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3d
Preclinical • Journal • PD(L)-1 Biomarker • IO biomarker
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • MET (MET proto-oncogene, receptor tyrosine kinase) • FGFR2 (Fibroblast growth factor receptor 2) • FGFR3 (Fibroblast growth factor receptor 3) • FGFR1 (Fibroblast growth factor receptor 1) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • FGFR4 (Fibroblast growth factor receptor 4) • IGF1R (Insulin-like growth factor 1 receptor) • ERBB4 (erb-b2 receptor tyrosine kinase 4) • FLT4 (Fms-related tyrosine kinase 4) • NKX2-1 (NK2 Homeobox 1) • TP63 (Tumor protein 63)
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PD-L1 expression • FGFR1 expression • IGF1R expression • FGFR2 expression • FGFR2b expression • FGFR3 expression • TTF1 negative
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picropodophyllin (AXL1717)
2ms
Hypoxia-induced TIMAP Upregulation in Endothelial Cells and TIMAP-dependent Tumour Angiogenesis. (PubMed, Am J Physiol Cell Physiol)
Conversely, hypoxia and the prolyl hydroxylase inhibitor Roxadustat raised TIMAP mRNA and protein levels by inhibiting the BMP9 pathway...Cultured breast cancer E0771 cells released mediators that raised TIMAP expression in endothelial cells, effects that were inhibited by the VEGF inhibitor Sunitinib in conjunction with the IGF-1 inhibitor Picropodophyllin. In the mouse E0771 breast cancer model in vivo, tumor growth and tumor angiogenesis were markedly attenuated in TIMAP deficient, compared to wild-type littermates. These findings indicate that TIMAP plays a critical pro-angiogenic function during tumor angiogenesis in vivo, likely through hypoxia-driven inhibition of the BMP9 pathway and through elaboration of angiogenic growth factors by tumor cells.
Journal
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IGF1 (Insulin-like growth factor 1) • TGFB1 (Transforming Growth Factor Beta 1)
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sunitinib • Evrenzo (roxadustat) • picropodophyllin (AXL1717)
over1year
Targeting HSP90 with picropodophyllin suppresses gastric cancer tumorigenesis by disrupting the association of HSP90 and AKT. (PubMed, Phytother Res)
Surface plasmon resonance and immunoprecipitation assay validated that PPP directly targets HSP90 and disrupts the binding of HSP90 to AKT, thereby suppressing GC cell proliferation. Thus, our study revealed that PPP may be a promising therapeutic compound for GC treatment.
Journal
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HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
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picropodophyllin (AXL1717)
over1year
Phase I/II Trial of AXL1717 in the Treatment of Recurrent Malignant Astrocytomas (clinicaltrials.gov)
P1/2, N=10, Terminated, Rush University Medical Center | N=30 --> 10 | Unknown status --> Terminated; Investigator went to another institution.
Enrollment change • Trial termination
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picropodophyllin (AXL1717)
2years
LIF-IGF Axis Contributes to the Proliferation of Neural Progenitor Cells in Developing Rat Cerebrum. (PubMed, Int J Mol Sci)
Further, LIF treatment enhanced cultured NPC proliferation, which was reduced by picropodophyllin, an IGF-1 receptor inhibitor, even under LIF supplementation. Our findings suggest that IGF expression and release from the NPCs of the fetal cerebrum in fetal CSF is induced by LIF, thus supporting the involvement of the LIF-IGF axis in cerebral cortical development in an autocrine/paracrine manner.
Preclinical • Journal
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IGF1 (Insulin-like growth factor 1) • IGF2 (Insulin-like growth factor 2) • IR (Insulin receptor)
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picropodophyllin (AXL1717)
2years
Cancer-associated fibroblasts potentiate colorectal cancer progression by crosstalk of the IGF2-IGF1R and Hippo-YAP1 signaling pathways. (PubMed, J Pathol)
IGF2 triggers nuclear accumulation of YAP1 and upregulates YAP1 target signatures, however, these effects were abolished by either IGF1R knockdown or inhibition with PPP (picropodophyllin, an IGF1R inhibitor). Using CRC organoid and in vivo studies, we found that co-targeting IGF1R and YAP1 with PPP and VP (verteporfin, a YAP1 inhibitor) enhanced anti-tumor effects compared with PPP treatment alone...In conclusion, this study revealed a novel molecular mechanism by which CAFs promote CRC progression. The findings highlight the translational potential of the IGF2-IGF1R-YAP1 axis as a prognostic biomarker and therapeutic target for CRC.
