Receptor Tyrosine Kinase Inhibitors for the Treatment of Recurrent and Unresectable Bone Sarcomas

Albarrán, Víctor; Villamayor, María; Chamorro, Jesús; Rosero, Diana; Pozas, Javier; Román-Gil, María San; Calvo, Juan; Aguado, Patricia Pérez de; Moreno, Jaime A.; Guerrero, Patricia; González, Carlos; Quevedo, Coral García de; Ballesteros, Pablo Álvarez; Vaz, María Ángeles

doi:10.3390/ijms232213784

Cited by 15 publications

(12 citation statements)

References 128 publications

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“…Cabozantinib targets VEGFR1/2/3, PDGFR, KIT, MET, RET, and AXL; it also demonstrated preclinical antitumor activity against OS. This TKI enhanced OS cell migration and proliferation via the ERK/AKT signaling pathways [ 58 ]. In clinical trials, cabozantinib increased the PFS to ~7 months [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

“…This TKI enhanced OS cell migration and proliferation via the ERK/AKT signaling pathways [ 58 ]. In clinical trials, cabozantinib increased the PFS to ~7 months [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

“…Although a significant proportion of OS patients achieved temporary disease stabilization, mild responses were achieved with TKIs in monotherapy [ 58 ]. Consistent with these clinical results, our findings reveal that VEGF blockade had a negligible effect on OS migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

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Endothelial Progenitor Cells Promote Osteosarcoma Progression and Invasiveness via AKT/PI3K Signaling

Doppelt-Flikshtain

Younis

Tamari

et al. 2023

Cancers

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Background: Osteosarcoma (OS) mortality is attributed to lung metastases. Endothelial progenitor cells (EPCs) mediate the angiogenic switch in several cancers. The spatial proximity between EPCs and OS in the bone led to the hypothesis that EPCs-osteosarcoma interactions may possibly promote OS progression and aggressiveness. Methods: A PI3K inhibitor, Bevacizumab (an anti-VEGF-A antibody), and an anti-FGF2 antibody were added to the EPCs’ conditioned medium (EPC-CM), and their impacts on OS cell (U2-OS and 143B) proliferation, migration, invasion, MMP9 expression, and AKT phosphorylation were determined. The autocrine role of VEGF-A was assessed using Bevacizumab treatment and VEGF-A silencing in OS cells. Toward this end, an orthotopic mouse OS model was established. Mouse and human tumors were immunolabeled with antibodies to the abovementioned factors. Results: EPC-CM enhanced osteosarcoma MMP9 expression, invasiveness, and migration via the PI3K/AKT pathway. The addition of Bevacizumab and an anti-FGF2 antibody to the EPC-CM diminished OS cell migration. The autocrine role of VEGF-A was assessed using Bevacizumab and VEGF-A silencing in OS cells, resulting in decreased AKT phosphorylation and, consequently, diminished invasiveness and migration. Consistently, OS xenografts in mice displayed high VEGF-A and FGF2 levels. Remarkably, lung metastasis specimens derived from OS patients exhibited marked immunolabeling of CD31, VEGF-A, and FGF2. Conclusions: EPCs promote OS progression not only by physically incorporating into blood vessels, but also by secreting cytokines, which act via paracrine signaling. EPCs induced in vitro MMP9 overexpression, invasion, and migration. Additional animal studies are warranted to further expand these results. These findings may pave the way toward the development of novel EPCs-targeted therapeutics aimed at blocking OS metastasis.

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Section: Discussionmentioning

confidence: 99%

“…This TKI enhanced OS cell migration and proliferation via the ERK/AKT signaling pathways [ 58 ]. In clinical trials, cabozantinib increased the PFS to ~7 months [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

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Endothelial Progenitor Cells Promote Osteosarcoma Progression and Invasiveness via AKT/PI3K Signaling

Doppelt-Flikshtain

Younis

Tamari

et al. 2023

Cancers

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“…In bone sarcomas, dubious results were also observed. In OS, sorafenib treatment blocked cell proliferation and was able to reduce tumor growth in murine models [ 820 , 821 , 822 ]. However, other studies showed that sorafenib was only able to reduce tumor growth when combined with everolimus, or palbociclib, probably due to the capacity of sorafenib to induce mTORC activation [ 821 , 823 ].…”

Section: Kinases As Druggable Targets—evidence and Limitationsmentioning

confidence: 99%

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

et al. 2023

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Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases’ functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.

