picropodophyllin (AXL1717) / Axelar - LARVOL DELTA

IGF1/IGF1R signaling promotes the expansion of liver CSCs and serves as a potential therapeutic target in HCC. (PubMed, Discov Oncol) - "Furthermore, IGF1R inhibition by inhibitor effectively eliminated liver CSCs and inhibited the growth of tumors and metastasis in vivo. These findings uncover the important role of IGF1/IGF1R signaling in liver CSCs, and also provide a promising diagnostic marker as well as therapeutic intervention for HCC."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • CD133 • IGF1 • IGF1R • THY1

Picropodophyllin induces ferroptosis via blockage of AKT/NRF2/SLC7A11 and AKT/NRF2/SLC40A1 axes in hepatocellular carcinoma as a natural IGF1R inhibitor. (PubMed, Phytomedicine) - "The natural IGF1R inhibitor PPP induced ferroptosis through blockage of PI3K/AKT/NRF2 signaling pathway and subsequent inhibition of downstream gene expression of SLC7A11 and SLC40A1 in hepatocellular carcinoma. Consequently, our findings provide a novel action and mechanism of PPP, as well as offer innovative and promising ferroptosis-inducing agents for the clinical treatment of HCC."

Journal • Hematological Disorders • Hepatocellular Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • GPX4 • SLC40A1 • SLC7A11

IGF-1 promotes trophectoderm cell proliferation of porcine embryos by activating the Wnt/β-catenin pathway. (PubMed, Cell Commun Signal) - "Our findings provide new insights into the interaction between IGF-1 and the Wnt/β-catenin signaling pathway during embryogenesis and highlight the potential of IGF-1 to improve reproductive outcomes by enhancing TE formation and quality."

Journal • Preclinical • IGF1

HBx/WDR5 enhances IGF-1 transcription in hepatocellular carcinoma cells and promotes recruitment, infiltration, and activity of Treg cells. (PubMed, Immunol Res) - "In the cell co-culture system, HBx/IGF-1 signaling in HCC cells promoted Treg cells expansion, IL-10 secretion, and infiltration, which was blocked by the IGF-1R inhibitor picropodophyllin...IGF-1/IGF-1R signaling plays an important role in the communication between HCC cells and Treg cells. Targeting WDR or IGF-1/IGF-1R would be beneficial for the treatment of HCC."

Journal • Hepatitis B • Hepatocellular Cancer • Hepatology • Infectious Disease • Oncology • Solid Tumor • IGF1 • IL10 • WDR5

Picropodophyllin, an IGF‑1 receptor inhibitor, enhances oxaliplatin efficacy in chemoresistant colorectal cancer HCT116 cells by reducing metastatic potential. (PubMed, Oncol Lett) - "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."

Journal • Colorectal Cancer • Oncology • Solid Tumor • CDH1 • IGF1 • VIM

IGF1R/ARRB1 Mediated Regulation of ERK and cAMP Pathways in Response to Aβ Unfolds Novel Therapeutic Avenue in Alzheimer's Disease. (PubMed, Mol Neurobiol) - "Here, we focused on the ARRB1 and IGF1R interaction and showed that picropodophyllin (PPP), an IGF1R-specific inhibitor, blocks this interaction and alters the ERK and cAMP status under disease conditions. Cell viability studies further revealed that the PPP substantially improved cell viability in the presence of Aβ. This highlights the role of the PPP in regulating these cascades and opens the arena for further therapeutic development for AD."

Journal • Alzheimer's Disease • CNS Disorders • ARRB1 • IGF1R • IR

Traditional pediatric massage exerted an antidepressant effect and activated IGF-1/Nrf2 pathway in CUMS-exposed adolescent rats. (PubMed, J Neuroimmunol) - "With the treatment of picropodophyllin, the inhibitor of IGF-1 receptor, the antidepressant effect of TPM was blocked, along with inhibited IGF-1/Nrf2 pathway which were closely related with anti-inflammatory and anti-ferroptosis actions. The results suggest that TPM enhanced the resilience of adolescent rats to CUMS and exerted an antidepressant effect partially via activating IGF-1/Nrf2 pathway."

Journal • Preclinical • CNS Disorders • Depression • Inflammation • Pediatrics • Psychiatry • IGF1

Interaction with IGF1 overrides ANXA2-mediated anti-inflammatory functions of IGFBP5 in vivo. (PubMed, Front Immunol) - "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-κB; 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."

Journal • Preclinical • Acute Lung Injury • Immunology • Inflammation • Inflammatory Arthritis • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • ANXA2 • IGF1 • IGFBP5 • IL1B • IL6

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, Thorac Cancer) - "We developed a novel new squamous cell lung carcinoma cell line, OMUL-1, that expresses IGF1R and PD-L1."