Journal
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IGF1R (Insulin-like growth factor 1 receptor) • YAP1 (Yes associated protein 1) • IGF2 (Insulin-like growth factor 2) • DLD (Dihydrolipoamide Dehydrogenase)
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IGF1R expression
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Visudyne (verteporfin) • picropodophyllin (AXL1717)
2years
JNC-1043, a Novel Podophyllotoxin Derivative, Exerts Anticancer Drug and Radiosensitizer Effects in Colorectal Cancer Cells. (PubMed, Molecules)
The objective of this study was to determine whether (5S)-5-(4-benzyloxy-3,5-dimethoxy-phenyl)-5,9-dihydro-8H-furo [3',4':6,7] naphtho [2,3-d] [1,3]dioxol-6-one (JNC-1043), which is a novel chemical derivative of β-apopicropodophyllin, acts as a novel potential anticancer reagent and radiosensitizer in colorectal cancer (CRC) cells...Finally, we found that suppression of ROS by N-acetylcysteine (NAC) blocked the apoptotic cell death induced by the combination of JNC-1043 and IR. The xenograft model also indicated that the combination of JNC-1043 and IR increased apoptotic cell death in tumor mass. These results collectively suggest that JNC-1043 acts as a radiosensitizer and exerts anticancer effects against CRC cells by promoting apoptosis mediated by mitochondrial ROS.
Journal
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ANXA5 (Annexin A5)
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picropodophyllin (AXL1717)
over2years
Survival of HT29 Cancer Cells Is Affected by IGF1R Inhibition via Modulation of Self-DNA-Triggered TLR9 Signaling and the Autophagy Response. (PubMed, Pathol Oncol Res)
HT29 cells were incubated with tumor-originated self-DNA with or without inhibitors of IGF1R (picropodophyllin), autophagy (chloroquine), and TLR9 (ODN2088), respectively. Autophagy, induced by different combinations of self-DNA and inhibitors is not sufficient to rescue HT29 cells from death but results in the survival of some CD133-positive stem-like HT29 cells. The creation of new types of combined IGF1R, autophagy, and/or TLR9 signaling inhibitors would play a significant role in the development of more personalized anti-tumor therapies for colorectal cancer.
Journal
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CD133 positive
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chloroquine phosphate • picropodophyllin (AXL1717)
almost3years
Expression of Insulin-like Growth Factor Type 1 Receptor is Linked to Inflammation in Adamantinomatous Craniopharyngioma. (PubMed, Neuroendocrinology)
Picropodophyllin, a specific inhibitor of IGF1R, increased the expression of p-ERK protein, and decreased the transcription level of interleukin-6...The high expression of IGF1R in tumor cell stem-like cells might inhibit the expression of p-ERK and promote the generation of inflammatory factors. Insulin-like growth factor type 1 receptor plays a stemness maintenance role in ACP and regulates the production of inflammatory factors through a p-ERK pathway, which suggests that targeting IGF1R and p-ERK might provide a new direction for alleviating tumor inflammation.
Journal
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IL6 (Interleukin 6) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • IGF1R (Insulin-like growth factor 1 receptor) • CD44 (CD44 Molecule)
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IGF1R expression • IGF1R overexpression • CD44 expression • CTNNB1 expression • IL6 expression
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picropodophyllin (AXL1717)
3years
Selective elimination of CML stem/progenitor cells by picropodophyllin in vitro and in vivo is associated with p53 activation. (PubMed, Biochem Biophys Res Commun)
The present study demonstrates that picropodophyllin (PPP) effectively induces apoptosis and inhibits colony formation in CML stem/progenitor cells as well as quiescent CML progenitors resistant to imatinib therapy, while sparing normal hematopoietic cells in vitro. Furthermore, PPP treatment preferentially leads to transcriptional activation of p53 in CML but not normal CD34 cells, upregulation of p53 protein in LSCs-enriched Sca-1 cells from CML mice, and increased phosphorylation of p53 and upregulation of Bax protein in Ku812 cells. These results suggest that the inhibitory effects of PPP on CML stem/progenitor cells are associated with selective activation of p53 pathway and propose that PPP is a potent agent that selectively targets CML LSCs, and may be of value in the CML therapy.
Preclinical • Journal
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CD34 (CD34 molecule) • BAX (BCL2-associated X protein)
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imatinib • picropodophyllin (AXL1717)
3years
Thrombolysis by PLAT/tPA increases serum free IGF1 leading to a decrease of deleterious autophagy following brain ischemia. (PubMed, Autophagy)
Interestingly, PLAT/tPA decreases autophagy to mediate neuroprotection by modulating the PI3K-AKT-MTOR pathways both in vitro and in vivo. We identified IGF1R (insulin-like growth factor I receptor; a tyrosine kinase receptor) as the effective receptor and showed in vitro, in vivo and in human stroke patients and that PLAT/tPA is able to degrade IGFBP3 (insulin-like growth factor binding protein 3) to increase IGF1 (insulin-like growth factor 1) bioavailability and thus IGF1R activation.Abbreviations: AKT/protein kinase B: thymoma viral proto-oncogene 1; EGFR: epidermal growth factor receptor; Hx: hypoxia; IGF1: insulin-like growth factor 1; IGF1R: insulin-like growth factor I receptor; IGFBP3: insulin-like growth factor binding protein 3; Ka: Kainate; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK/ERK: mitogen-activated protein kinase; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OGD: oxygen and glucose deprivation; OGD: oxygen and glucose deprivation + reoxygentation; PepA: pepstatin A1; PI3K: phosphoinositide 3-kinase; PLAT/tPA: plasminogen activator, tissue; PPP: picropodophyllin; SCH77: SCH772984; ULK1: unc-51 like kinase 1; Wort: wortmannin.