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“…For all these trials, there are only two main types of OS: soft and solid, as observed in the table. The following active pharmaceutical ingredients (API) are appropriate for OS: topotecan (Tpt) [45], pazopanib (Pzp) [46], placebo (Plb) [47], gemcitabine (Gct) [48], M6620 [49][50], regorafenib (Rgf) [51][52], glembatumumab vedotin (GV) [53][54], lenvatinib [55], etoposide and ifosfamide (EnI) [56], nab-rapamycin (Rpm) [57][58], cyclophosphamide (Cfa) [59], simvastatin (Sim) [60], myeloid growth factor (MGF) [61], nab-paclitaxel [62][63], methotrexate (Mtx) [64], and doxorubicin (Dox) [65]. Besides, the primary tests, such as laboratory biomarker analyses [66] and dose escalation studies [67], were conducted for these successful triumphs.…”

Section: Clinical Advancementmentioning

confidence: 99%

Relationship between Osteosarcoma Therapy and Tumorigenesis, Metastasis, Immune Evasion, and Chemoresistance

Zaidi¹,

Haque²,

Miskon³

2023

Preprint

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There has been no significant efficacy in treatment for osteosarcoma (OS) metastasis after nearly four decades of trials. This motivates us to elucidate OS therapies according to their four bidirectional mutation stages. To refresh the OS therapy status quo, the historical developments and clinical advancements are briefly described. However, the main issue of metastasis remains unresolved, accounting for 90% of pulmonary metastasis deaths. Thus, this metastasis problem is related to immune evasion and chemoresistance that are being induced after long-term treatment by the use of immunotherapy for tumorigenesis. Therefore, it is rationale to discuss the relationship cycles of mutation stages including tumorigenesis, metastasis, immune evasion, and chemoresistance. Even though many combinational and targeted therapies have been developed to intensify these mutation treatments, successful clinical translations with higher cure rates are still rare. Through this review, an in-depth understanding of the bidirectional relationship between the four OS mutation stages and their respective therapies is provided. Herein, we summarise the medicines used to treat tumorigenesis, including COLGALT2 inhibitors, Tra2B, and AGAP1, miR-148a and miR-21-5p EVs, and the lncRNA LIFR-AS1. Following the medicines used to treat metastasis are AXL, miR-135a-5p, mRNA BCL6, TGFβ1, Tim-3, SOCS5, CASC15, KLF3-AS1, PDCD4, ATG5, and Rab22a-NeoF1. Then the medicines used to treat immune evasion are N-cadherin, anti-IL-9, USP12 inhibitor, IgG-4+ B-cells, LAP inhibitor, anti-Wnt2 mAb, anti-αvβ8 integrin, HK2-mediated IκBα, IDO inhibitor with NO, and TGF-βRII with anti-IgG1. Finally, the medicines used to treat chemoresistance are DHFR, FPGS, HSP-90AA1, XCT-790, ATKI, and IGF1. As a result, this contribution is expected to serve as a reference and guide for scientists and clinicians.

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Receptor Tyrosine Kinase Inhibitors for the Treatment of Recurrent and Unresectable Bone Sarcomas

Cited by 15 publications

References 128 publications

Endothelial Progenitor Cells Promote Osteosarcoma Progression and Invasiveness via AKT/PI3K Signaling

Endothelial Progenitor Cells Promote Osteosarcoma Progression and Invasiveness via AKT/PI3K Signaling

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

Relationship between Osteosarcoma Therapy and Tumorigenesis, Metastasis, Immune Evasion, and Chemoresistance

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