IO biomarker • Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • EGFR • ERBB3 • ERBB4 • FGFR1 • FGFR2 • FGFR3 • FGFR4 • FLT4 • HER-2 • IGF1R • MET • NKX2-1 • PDGFRA • PDGFRB • PD-L1 • TP63

oHSV and radiation therapies sensitize glioblastoma to IGF1R-targeted therapy and synergize in triple combination therapy (SNO 2024) - "While IGF1R targeting therapies (e.g., OSI-966, Picropodophyllin (PPP)) have displayed limited efficacy in clinical trials, they significantly increased oHSV-induced cytotoxicity in all tested primary GBM cells compared to either agent alone in vitro and in vivo, resulting in a dose-dependent increase in PARP and caspase 3 activity by western blot and immunohistochemistry...Triple combination therapy with oHSV, IGF1R inhibition, and RTx significantly increased tumor cell killing in vitro and improved survival of orthotopic GBM tumor-bearing mice. Collectively, our study provides preclinical evidence of enhanced therapeutic efficacy of oHSVs and RTx in combination with IGF1R blockade, supporting future use of IGF1R inhibitors in combination with the standard of care and FDA-approved oHSV therapies in patients with GBM."

Combination therapy • IO biomarker • Brain Cancer • CNS Tumor • Glioblastoma • Herpes Simplex • Infectious Disease • Oncology • Solid Tumor • CASP3 • IDH1 • IGF2

TLR9-dependent autophagy and IGF1R inhibition affect apoptosis and stem cell phenotype in the HT29 cell line (DGHO 2024) - " HT29 tumor cells were treated with cell-free DNA (Kg), IGF1R inhibitor picropodophyllin (P), autophagy inhibitor chloroquine (C), and in a triple combination (gPC), in addition to control (K) cells. 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."

IO biomarker • Preclinical • Oncology • AKT1 • BAX • BCL2 • CASP3 • CASP8 • CASP9 • CD133 • PI3K • TLR9

Tumor-derived cell-free DNA in combination with IGF1R inhibition results in a strong antiproliferative effect but increases the survival of stem-like HT29 cells (DGHO 2024) - " HT29 tumor cells were treated with free-DNA (Kg), IGF1R inhibitor picropodophyllin (P), and a combination of free-DNA and IGF1R inhibitor (gP), in addition to control (K) cells... Active mTOR in gP-treated HT29 cells suggests autophagy inhibition. Increased CD133 expression suppresses autophagy by limiting ULK1 activation, thereby promoting the maintenance of an undifferentiated, CD133+ stem cell-like phenotype via activation of NF-kB. The gP combined treatment has a potent antiproliferative effect but also promotes the formation of cancer stem cells, which may play a role in disease recurrence."

Cell-free DNA • Combination therapy • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • ATG16L1 • BECN1 • CD133 • TLR9

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 • Breast Cancer • Oncology • Solid Tumor • IGF1 • TGFB1

Targeting IGF1/IGF1r signaling relieve pain and autophagic dysfunction in NTG-induced chronic migraine model of mice. (PubMed, J Headache Pain) - "Our findings demonstrate that in the chronic migraine (CM) model in mice, there is a significant increase in IGF1 expression in the TNC region. This upregulation of IGF1 leads to enhanced phosphorylation of IGF1 receptors on neurons. Targeting and inhibiting this signaling pathway may offer potential preventive strategies for mitigating the progression of chronic migraine."

Journal • Preclinical • CNS Disorders • Immunology • Migraine • Pain • FOS • IGF1

Neohesperidin alleviates the inhibitory effect of bisphenol A on the myogenic differentiation of umbilical cord mesenchymal stem cells via the IGF1R/AKT1/RHOA signaling pathway. (PubMed, Ecotoxicol Environ Saf) - "Western blot results showed that NEO could reverse the down-regulation of the pathway proteins induced by BPA, and counteract the effects of picropodophyllin (PPP) or MK-2206 dihydrochloride (MK-2206) in the myogenic differentiation of sheep UC-MSCs. Taken together, the mechanisms of NEO resistance to BPA involved the IGF1R/AKT1/RHOA signaling pathway. These findings provide a scientific basis for alleviating BPA toxicity, preventing and treating muscular dysplasia, and promoting muscle damage repair."

Journal • AKT1 • RHOA

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, Heliyon) - "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."