Journal
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EGFR (Epidermal growth factor receptor) • IGF1 (Insulin-like growth factor 1) • IGFBP3 (Insulin-like growth factor binding protein 3)
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SCH772984 • picropodophyllin (AXL1717)
over3years
IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms. (PubMed, J Immunother Cancer)
Altogether, these results suggest that IGF1R may constitute a novel and druggable therapeutic target for the treatment of cancer in conjunction with chemoimmunotherapies.
Journal • PD(L)-1 Biomarker • IO biomarker
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AKT1 (V-akt murine thymoma viral oncogene homolog 1) • IGF1R (Insulin-like growth factor 1 receptor) • IGF1 (Insulin-like growth factor 1)
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picropodophyllin (AXL1717)
over3years
N-cadherin upregulation mediates adaptive radioresistance in glioblastoma. (PubMed, J Clin Invest)
Mechanistically, elevated N-cadherin expression resulted in the accumulation of β-catenin at the cell surface, which suppressed Wnt/β-catenin proliferative signaling, reduced neural differentiation, and protected against apoptosis through Clusterin secretion. N-cadherin upregulation was induced by radiation-induced IGF1 secretion, and the radiation resistance phenotype could be reverted with picropodophyllin, a clinically applicable blood-brain-barrier permeable IGF1 receptor inhibitor, supporting clinical translation.
Journal
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IGF1 (Insulin-like growth factor 1) • CLU (Clusterin)
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picropodophyllin (AXL1717)
almost4years
Linalool Prevents Cisplatin Induced Muscle Atrophy by Regulating IGF-1/Akt/FoxO Pathway. (PubMed, Front Pharmacol)
In vitro, LIN alleviated DDP induced C2C12 myotube atrophy, and IGF-1 receptor inhibitor Picropodophyllin (PIC), which had no adverse effect on C2C12 myotube cells, could reverse the protective effect of LIN. These results indicate that LIN down-regulates the expression of Atrogin1 and MuRF1 through the IGF-1/Akt/FoxO pathway, alleviating DDP-induced muscle atrophy and improving cachexia symptoms. LIN has the potential to be developed as a drug against cancer cachexia.
Journal
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IGF1 (Insulin-like growth factor 1)
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cisplatin • picropodophyllin (AXL1717)
almost4years
Inhibition of SNCG suppresses the proliferation of lung cancer cells induced by high glucose. (PubMed, Mol Med Rep)
The effect of AXL1717 (an IGF-1R inhibitor) treatment on cells was consistent with that of SNCG knockdown. In conclusion, inhibition of SNCG suppresses proliferation of lung cancer cells induced by high glucose.
Journal
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IGF1 (Insulin-like growth factor 1)
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picropodophyllin (AXL1717)
over4years
Dual inhibition of IGF-IR and ALK as an effective strategy to eradicate NPM-ALK T-cell lymphoma. (PubMed, J Hematol Oncol)
Combined targeting of IGF-IR and ALK is more effective than targeting IGF-IR or ALK alone in NPM-ALK T cell lymphoma. This strategy might also limit emergence of resistance to high doses of ALK inhibitors. Therefore, it could represent a successful therapeutic approach to eradicate this aggressive lymphoma. Importantly, combined inhibition is feasible because of the clinical availability of IGF-IR and ALK inhibitors. Our findings are applicable to other types of cancer where IGF-IR and ALK are simultaneously expressed.
Journal
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ALK (Anaplastic lymphoma kinase) • NPM1 (Nucleophosmin 1)
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ASP-3026 • picropodophyllin (AXL1717)
over4years
Pericyte-secreted IGF2 promotes breast cancer brain metastasis formation. (PubMed, Mol Oncol)
By inhibiting IGF2 signaling using silencing or picropodophyllin (PPP), we could block the proliferation increasing effect of pericytes on breast cancer cells...Taken together, our results indicate that brain pericytes have significant pro-metastatic features, especially in breast cancer. Our study underlines the importance of targeting pericytes and the IGF axis as potential strategies in brain metastatic diseases.
Journal
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IGF2 (Insulin-like growth factor 2)
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picropodophyllin (AXL1717)