- |||||||||| oxaliplatin / Generic mfg., picropodophyllin (AXL1717) / Axelar
Journal: Picropodophyllin, an IGF?1 receptor inhibitor, enhances oxaliplatin efficacy in chemoresistant colorectal cancer HCT116 cells by reducing metastatic potential. (Pubmed Central) - Mar 19, 2025
Immunofluorescence staining revealed that this combination also significantly increased E-cadherin expression, by 1.37- and 1.63-fold, respectively (P<0.05), indicating the role of PPP in enhancing epithelial characteristics and reducing EMT-related drug resistance. These findings highlight the potential for combining PPP with OX to enhance the cytotoxic and anti-metastatic effects of OX in chemo-resistant CRC cells, thus offering a promising strategy for overcoming drug resistance and improving patient outcomes in CRC treatment.
- |||||||||| picropodophyllin (AXL1717) / Axelar
Preclinical, Journal: Interaction with IGF1 overrides ANXA2-mediated anti-inflammatory functions of IGFBP5 in vivo. (Pubmed Central) - Jan 27, 2025
An IGF1R inhibitor picropodophyllin antagonized functions of IGF1/IGF1R too, but didn't reinforce the effects of IGFBP5. IGFBP5 eases inflammation by interacting with ANXA2, an activator of NF-?B; as an antagonist of IGF1/IGF1R, IGFBP5 may disrupt immune homeostasis in vivo, due to impairment of the latter's anti-inflammatory functions; excessive IGFBP from adipocytes would be a pathogenic factor in certain diseases.
- |||||||||| picropodophyllin (AXL1717) / Axelar
Preclinical, Journal, PD(L)-1 Biomarker, IO biomarker: Establishing a new human lung squamous cell carcinoma cell line, OMUL-1, expressing insulin-like growth factor 1 receptor and programmed cell death ligand 1. (Pubmed Central) - Jan 13, 2025
IGFBP5 eases inflammation by interacting with ANXA2, an activator of NF-?B; as an antagonist of IGF1/IGF1R, IGFBP5 may disrupt immune homeostasis in vivo, due to impairment of the latter's anti-inflammatory functions; excessive IGFBP from adipocytes would be a pathogenic factor in certain diseases. We developed a novel new squamous cell lung carcinoma cell line, OMUL-1, that expresses IGF1R and PD-L1.
- |||||||||| picropodophyllin (AXL1717) / Axelar, Evrenzo (roxadustat) / FibroGen, sunitinib / Generic mfg.
Journal: Hypoxia-induced TIMAP Upregulation in Endothelial Cells and TIMAP-dependent Tumour Angiogenesis. (Pubmed Central) - Nov 13, 2024
Conversely, hypoxia and the prolyl hydroxylase inhibitor Roxadustat raised TIMAP mRNA and protein levels by inhibiting the SMAD1/5/8 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.
- |||||||||| picropodophyllin (AXL1717) / Axelar
TLR9-dependent autophagy and IGF1R inhibition affect apoptosis and stem cell phenotype in the HT29 cell line (Sydney) - Oct 13, 2024 - Abstract #DGHO2024DGHO_686;
Co-inhibition of TLR9-mediated autophagy and IGF1R signaling by increasing the Bax/Bcl2 ratio substantially enhances the apoptosis sensitivity of HT29 cells (high Bax/Bcl-2 ratio, increased caspase 3, 8, and 9 activity). At the same time, MAPK/NF-kB activation may contribute to the survival of CD133+ stem cell phenotype HT29 cells.
- |||||||||| picropodophyllin (AXL1717) / Axelar
Preclinical, Journal: Caffeic acid and diabetic neuropathy: Investigating protective effects and insulin-like growth factor 1 (IGF-1)-related antioxidative and anti-inflammatory mechanisms in mice. (Pubmed Central) - Jul 8, 2024
Additionally, to determine the specific contribution of IGF-1 signaling to the observed benefits, IGF1R inhibitor Picropodophyllin (PPP) was co-administered with caffeic acid...Our findings delineate the capability of caffeic acid to mitigate DN symptoms, particularly through reducing spinal oxidative stress and inflammation, and pinpoint the integral role of IGF-1 signaling in these protective mechanisms. The insights gleaned from this study not only position caffeic acid as a promising dietary adjunct for managing diabetic neuropathy but also highlight the therapeutic potential of targeting spinal IGF-1 signaling as part of a strategic treatment approach.
- |||||||||| LY294002 / Eli Lilly, picropodophyllin (AXL1717) / Axelar
Preclinical, Journal: Suppression of overactive IGF-1 attenuates trauma-induced heterotopic ossification in mice. (Pubmed Central) - Feb 19, 2024
Inhibitors of PI3K (LY294002) and mTOR (Rapamycin) both suppressed the IGF-1-stimulated mTOR signal and mitigated the formation of ectopic bones significantly. In conclusion, our results indicated that IGF-1 mediated the progression of traumatic HO through PI3K/Akt/mTOR signaling, and suppressing IGF-1 signaling cascades attenuated HO formation, providing a promising therapeutic strategy targeting HO.
