IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients

Vewinger, Nadine; Huprich, Sabrina; Seidmann, Larissa; Russo, Alexandra; Alt, Francesca; Bender, Hannah; Sommer, Clemens; Samuel, David; Lehmann, Nadine; Backes, Nora; Roth, Lea; Harter, Patrick N.; Filipski, Katharina; Faber, Jörg; Paret, Claudia

doi:10.3390/ijms20123027

Cited by 18 publications

(23 citation statements)

References 35 publications

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“…A recent study also demonstrates that ceritinib inhibits InsR phosphorylation and induces tumor regression in a pediatric patient with an unclassified brain tumor [204]. Another study suggests that IGF-IR is as an attractive target for treating patients with BCOR-alternated highgrade neuroepithelial tumor of the central nervous system [205]. It is worthwhile to ensure whether ceritinib can be repurposed to treat IGF-IR-activated cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Rather than targeting IGF-IR/InsR themselves, an alternative strategy would be inhibition of the master regulators of RTKs or downstream signaling hubs such as IRS1/2 [205][206][207][208]. Moreover, IGF-IR has kinaseindependent functions, such as nuclear translocation and regulation of gene expression, and interaction with SGLT1 to maintain intracellular glucose levels [209].…”

Section: Discussionmentioning

confidence: 99%

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Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy

et al. 2020

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Insulin-like growth factors (IGFs) play important roles in mammalian growth, development, aging, and diseases. Aberrant IGFs signaling may lead to malignant transformation and tumor progression, thus providing the rationale for targeting IGF axis in cancer. However, clinical trials of the type I IGF receptor (IGF-IR)-targeted agents have been largely disappointing. Accumulating evidence demonstrates that the IGF axis not only promotes tumorigenesis, but also confers resistance to standard treatments. Furthermore, there are diverse pathways leading to the resistance to IGF-IR-targeted therapy. Recent studies characterizing the complex IGFs signaling in cancer have raised hope to refine the strategies for targeting the IGF axis. This review highlights the biological activities of IGF-IR signaling in cancer and the contribution of IGF-IR to cytotoxic, endocrine, and molecular targeted therapies resistance. Moreover, we update the diverse mechanisms underlying resistance to IGF-IR-targeted agents and discuss the strategies for future development of the IGF axis-targeted agents.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy

et al. 2020

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“…Internal tandem duplications in the C-terminus of BCOR in CNS-HGNET-BCOR tumors exhibit upregulation of IGF2 (Vewinger et al 2019), suggesting that suppression of IGF2 expression may be a general feature of BCOR function across pediatric brain tumor entities. Importantly, CNS-HGNET-BCOR tumors exhibit aberrant activation of the SHH pathway (Paret et al 2016), suggesting that both SHH pathway activation and BCOR aberrations cooperate to activate IGF2, similar to our Ptch1+/-;Bcor ΔE9-10 tumors.…”

Section: Igf2 Overexpression May Be a General Feature Of Bcor Alteredmentioning

confidence: 99%

Functional loss of a non-canonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation

Kutscher

Okonechnikov

Batora

et al. 2020

Preprint

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Medulloblastoma is a childhood brain tumor arising from the developing cerebellum. In Sonic Hedgehog (SHH)-subgroup medulloblastoma, aberrant activation of SHH signaling causes increased proliferation of granule neuron progenitors (GNPs) and predisposes these cells to tumorigenesis. A second, cooperating genetic hit is often required to push these hyperplastic cells to malignancy and confer mutation-specific characteristics associated with oncogenic signaling. Somatic loss-of-function mutations of the transcriptional co-repressor BCOR are recurrent and highly enriched in SHH-medulloblastoma. To investigate BCOR as a putative tumor suppressor, we used a germline genetically engineered mouse model to delete exons 9/10 of Bcor (BcorΔE9-10) in GNPs during development. This leads to reduced expression of C-terminally truncated BCOR (BCORΔE9-10). While BcorΔE9-10 alone did not promote tumorigenesis or affect GNP differentiation, BcorΔE9-10 combined with loss of the SHH-receptor gene Ptch1 resulted in highly penetrant medulloblastomas. In Ptch1+/-;BcorΔE9-10 tumors, the growth factor gene Igf2 was aberrantly upregulated, and ectopic Igf2 overexpression was sufficient to drive tumorigenesis in Ptch1+/- GNPs. BCOR directly regulates Igf2, likely through the PRC1.1 complex; the repressive histone mark H2AK119Ub is decreased at the Igf2 promoter in Ptch1+/-;BcorΔE9-10 tumors. Overall, our data suggests that BCOR-PRC1.1 disruption leads to Igf2 overexpression, which transforms preneoplastic cells to malignant tumors.

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“…Overexpression [7] and mutations [8] in members of the IGF pathway in OS have been described but neither small molecule inhibitors nor monoclonal antibodies have been approved by the US Food and Drug Administation (FDA) so far. However, we have recently shown that the IGF pathway can be targeted in vitro and in vivo using ceritinib [9,10]. Ceritinib is approved for the treatment of patients with Anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) but can also inhibit the insulin receptor (INSR), the insulin-like growth factor 1 receptor (IGF1R) and ROS proto-oncogene 1 (ROS1) [11].…”

Section: Introductionmentioning

confidence: 99%

Safety and Activity of the Combination of Ceritinib and Dasatinib in Osteosarcoma

Beck

Paret

Russo

et al. 2020

Cancers

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Osteosarcoma (OS) is the second most common cause of cancer-related death in pediatric patients. The insulin-like growth factor (IGF) pathway plays a relevant role in the biology of OS but no IGF targeted therapies have been successful as monotherapy so far. Here, we tested the effect of three IGF specific inhibitors and tested ceritinib as an off-target inhibitor, alone or in combination with dasatinib, on the proliferation of seven primary OS cells. Picropodophyllin, particularly in combination with dasatinib and the combination ceritinib/dasatinib were effective in abrogating the proliferation. The ceritinib/dasatinib combination was applied to the primary cells of a 16-year-old girl with a long history of lung metastases, and was more effective than cabozantinib and olaparib. Therefore, the combination was used to treat the patient. The treatment was well tolerated, with toxicity limited to skin rush and diarrhea. A histopathological evaluation of the tumor after three months of therapy indicated regions of high necrosis and extensive infiltration of macrophages. The extension of the necrosis was proportional to the concentration of dasatinib and ceritinib in the area, as analysed by an ultra performance liquid chromatography–tandem mass spectrometer (UPLC-MS/MS). After the cessation of the therapy, radiological analysis indicated a massive growth of the patient’s liver metastases. In conclusion, these data indicate that the combination of ceritinib/dasatinib is safe and may be used to develop new therapy protocols.

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IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients

Cited by 18 publications

References 35 publications

Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy

Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy

Functional loss of a non-canonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation

Safety and Activity of the Combination of Ceritinib and Dasatinib in Osteosarcoma

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