Sunitinib-induced hypothyroidism predicts progression-free survival in metastatic renal cell carcinoma patients

Buda-Nowak, Anna; Kucharz, Jakub; Dumnicka, Paulina; Kuźniewski, Marek; Herman, R. M.; Zygulska, Aneta L.; Kuśnierz-Cabała, Beata

doi:10.1007/s12032-017-0928-z

Cited by 36 publications

(27 citation statements)

References 19 publications

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“…Sunitinib treatment resulted in human equivalent grade 2 proteinuria (30–100 mg dL −1 of protein in the urine; 1–2 g per day). The effect of sunitinib on thyroid morphology and function was also assessed to investigate preclinical evidence of clinically reported thyroid AEs . A significant decrease in thyroid epithelial cell height in the thyroids of mice ( N = 3 per group) treated with 40 mg kg −1 sunitinib was observed (Figure C,D).…”

Section: Resultsmentioning

confidence: 99%

Implementing Reverse Phase Protein Array Profiling as a Sensitive Method for the Early Pre‐Clinical Detection of Off‐Target Toxicities Associated with Sunitinib Malate

O’Farrell

Miller

Evans

et al. 2019

Proteomics Clinical Apps

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Purpose: The tyrosine kinase inhibitor (TKI) sunitinib is a multi-targeted agent approved across multiple cancer indications. Nevertheless, since approval, data has emerged to describe a worrisome side effect profile including hypertension, hand-foot syndrome, fatigue, diarrhea, mucositis, proteinuria, and (rarely) congestive heart failure. It has been hypothesized that the observed multi-parameter toxicity profile is related to "on-target" kinase inhibition in "off-target" tissues. Experimental Design: To interrogate off-target effects in pre-clinical studies, a reverse phase protein array (RPPA) approach is employed. Mice are treated with sunitinib (40 mg kg −1 ) for 4 weeks, following which critical organs are removed. The Zeptosens RPPA platform is employed for protein expression analysis. Results: Differentially expressed proteins associated with damage and/or stress are found in the majority of organs from treated animals. Proteins differentially expressed in the heart are associated with myocardial hypertrophy, ischaemia/reperfusion, and hypoxia. However, hypertrophy is not evidenced on histology. Mild proteinuria is observed; however, no changes in renal glomerular structure are visible via electron microscopy. In skin, proteins associated with cutaneous inflammation, keratinocyte hyper-proliferation, and increased inflammatory response are differentially expressed. Conclusions and Clinical Relevance: It is posited that pre-clinical implementation of a combined histopathological/RPPA approach provides a sensitive method to mechanistically elucidate the early manifestation of TKI on-target/organ offtarget toxicities.

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Section: Resultsmentioning

confidence: 99%

Implementing Reverse Phase Protein Array Profiling as a Sensitive Method for the Early Pre‐Clinical Detection of Off‐Target Toxicities Associated with Sunitinib Malate

O’Farrell

Miller

Evans

et al. 2019

Proteomics Clinical Apps

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“…The "preclinical" state is an elevation of circulating TSH with normal range serum T4 and T3 concentrations. An extensive clinical literature documents that response of metastatic RCC to TKIs sorafenib and sunitinib is importantly enhanced when drug-induced hypothyroidism complicates tumor management [28,30,[44][45][46][47][48]. TKIs may cause hypothyroidism in up to 40% of treated patients.…”

Section: Renal Cell Carcinomamentioning

confidence: 99%

Thyroid Hormone Replacement Therapy in Patients with Various Types of Cancer

Hercbergs¹,

Davis²,

Lin³

et al. 2020

Hormone Therapy and Replacement in Cancer and Aging-Related Diseases

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Primary hypothyroidism is a common endocrine disorder that is effectively treated with l-thyroxine (T4) replacement. Preclinical and limited clinical evidence, however, indicates that T4 is a growth factor for a variety of cancers, acting at the thyroid hormone receptor on plasma membrane integrin αvβ3. T4 is the primary ligand for this receptor, whereas 3,5,3′-triiodo-l-thyronine (T3) is the principal intracellular thyroid hormone analogue. The evidence is reviewed here that T4 is a proliferative for breast, lung, kidney and prostate cancers and for glioblastoma, regulates cancer cell respiration and is a pro-angiogenic factor in established tumors. The recommendation is made that T3 be considered alternative replacement treatment for patients with primary hypothyroidism who also have cancer.

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“…21 In other studies, when comparing the PFS and OS between patients developed hypothyroidism or not, researchers are more likely to hold that the occurrence of hypothyroidism can suggest a better prognosis, showing longer PFS and OS. 19,29,[33][34][35][36] As shown in Table 1.…”

Section: The Relationship Between Hypothyroidism and Prognosismentioning

confidence: 99%

<p>Acquired Hypothyroidism in Patients with Metastatic Renal Cell Carcinoma Treated with Tyrosine Kinase Inhibitors</p>

Huang

2020

DDDT

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Purpose: We analyze a number of studies that describe the relationship between the onset of hypothyroidism and the prognosis of patients with metastatic renal cell carcinoma (mRCC) treated with TKIs. Patients and Methods: Targeted therapies are currently considered as the first-line treatment for patients with mRCC. The occurrence of hypothyroidism in the treatment of mRCC with TKIs is a major side effect. A comprehensive search was performed in Pubmed, Cochrane Library, Institute for Scientific Information, and CKNI. The following keywords and descriptors were used during the search and were combined in a number of sequences in English and Chinese languages: protein kinase inhibitors (including sunitinib, pazopanib, tivozanib, cabozantinib, axitinib, sorafenib), hypothyroidism and renal cell carcinoma. Results: Scholars have studied the clinical relationship between hypothyroidism and TKI treatment and its molecular biology mechanism. Most studies hold that hypothyroidism occurring during TKI therapy may serve as potential biomarkers of response and efficacy of treatment, but there is no consensus on this point. Conclusion: The mechanism of hypothyroidism occurring is still unclear. Therefore, more studies are needed to clarify whether better outcomes are associated with TKI-induced hypothyroidism in mRCC patients, helping to maximize the treatment outcome of mRCC patients.

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Sunitinib-induced hypothyroidism predicts progression-free survival in metastatic renal cell carcinoma patients

Cited by 36 publications

References 19 publications

Implementing Reverse Phase Protein Array Profiling as a Sensitive Method for the Early Pre‐Clinical Detection of Off‐Target Toxicities Associated with Sunitinib Malate

Implementing Reverse Phase Protein Array Profiling as a Sensitive Method for the Early Pre‐Clinical Detection of Off‐Target Toxicities Associated with Sunitinib Malate

Thyroid Hormone Replacement Therapy in Patients with Various Types of Cancer

<p>Acquired Hypothyroidism in Patients with Metastatic Renal Cell Carcinoma Treated with Tyrosine Kinase Inhibitors</p>

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