A Comprehensive Overview of Targeted Therapy in Metastatic Renal Cell Carcinoma

Mihály, Zsuzsanna; Sztupinszki, Zsófia; Surowiak, Paweł; Győrffy, Balázs

doi:10.2174/156800912802429265

Cited by 50 publications

(40 citation statements)

References 98 publications

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“…Since 2005, seven targeted agents have been approved by regulatory authorities for various uses in advanced RCC or mRCC patients. 24 However, the response rates (<50%) and increased length of progression-free survival (≤6 months) for these agents are far from satisfactory. 24 In particular, the objective response rate in mRCC for temsirolimus is low, and patients rapidly develop resistance.…”

Section: Discussionmentioning

confidence: 99%

Preclinical trial of a new dual mTOR inhibitor, MLN0128, using renal cell carcinoma tumorgrafts

et al. 2013

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mTOR is a rational target in renal cell carcinoma (RCC) because of its role in disease progression. However, the effects of temsirolimus, the only first-generation mTOR inhibitor approved by the FDA for first-line treatment of metastatic RCC, on tumor reduction and progression-free survival are minimal. Second-generation mTOR inhibitors have not been evaluated on RCC. We compared the effects of temsirolimus and MLN0128, a potent second-generation mTOR inhibitor, on RCC growth and metastasis using a realistic patient-derived tissue slice graft (TSG) model. TSGs were derived from three fresh primary RCC specimens by subrenal implantation of precision-cut tissue slices into immunodeficient mice that were randomized and treated with MLN0128, temsirolimus, or placebo. MLN0128 consistently suppressed primary RCC growth, monitored by magnetic resonance imaging (MRI), in three TSG cohorts for up to 2 months. Temsirolimus, in contrast, only transiently inhibited the growth of TSGs in one of two cohorts before resistance developed. In addition, MLN0128 reduced liver metastases, determined by human-specific quantitative polymerase chain reaction, in two TSG cohorts, whereas temsirolimus failed to have any significant impact. Moreover, MLN0128 decreased levels of key components of the two mTOR subpathways including TORC1 targets 4EBP1, p-S6K1, HIF1α and MTA1 and the TORC2 target c-Myc, consistent with dual inhibition. Our results demonstrated that MLN0128 is superior to temsirolimus in inhibiting primary RCC growth as well as metastases, lending strong support for further clinical development of dual mTOR inhibitors for RCC treatment.

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Section: Discussionmentioning

confidence: 99%

Preclinical trial of a new dual mTOR inhibitor, MLN0128, using renal cell carcinoma tumorgrafts

et al. 2013

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“…Sunitinib, a tyrosine kinase inhibitor, and other targeted systemic therapies have become the standard of care for mrcc 10 . These agents significantly prolong progression-free survival and overall survival, and improve quality of life for patients with mrcc 11 . Patient 1 responded well to treatment, displaying disease regression with minimal side effects.…”

Section: Discussionmentioning

confidence: 99%

Metastatic Renal Cell Carcinoma without Evidence of a Primary Renal Tumour

et al. 2014

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new cases of rcc and 13,500 deaths every year are attributed to this type of renal cancer 1 . In recent decades, the incidence of rcc has been increasing, and the average tumour size at diagnosis has been declining 2 . Those trends are partially attributable to the widespread use of noninvasive abdominal imaging modalities, which have allowed for more incidental findings of asymptomatic tumours. Renal cell carcinoma is about 50% more common in men than in women, and it is unusual in patients under 40 years of age 1 . Several distinct subtypes of rcc have been identified, including the clear cell, papillary, chromophobe, and collecting duct variants 3 . Clear cell rcc, the most common subtype, accounts for 75% of all rcc tumours 2 .Metastatic rcc (mrcc) generally presents with evidence of a primary renal mass, except in cases of metachronous mrcc after nephrectomy for rcc. Here, we present two unusual cases of metastatic clear cell rcc with no evidence of a primary renal tumour. CASE DESCRIPTIONS Patient 1A 70-year-old man was admitted for a fall-induced hip fracture and subsequently underwent arthroplasty. He was readmitted to hospital 8 months later for hypercalcemia and confusion. At that time, computerized tomography (ct) imaging showed bilateral native kidneys in situ; bony lesions in the left scapula, seventh right rib, fifth left rib, and left sternoclavicular joint; and two nodules in the upper lobe of the left lung. There was also destruction of the left pubo-iliac bone from a multi-lobulated lesion (measuring 11 cm) replacing bone, and no evidence of soft-tissue disease (Figure 1).An ABSTRACTAlthough metastases are common in patients with renal cell carcinoma (rcc), it is extremely rare for patients to present with metastatic rcc (mrcc) without evidence of a primary mass in the kidney. Two cases of mrcc with no detectable primary renal mass are reported here. Both patients had bilateral native kidneys in situ and no significant prior urologic history. The first patient presented with a hip fracture and was found to have multiple radiologic bony and lung metastases. Biopsy of a mass involving the pubic bone demonstrated clear cell mrcc. Multiple scans by computed tomography (ct) and confirmatory imaging by magnetic resonance demonstrated no renal mass. This first patient had disease stabilization for 18 months on sunitinib and was still alive at last follow-up. The second patient was diagnosed with clear-cell mrcc after thickened synovium was discovered and biopsied during a knee arthroplasty. Multiple scans by ct in this second patient demonstrated no primary renal mass. Sunitinib and radiotherapy to the knee lesion were initiated, but unfortunately, the patient deteriorated clinically and passed away from disease progression shortly after diagnosis. Because of the rare nature of these cases, a standardized course of action has not yet been established. However, we hypothesize that it is reasonable to manage metastases in these patients by following established mrcc protocols. KEY WORDSMetastatic renal...

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“…Temsirolimus (Torisel, Pfizer) was FDA approved in 2007 because of its ability to increase overall and progression-free survival in patients with advanced RCC, particularly in patients with non-clear cell histology [84,85]. The orally administered mammalian target of rapamycin inhibitor Everolimus (Afinitor, Novartis) first received FDA approval in 2009 for the treatment of advanced RCC and has since received FDA approval for multiple cancers, including subependymal giant cell astrocytoma, advanced hormone receptorpositive ERBB2-negative breast cancer, and pancreatic neuroendocrine tumors.…”

Section: Renal Cell Carcinoma: Mammalian Target Of Rapamycin Inhibitorsmentioning

confidence: 99%

Beyond the Vascular Endothelial Growth Factor Axis: Update on Role of Imaging in Nonantiangiogenic Molecular Targeted Therapies in Oncology

Howard

Rosenthal

Jagannathan

et al. 2015

American Journal of Roentgenology

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A Comprehensive Overview of Targeted Therapy in Metastatic Renal Cell Carcinoma

Cited by 50 publications

References 98 publications

Preclinical trial of a new dual mTOR inhibitor, MLN0128, using renal cell carcinoma tumorgrafts

Preclinical trial of a new dual mTOR inhibitor, MLN0128, using renal cell carcinoma tumorgrafts

Metastatic Renal Cell Carcinoma without Evidence of a Primary Renal Tumour

Beyond the Vascular Endothelial Growth Factor Axis: Update on Role of Imaging in Nonantiangiogenic Molecular Targeted Therapies in Oncology

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