- |||||||||| Tabrecta (capmatinib) / Incyte, Novartis, picropodophyllin (AXL1717) / Axelar
ANALYSIS OF SIGNALING PATHWAYS THAT CONTROL PROGENITOR EPITHELIAL CELL PROLIFERATION & DIFFERENTIATION USING HUMAN LUNG ORGANOIDS (Rehearsal Room (Sunset Center)) - Dec 13, 2023 - Abstract #WRMC2024WRMC_159;
The studies using the distal lung tips that contain pluripotent progenitor cells demonstrate that at least some of the functional findings regarding the role of IGF1 and HGF signaling pathways in niche-epithelial cell cross-communication may be conserved between mouse and human. Current studies are underway to elucidate the function of this cross-communication in more detail.
- |||||||||| picropodophyllin (AXL1717) / Axelar
Enrollment change, Trial termination: Phase I/II Trial of AXL1717 in the Treatment of Recurrent Malignant Astrocytomas (clinicaltrials.gov) - May 22, 2023
P1/2, N=10, Terminated,
Thus, our study revealed that PPP may be a promising therapeutic compound for GC treatment. N=30 --> 10 | Unknown status --> Terminated; Investigator went to another institution.
- |||||||||| picropodophyllin (AXL1717) / Axelar
Preclinical, Journal: LIF-IGF Axis Contributes to the Proliferation of Neural Progenitor Cells in Developing Rat Cerebrum. (Pubmed Central) - Nov 16, 2022
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.
- |||||||||| picropodophyllin (AXL1717) / Axelar, Visudyne (verteporfin) / Novartis
Journal: Cancer-associated fibroblasts potentiate colorectal cancer progression by crosstalk of the IGF2-IGF1R and Hippo-YAP1 signaling pathways. (Pubmed Central) - Nov 15, 2022
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.
- |||||||||| picropodophyllin (AXL1717) / Axelar, Vonjo (pacritinib) / CTI BioPharma
Journal: Cytochrome P450 27C1 Level Dictates Lung Cancer Tumorigenicity and Sensitivity towards Multiple Anticancer Agents and Its Potential Interplay with the IGF-1R/Akt/p53 Signaling Pathway. (Pubmed Central) - Jul 29, 2022
In addition, aberrant IGF-1R/Akt/p53 signal transduction was also detected in stable CYP27C1-knockdown human lung cancer cells, which exhibited greater tolerance towards the treatments of anticancer agents (including vinorelbine, picropodophyllin, pacritinib, and SKLB610). This work, for the first time, reveals that CYP27C1 impacts lung cancer cell development by participating in the regulation of the IGF-1R/Akt/p53 signaling pathway, and the level of CYP27C1 plays indispensable roles in dictating the cellular sensitivity towards multiple anticancer agents.
- |||||||||| picropodophyllin (AXL1717) / Axelar, SCH772984 / Otsuka
Journal: Thrombolysis by PLAT/tPA increases serum free IGF1 leading to a decrease of deleterious autophagy following brain ischemia. (Pubmed Central) - Jun 22, 2022
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.
- |||||||||| FR900359 / Sidney Kimmel Cancer Center, Thomas Jefferson University, Icahn School of Medicine at Mount Sinai, picropodophyllin (AXL1717) / Axelar
Journal: The application of natural compounds in uveal melanoma drug discovery. (Pubmed Central) - May 26, 2022
The molecular mechanisms underpinning the anti-UM properties of these compounds remain largely undefined. Further studies are required to evaluate the in-vivo anticancer activity, appropriate dosage regimen and safety of natural compounds that could be developed for use in UM.
- |||||||||| picropodophyllin (AXL1717) / Axelar
Preclinical, Journal: Exogenous IGF-1 improves tau pathology and neuronal pyroptosis in high-fat diet mice with cognitive dysfunction. (Pubmed Central) - Apr 8, 2022
During in vitro experiment, C57BL/6J mice were fed with high-fat diet, and were treated with PEG-IGF-1, IGF-1 receptor blocker AXL1717, HO-1 blocker Znpp IX or their combinations...During in vivo experiment, inhibition of pyroptosis using nonecrosulfonamide improved tau pathology in palmitic acid-treated HN-h cells. Exogenous IGF-1 improved tau pathology induced by high-fat diet through inhibition of neuronal pyroptosis and activation of Nrf2/HO-1 signaling pathway.
