Pexidartinib: First Approval

Lamb, Yvette N.

doi:10.1007/s40265-019-01210-0

Cited by 157 publications

(111 citation statements)

References 25 publications

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“…c-KIT tyrosine kinase signaling is involved in several cellular functions such as cell proliferation and survival and plays a decisive role inter alia in hematopoiesis and melanogenesis. c-KIT acts as proto-oncogene in tumors and pharmacological inhibitors of the c-KIT axis are used for therapeutic interventions 28 . Besides the oncologic importance of c-KIT signaling, few studies exist on the importance of c-KIT in the pulmonary and cardiovascular field.…”

Section: Discussionmentioning

confidence: 99%

Blood-based protein profiling identifies serum protein c-KIT as a novel biomarker for hypertrophic cardiomyopathy

Sonnenschein

Fiedler

Gonzalo-Calvo

et al. 2021

Sci Rep

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Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary heart diseases and can be classified into an obstructive (HOCM) and non-obstructive (HNCM) form. Major characteristics for HCM are the hypertrophy of cardiomyocytes and development of cardiac fibrosis. Patients with HCM have a higher risk for sudden cardiac death compared to a healthy population. In the present study, we investigated the abundancy of selected proteins as potential biomarkers in patients with HCM. We included 60 patients with HCM and 28 healthy controls and quantitatively measured the rate of a set of 92 proteins already known to be associated with cardiometabolic processes via protein screening using the proximity extension assay technology in a subgroup of these patients (20 HCM and 10 healthy controls). After validation of four hits in the whole cohort of patients consisting of 88 individuals (60 HCM patients, 28 healthy controls) we found only one candidate, c-KIT, which was regulated significantly different between HCM patients and healthy controls and thus was chosen for further analyses. c-KIT is a tyrosine-protein kinase acting as receptor for the stem cell factor and activating several pathways essential for cell proliferation and survival, hematopoiesis, gametogenesis and melanogenesis. Serum protein levels of c-KIT were significantly lower in patients with HCM than in healthy controls, even after adjusting for confounding factors age and sex. In addition, c-KIT levels in human cardiac tissue of patients with HOCM were significant higher compared to controls indicating high levels of c-KIT in fibrotic myocardium. Furthermore, c-KIT concentration in serum significantly correlated with left ventricular end-diastolic diameter in HOCM, but not HCM patients. The present data suggest c-KIT as a novel biomarker differentiating between patients with HCM and healthy population and might provide further functional insights into fibrosis-related processes of HOCM.

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Section: Discussionmentioning

confidence: 99%

Blood-based protein profiling identifies serum protein c-KIT as a novel biomarker for hypertrophic cardiomyopathy

Sonnenschein

Fiedler

Gonzalo-Calvo

et al. 2021

Sci Rep

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“…In a syngeneic mouse model of melanoma, pexidartinib, a potent inhibitor of the CSF-1 receptor (CSF-1R), conferred anti-tumoral response associated with TAMs reduction ( Mok et al, 2014 ; Figure 2F ). Pexidartinib is approved for the treatment of tenosynovial giant cell tumor ( Lamb, 2019 ) and is currently being tested in several clinical trials, none of them for SCC but with great potential ( Benner et al, 2020 ). CCL2, also known as MCP-1, is another monocyte chemoattractant that promotes carcinogenesis by recruiting TAMs and inducing immune evasion through PD-1 signaling ( Yang et al, 2020 ; Figure 2E ).…”

Section: Evasion Of the Immune Response: Potential Targets For Immunomentioning

confidence: 99%

The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

Amôr

Santos

Campanelli

2021

Front. Cell Dev. Biol.

