is resistant to most DNA and DNA repair targeted chemotherapy; although moderate response rates to nucleotide analog based therapy have been reported. Bevacizumab also has activity. We thus performed a phase II trial of gemcitabine, capecitabine, and bevacizumab in patients with metastatic renal cancer., Methods: Following significant hematotoxicity, dosing was modified to gemcitabine 1000 mg/m (Days 1, 8), capecitabine 1000 mg twice daily (Days 1-14), and bevacizumab 15 mg/kg (Day 1) on a 21-day cycle with evaluation every 3 cycles. Primary end point was objective response rate., Results: Twenty-nine patients were enrolled between March 2005 and May 2008. Most patients had been previously treated with a vascular endothelial growth factor receptor tyrosine kinase inhibitor. Seven patients (24%) had a partial response. Median overall and progression-free survival were 9.8 months (95% confidence interval: 6.2, 14.9) and 5.3 months (95% confidence interval: 3.9, 9.9), respectively. The regimen was well tolerated with hematologic toxicity, fatigue, and rash being most common., Conclusion: The trial was terminated early despite not meeting criteria for success or futility because of slow accrual and because the historical response rate became irrelevant with emerging data using sequential vascular endothelial growth factor therapies. Nevertheless, the observed progression-free and overall survival compare favorably to other phase II trials in this heavily pretreated population.

Background: A 42-year-old white man with no significant prior medical history presented with macroscopic hematuria of 2 months' duration. His family history was notable for a maternal grandfather with kidney cancer., Investigations: Urinalysis, CT, microscopic examination of tumor, immunohistochemical analysis of tumor, hemoglobin electrophoresis, molecular cytogenetic analysis, gene sequencing., Diagnosis: Renal medullary-like carcinoma in an adult without sickle cell trait, sickle cell disease or other hemoglobinopathies., Management: The patient underwent laparoscopic nephrectomy to remove the tumor and received adjuvant sorafenib (400 mg per day) as part of the E2805 ASSURE (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma) trial. Metastatic recurrence of the tumor occurred 9 months after nephrectomy, for which the patient underwent tumor debulking and retroperitoneal lymph node dissection, followed by chemotherapy consisting of gemcitabine (2,000 mg/m(2)) and doxorubicin (50 mg/m(2)), both given on day 1 of a 14-day cycle. After six cycles of drug treatment, the patient had achieved a partial response. The patient was managed by active surveillance for 4 months, when he developed further symptoms and disease progression was detected. Third-line systemic therapy in the form of 21-day cycles of cisplatin (80 mg/m(2) on day 1) and etoposide (100 mg/m(2) on days 1-3) has recently been initiated.

Background: Cytotoxic chemotherapy has not been well investigated in non-clear-cell renal cell carcinoma (RCC). A phase II study was thus conducted to assess the efficacy of carboplatin and paclitaxel in such patients., Patients and Methods: Patients were treated with carboplatin (area under the curve of 6) and paclitaxel 225 mg/m2 every 21 days and assessed for measurable disease response every 2 cycles. An initial 20 patients were planned to be enrolled to rule out a null hypothesized 15% response rate., Results: Seventeen patients were enrolled, of which 16 patients had papillary and 1 had collecting duct histology. The patient with collecting duct histology had a complete response, but no responses were observed in patients with papillary histology and the trial was thus terminated early. Toxicities were as expected for the carboplatin and paclitaxel regimen., Conclusion: Carboplatin and paclitaxel is not an active regimen in patients with metastatic papillary RCC. Future studies should explore the role of this or similar regimens in collecting duct carcinoma.

Introduction: Ixabepilone (BMS-247550) is a semi-synthetic analog of epothilone B that has been characterized as a microtubule stabilizing agent with a mechanism of action distinct from taxanes. Suggestion of activity in renal cell carcinoma (RCC) has been seen in early clinical studies., Methods: Eligible patients had metastatic RCC as well as ECOG performance status 0-2 and normal organ function. Patients received ixabepilone at a dose of 40 mg/m2 intravenously over three hours every 21 days. There was no restriction on RCC histology or prior treatment type, but prior treatment with tubule inhibitors was not allowed. The primary endpoint was RECIST defined response and radiographic evaluations were performed every three cycles. Toxicity evaluations utilized CTCAE v3.0 and were performed every cycle. Using a Simon two-stage optimal design with alpha = 0.1, beta = 0.1, a null hypothesized response rate of 0.05 and an alternative response rate of 0.2, an initial 12 patients were to be accrued with full accrual of 37 patients if at least one response were observed., Results: A median of five cycles were administered. No objective responses were observed in the first 12 evaluable patients, and six patients showed stable disease for more than 18 weeks on therapy. Median time to progression among those with objective progression was nine weeks. One patient experienced grade 4 anemia and lymphopenia. Grade 3 adverse events included lymphopenia, neutropenia, leukopenia, diarrhea, and infection. Common grade 2 toxicities included alopecia, fatigue and anemia., Conclusion: Ixabepilone administered at a dose of 40 mg/m2 every 21 days should not be advanced for further study in metastatic RCC. Given previous results, however, other dosing schedules may be worthy of further investigation.