- |||||||||| picropodophyllin (AXL1717) / Axelar
Novel β-Apopicropodophyllin derivative, JNC-1043, exerts anti-cancer and radiosensitizing effects (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_7757;
In vivo xenograft experiment, combination of JNC-1043 and IR reduced tumor sizes less 50 % and increased apoptosis more 30~40% than those of JNC-1043 only- or IR only-treatment. These results implied anti-cancer and radiosensitizing effect of JNC-1043 resulted from promotion of apoptosis via enhancement of ROS production.
- |||||||||| picropodophyllin (AXL1717) / Axelar
N-cadherin is a driver of adaptive radioresistance in malignant brain tumors (Section 1) - Mar 9, 2022 - Abstract #AACR2022AACR_4318;
The N-cadherin-mediated radioresistance phenotype could be reverted with picropodophyllin (PPP), a clinically applicable blood-brain-barrier permeable IGF1 receptor inhibitor...These findings also confirmed that our radioresistant models effectively identify new adaptive resistance mechanisms in malignant brain tumors. (
- |||||||||| picropodophyllin (AXL1717) / Axelar, linsitinib (ASP7487) / Astellas
Journal: Autophagy induction by IGF1R inhibition with picropodophyllin and linsitinib. (Pubmed Central) - Jan 18, 2022
Moreover, in human triple-negative breast cancer, phosphorylation of IGF1R correlates with reduced autophagy, an unfavorable local immune profile and poor prognosis. In summary, IGF1R inhibition may constitute a novel strategy for the treatment of cancer in the context of chemoimmunotherapy.
- |||||||||| picropodophyllin (AXL1717) / Axelar
Preclinical, Journal: Selective elimination of CML stem/progenitor cells by picropodophyllin in vitro and in vivo is associated with p53 activation. (Pubmed Central) - Dec 29, 2021
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.
- |||||||||| picropodophyllin (AXL1717) / Axelar
Journal: Gamma-Aminobutyric Acid (GABA) Promotes Growth in Zebrafish Larvae by Inducing IGF-1 Expression via GABA and GABA Receptors. (Pubmed Central) - Dec 16, 2021
In zebrafish larvae, the GABA-induced growth rate was remarkably decreased in the presence of an IGF-1R inhibitor, picropodophyllin (PPP), which indicates that GABA-induced IGF-1 enhances growth rate via IGF-1R...Furthermore, treatment with bicuculline and CGP 46381 significantly downregulated GABA-induced IGF-1 release in MC3T3-E1 cells. These data indicate that GABA stimulates IGF-1 release via GABA and GABA receptors and leads to growth promotion performance via IGF-1R.
- |||||||||| picropodophyllin (AXL1717) / Axelar
[VIRTUAL] Insulin-Like Growth Factor 1 Receptor (IGF1R) Suppression in the Glomerular Podocyte Has Beneficial and Detrimental Consequences Dependent on the Level of Inhibition () - Oct 17, 2021 - Abstract #KIDNEYWEEK2021KIDNEY_WEEK_3103;
Results Transgenic mice with partial podocyte-specific IGF1R knockout, generated using conventional Cre recombinase, had no apparent basal renal phenotype but unexpectedly, were protected from doxorubicin-induced nephropathy...Proteomic analysis revealed that near complete IGF1R suppression results in downregulation of mitochondrial respiratory complex I and DNA damage repair proteins whilst partial IGF1R inhibition promotes expression of respiratory complexes. Conclusion Altered mitochondrial function, impairment of DNA damage responses and resistance to oxidative stress in podocytes is dependent on the level of IGF1R suppression and determines whether receptor inhibition is protective or mildly detrimental.
- |||||||||| picropodophyllin (AXL1717) / Axelar
Journal: N-cadherin upregulation mediates adaptive radioresistance in glioblastoma. (Pubmed Central) - Oct 1, 2021
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.
- |||||||||| picropodophyllin (AXL1717) / Axelar
Journal: Pericyte-secreted IGF2 promotes breast cancer brain metastasis formation. (Pubmed Central) - Jul 8, 2021
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.
- |||||||||| picropodophyllin (AXL1717) / Axelar AB
Journal: Fermented Oyster Extract Promotes Insulin-Like Growth Factor-1-Mediated Osteogenesis and Growth Rate. (Pubmed Central) - May 14, 2021
Pharmacological inhibition of IGF-1 receptor (IGF-1R) using picropodophyllin (PPP) significantly reduced FO-mediated vertebrae formation (from 9.19 ± 0.31 to 5.53 ± 0.35) and growth performance (from 3.91 ± 0.02 to 3.69 ± 0.01 mm) in zebrafish larvae at 9 dpf...Altogether, these results indicate that FO increased phosphorylated GSK-3β at Ser9 by activating the autocrine IGF-1-mediated IGF-1R signaling pathway, thereby promoting osteogenesis and growth performance. Therefore, FO is a potential nutritional supplement for bone formation and growth.
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