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Squamous cell carcinoma (SCC) is the second most common skin cancer worldwide and, despite the relatively easy visualization of the tumor in the clinic, a sizeable number of SCC patients are diagnosed at advanced stages with local invasion and distant metastatic lesions. In the last decade, immunotherapy has emerged as the fourth pillar in cancer therapy via the targeting of immune checkpoint molecules such as programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). FDA-approved monoclonal antibodies directed against these immune targets have provide survival benefit in a growing list of cancer types. Currently, there are two immunotherapy drugs available for cutaneous SCC: cemiplimab and pembrolizumab; both monoclonal antibodies (mAb) that block PD-1 thereby promoting T-cell activation and/or function. However, the success rate of these checkpoint inhibitors currently remains around 50%, which means that half of the patients with advanced SCC experience no benefit from this treatment. This review will highlight the mechanisms by which the immune checkpoint molecules regulate the tumor microenvironment (TME), as well as the ongoing clinical trials that are employing single or combinatory therapeutic approaches for SCC immunotherapy. We also discuss the regulation of additional pathways that might promote superior therapeutic efficacy, and consequently provide increased survival for those patients that do not benefit from the current checkpoint inhibitor therapies.

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“…PLX3397 was designed to stabilize CSF-1R in the auto-inhibited state by interacting with the CSF-1R juxtamembrane region, thus resulting in the inactivation of the kinase domain and the prevention of CSF-1 and adenosine triphosphate (ATP) binding [ 66 ]. The oral administration of PLX3397 (Turalio ® ) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of unresectable tenosynovial giant cell tumor, which is a rare and locally aggressive non-malignant tumor that overexpresses CSF-1 [ 67 , 68 , 69 ]. This drug is currently under investigation with sirolimus in a phase I/II trial for unresectable sarcomas, including Ewing’s sarcoma, liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma, and rhabdomyosarcoma (NCT02584647).…”

Section: Therapeutic Trials Targeting Tams In Sarcomasmentioning

confidence: 99%

“…The presumed hurdle of targeting TAMs could be drug toxicity, since the systemic depletion of macrophages may lead to increased infections or impaired tissue-resident macrophages [ 104 ]. In a phase II trial of PLX3397 for tenosynovial giant cell tumor, treatment-emergent adverse events resulted in permanent treatment discontinuation in 13% of PLX3397 recipients, in whom most of these adverse events were hepatotoxicity [ 68 , 105 ]. These findings underscore the necessity for the development of a novel approach that reduces the toxicity of TAM-targeted drugs.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Role of Tumor-Associated Macrophages in Sarcomas

Fujiwara

Healey

Yoshida

et al. 2021

Cancers

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Sarcomas are complex tissues in which sarcoma cells maintain intricate interactions with their tumor microenvironment. Tumor-associated macrophages (TAMs) are a major component of tumor-infiltrating immune cells in the tumor microenvironment and have a dominant role as orchestrators of tumor-related inflammation. TAMs promote tumor growth and metastasis, stimulate angiogenesis, mediate immune suppression, and limit the antitumor activity of conventional chemotherapy and radiotherapy. Evidence suggests that the increased infiltration of TAMs and elevated expression of macrophage-related genes are associated with poor prognoses in most solid tumors, whereas evidence of this in sarcomas is limited. Based on these findings, TAM-targeted therapeutic strategies, such as inhibition of CSF-1/CSF-1R, CCL2/CCR2, and CD47/SIRPα, have been developed and are currently being evaluated in clinical trials. While most of the therapeutic challenges that target sarcoma cells have been unsuccessful and the prognosis of sarcomas has plateaued since the 1990s, several clinical trials of these strategies have yielded promising results and warrant further investigation to determine their translational benefit in sarcoma patients. This review summarizes the roles of TAMs in sarcomas and provides a rationale and update of TAM-targeted therapy as a novel treatment approach for sarcomas.

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Pexidartinib: First Approval

Cited by 157 publications

References 25 publications

Blood-based protein profiling identifies serum protein c-KIT as a novel biomarker for hypertrophic cardiomyopathy

Blood-based protein profiling identifies serum protein c-KIT as a novel biomarker for hypertrophic cardiomyopathy

The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

Role of Tumor-Associated Macrophages in Sarcomas

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