Combination therapy for metastatic renal cell carcinoma

Buonerba, Carlo; Lorenzo, Giuseppe Di; Sonpavde, Guru

doi:10.21037/atm.2016.01.31

Cited by 18 publications

(10 citation statements)

References 22 publications

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“…This study suggests that rapalogs in combination with multiple kinase inhibitors may improve therapeutic efficacy for TSC-associated solid tumors. The challenge of combination therapy is the increased toxicity as observed in this study and in sporadic RCC patients treated with both rapalogs and angiogenesis inhibitors together [18]. Lenvatinib is a kinase inhibitor targeting multiple kinases including VEGFR1, VEGFR2, and VEGFR3 and was first approved by the US Food and Drug Administration in 2015 for the treatment of locally recurrent or metastatic thyroid cancer [19].…”

Section: Discussionmentioning

confidence: 88%

Combination of Everolimus with Sorafenib for Solid Renal Tumors in Tsc2+/− Mice Is Superior to Everolimus Alone

et al. 2017

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Tuberous sclerosis (TSC) is an inherited tumor syndrome caused by mutations in TSC1 or TSC2 that lead to aberrant activation of mTOR and development of tumors in multiple organs including the kidneys. The mTOR inhibitors rapamycin and everolimus (rapalogs) have demonstrated clinical efficacy in treating TSC-associated tumors including renal angiomyolipomas. However, tumor responses are usually only partial, and regrowth occurs after drug withdrawal. TSC-associated tumors are highly vascular, and TSC patients with renal angiomyolipomas have elevated levels of circulating vascular endothelial growth factor (VEGF) A and VEGFD. Sorafenib inhibits multiple kinases including VEGF receptors and has been used to treat metastatic epithelioid angiomyolipoma in one case, but formal trials have not been undertaken. In this study, we investigated tumor angiogenesis and the therapeutic efficacy of everolimus in combination with sorafenib for renal tumors in Tsc2+/− mice. We found that these tumors exhibited remarkably variable angiogenesis despite consistent aberrant activation of mTOR and increased expression of HIF1α and VEGFA. Treatment of 11-month-old Tsc2+/− mice for 2 months with a combination of everolimus and sorafenib significantly reduced the number and size of solid renal tumors, whereas everolimus or sorafenib alone did not. These results suggest that inhibition of mTOR and multiple kinases including VEGF receptors using combination therapy could hold promise for the treatment of TSC-associated tumors that have responded inadequately to a rapalog alone.

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Section: Discussionmentioning

confidence: 88%

Combination of Everolimus with Sorafenib for Solid Renal Tumors in Tsc2+/− Mice Is Superior to Everolimus Alone

et al. 2017

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“…Tumor growth was measured by calipers, and mean tumor volumes with SEs presented (n ¼ 10 per group). (42,43). Interestingly, in a DLL4 cellular assay that measures the activity of cell-bound DLL4 to activate the endogenous Notch pathway, ABT-165 exhibited enhanced anti-DLL4 activity in the presence of VEGF, a phenomenon not observed with the parental mAb combinations.…”

Section: Discussionmentioning

confidence: 97%

ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, Demonstrates Superior Efficacy and Favorable Safety Profiles in Preclinical Models

Hickson

Ambrosi

et al. 2018

Molecular Cancer Therapeutics

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Antiangiogenic therapy is a clinically validated modality in cancer treatment. To date, all approved antiangiogenic drugs primarily inhibit the VEGF pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGFindependent angiogenesis and tumor-initiating cell (TIC) survival. A dual-specific biologic targeting both VEGF and DLL4 could be an attractive strategy to improve the effectiveness of anti-VEGF therapy. ABT-165 was uniquely engineered using a proprietary dual-variable domain immunoglobulin (DVD-Ig) technology based on its ability to bind and inhibit both DLL4 and VEGF. In vivo, ABT-165 induced significant tumor growth inhibition compared with either parental antibody treatment alone, due, in part, to the disruption of functional tumor vasculature. In combination with chemotherapy agents, ABT-165 also induced greater antitumor response and outperformed anti-VEGF treatment. ABT-165 displayed nonlinear pharmacokinetic profiles in cynomolgus monkeys, with an apparent terminal half-life > 5 days at a target saturation dose. In a GLP monkey toxicity study, ABT-165 was well-tolerated at doses up to 200 mg/kg with non-adverse treatment-related histopathology findings limited to the liver and thymus. In summary, ABT-165 represents a novel antiangiogenic strategy that potently inhibits both DLL4 and VEGF, demonstrating favorable in vivo efficacy, pharmacokinetic, and safety profiles in preclinical models. Given these preclinical attributes, ABT-165 has progressed to a phase I study.

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“…Thus, in the future, immunotherapy, together with other treatments, will likely cause a paradigm shift in the clinical management of mRCC patients. However, the combination of immunotherapeutic agents does have considerable toxicities such as gastrointestinal and hepatic toxicities, and careful patient selection must be guaranteed [90,91]. Therefore, much more studies must be taken to define the role of combination treatment with immunotherapy agents in mRCC.…”

Section: Combined Therapymentioning

confidence: 99%

Immunotherapy for Renal Cell Carcinoma

Qu¹,

Wu²,

He³

et al. 2020

Evolving Trends in Kidney Cancer

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Despite the rapid development of therapeutic modalities for advanced or metastatic renal cell carcinoma (mRCC) over the past decade to include traditional immunotherapy, such as high-dose interleukin-2 and interferon-α, as well as a number of targeted antiangiogenic therapies, mRCC continues to be associated with poor prognosis. Currently, immunotherapy has seen tremendous development in the form of immune checkpoint inhibition and vaccines at a dizzying pace, which are being studied in mRCC and are showing promise as important steps in the management of this disease. With so many drugs available to clinicians and patients, properly integrating immunotherapy especially immune checkpoint blockade (ICB) into the treatment paradigm is challenging. Emerging research with additional ICB agents and novel combination strategies is likely to further impact clinical decision-making. The further development of biomarkers for predicting a response is required to achieve optimal efficacy with these therapeutic interventions. This chapter summarizes the current landscape of standard and emerging immune therapeutics and other modalities for mRCC.

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Combination therapy for metastatic renal cell carcinoma

Cited by 18 publications

References 22 publications

Combination of Everolimus with Sorafenib for Solid Renal Tumors in Tsc2+/− Mice Is Superior to Everolimus Alone

Combination of Everolimus with Sorafenib for Solid Renal Tumors in Tsc2+/− Mice Is Superior to Everolimus Alone

ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, Demonstrates Superior Efficacy and Favorable Safety Profiles in Preclinical Models

Immunotherapy for Renal Cell Carcinoma

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