Journal • Preclinical • Diabetes • Diabetic Neuropathy • Inflammation • Metabolic Disorders • Pain • IGF1

Insulin-like Growth Factor Receptor Type-1 in Schwann Cells Regulates Pain in a mouse model of Metastatic Bone Cancer Pain (EACR 2024) - "Adeno-associated virus-based shRNA selective silencing of IGF-1R in Schwann cells or systemic administration of the IGF-1R inhibitor, picropodophyllin (PPP), attenuated pain-like behaviors...Activated TRPA1 releases macrophage-colony stimulating factor (M-CSF) that promotes endoneurial macrophage expansion and the ensuing reacConclusion In the present MBCP model, E0771 breast carcinoma cells growing in the femur metastasis release osteoclasts to liberate IGF-1. Schwann cell IGF-1R signaling promoted an endothelial nitric oxide synthase-mediated TRPA1 activation and release of ROS that, via M-CSF-dependent endoneurial macrophage expansion, sustained pain-like behaviors."

Metastases • Preclinical • Breast Cancer • Oncology • Osteosarcoma • Pain • Sarcoma • Solid Tumor • CSF1 • IGF1 • TRPA1

ANALYSIS OF SIGNALING PATHWAYS THAT CONTROL PROGENITOR EPITHELIAL CELL PROLIFERATION & DIFFERENTIATION USING HUMAN LUNG ORGANOIDS (WRMC 2024) - "Consistent with the latter findings, inhibition of IGF1R by picropodophyllin (PPP) reduced cell proliferation. In contrast to IGF1, blocking HGF signaling by capmatinib affected both cell proliferation and AT1 lineage gene expression as evidenced by robust increased expression of HOPX. 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."

Bronchopulmonary Dysplasia • Pulmonary Disease • Respiratory Diseases • IGF1 • SOX2 • SOX9

Suppression of overactive IGF-1 attenuates trauma-induced heterotopic ossification in mice. (PubMed, Am J Pathol) - "Blocking IGF-1 activity with IGF-1 antibody or IGF-1 receptor (IGF-1R) inhibitor Picropodophyllin significantly inhibited HO formation. 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."

Journal • Preclinical • Orthopedics • Thermal Injury • IGF1

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 • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HSP90AA1

Combined inhibition of Insulin Growth Factor-1 Receptors and Autophagy to hinder Colorectal Cancer Metastasis: A Novel Therapeutic Approach (EACR 2023) - "We compared the autophagy genes expression, migration (wound healing assay) as well as the expression epithelial-mesenchymal transition markers; E-cadherin, N-cadherin, Snail1 and Zeb1 (Western Blotting) in different cell lines [isogenic cell lines, HCT116, LOVO, SKCO1, treated with IGF-1, knocked down for IGFR or using its inhibitor (picropodophyllin; PPP)].Results and DiscussionsThere was an increase in basal autophagosome formation as well as autophagy flux subsequent to IGF-1 treatment; revealed by ATG5 and ATG7 increased levels (WB (, whereas suppressed by PPP...Combined suppression of IGF-1 and autophagy represents a potential therapeutic modality for fighting metastasis in advanced colorectal cancer. *The study is funded by MBRU-Al-Mahmeed Research Award (ALM#1914)."

Colorectal Cancer • Gastrointestinal Cancer • Metabolic Disorders • Oncology • Solid Tumor • ATG7 • CDH1 • CDH2 • SNAI1 • ZEB1

Phase I/II Trial of AXL1717 in the Treatment of Recurrent Malignant Astrocytomas (clinicaltrials.gov) - P1/2 | N=10 | Terminated | Sponsor: Rush University Medical Center | N=30 ➔ 10 | Unknown status ➔ Terminated; Investigator went to another institution.

Enrollment change • Trial termination • Anaplastic Astrocytoma • Anaplastic Oligoastrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Ependymoma • Glioblastoma • Glioma • Gliosarcoma • Oligodendroglioma • Oncology • Sarcoma • Solid Tumor

Effect of insulin-like growth factor system on luteinising angiogenesis. (PubMed, Reprod Fertil) - "Bovine luteinising follicular angiogenesis cultures were treated with 1) LR3-IGF1 (10 or 100ng/ml) under basal and angiogenic-stimulated conditions or 2) IGF1 receptor inhibitor (picropodophyllin (PPP); 1µM) in the presence or absence of LR3-IGF1, IGF2, or combined LR3-IGF1+IGF2 (10ng/ml). IGF1 was detected in cell conditioned media and was increased by LH (50ng/ml) (p<0.001). In conclusion, exogenous IGF1 and IGF2 had minimal effects on luteinising follicular angiogenesis and progesterone production, but the inhibitory effect of the IGFR1 inhibitor (PPP) suggests that IGF1 receptor signalling is critical for the development of EC networks and progesterone production in luteinising follicular cells."

Journal • IGF1 • IGF2

Repurposing picropodophyllin as a potential thyroid eye disease treatment via delaying mitotic clonal expansion through a patient-derived preclinical platform. (PubMed, Clin Transl Med) - No abstract available

Journal • Preclinical • Ophthalmology • Thyroid Eye Disease

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 • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CAFs • DLD • IGF1R • IGF2 • YAP1