Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options.

Aberrant bioactivity of the insulin-like growth factor (IGF) system results in the development and progression of several pathologic conditions including cancer. Preclinical studies have shown promising anti-cancer therapeutic potentials for anti-IGF targeted therapies. However, a clear but limited clinical benefit was observed only in a minority of patients with sarcomas. The molecular complexity of the IGF system, which comprises multiple regulators and interactions with other cancer-related pathways, poses a major limitation in the use of anti-IGF agents and supports the need of combinatorial therapeutic strategies to better tackle this axis. In this review, we will initially highlight multiple mechanisms underlying IGF dysregulation in cancer and then focus on the impact of the IGF system and its complexity in sarcoma development and progression as well as response to anti-IGF therapies. We will also discuss the role of Ephrin receptors, Hippo pathway, BET proteins and CXCR4 signaling, as mediators of sarcoma malignancy and relevant interactors with the IGF system in tumor cells. A deeper understanding of these molecular interactions might provide the rationale for novel and more effective therapeutic combinations to treat sarcomas.

Artificial Intelligence Approach To Investigate the Longevity Drug.

Longevity is a very important and interesting topic, and Klotho has been demonstrated to be related to longevity. We combined network pharmacology, machine learning, deep learning, and molecular dynamics (MD) simulation to investigate potent lead drugs. Related protein insulin-like growth factor 1 receptor (IGF1R) and insulin receptor (IR) were docked with the traditional Chinese medicine (TCM) database to screen out several novel candidates. Besides, nine different machine learning algorithms were performed to build reliable and accurate predicted models. Moreover, we used the novel deep learning algorithm to build predicted models. All of these models obtained significant R2, which are all greater than 0.87 on the training set and higher than 0.88 for the test set, respectively. The long time 500 ns molecular dynamics simulation was also performed to verify protein-ligand properties and stability. Finally, we obtained Antifebrile Dichroa, Holarrhena antidysenterica, and Gelsemium sempervirens, which might be potent TCMs for two targets.

Selenium deficiency induces splenic growth retardation by deactivating the IGF-1R/PI3K/Akt/mTOR pathway.

Selenium (Se) deficiency impairs the development and function of immune system in human beings and animals. We investigated the effect and molecular mechanism of Se deficiency on spleen development in chicken. The concentration of Se in blood and spleen, the spleen weight and splenocyte number, the histological characteristics of spleen, the concentration of growth factors in serum, the transcription level of growth factor receptor gene and the activity of growth and proliferation pathway in spleen were investigated. We found that the growth of the spleen and the splenocyte number were significantly lower in the chicken fed with Se-deficient diet for 21 and 35 days. The ELISA and qRT-PCR results showed that the serum IGF-I concentration and the transcription level of IGF1R gene in spleen were significantly lower in the SD group. The Western blotting and immunohistochemistry results showed that Se deficiency could deactivate the PI3K/Akt/mTOR pathway in spleen. In summary, the results indicated that Se deficiency decreases the growth rate of spleen and the number of splenic lymphocytes by deactivating the IGF-1R/PI3K/Akt/mTOR pathway.

miR-130a and miR-145 reprogram Gr-1+CD11b+ myeloid cells and inhibit tumor metastasis through improved host immunity.

Tumor-derived soluble factors promote the production of Gr-1+CD11b+ immature myeloid cells, and TGFß signaling is critical in their immune suppressive function. Here, we report that miR-130a and miR-145 directly target TGFß receptor II (TßRII) and are down-regulated in these myeloid cells, leading to increased TßRII. Ectopic expression of miR-130a and miR-145 in the myeloid cells decreased tumor metastasis. This is mediated through a downregulation of type 2 cytokines in myeloid cells and an increase in IFNγ-producing cytotoxic CD8 T lymphocytes. miR-130a- and miR-145-targeted molecular networks including TGFß and IGF1R pathways were correlated with higher tumor stages in cancer patients. Lastly, miR-130a and miR-145 mimics, as well as IGF1R inhibitor NT157 improved anti-tumor immunity and inhibited metastasis in preclinical mouse models. These results demonstrated that miR-130a and miR-145 can reprogram tumor-associated myeloid cells by altering the cytokine milieu and metastatic microenvironment, thus enhancing host antitumor immunity.

Insulin-like growth factor-I regulates LH release by modulation of kisspeptin and NMDA-mediated neurotransmission in young and middle-aged female rats.

This study investigated potential mechanisms by which age and IGF-I receptor (IGF-Ir) signaling in the neuroendocrine hypothalamus affect estradiol-positive feedback effects on GnRH neuronal activation and on kisspeptin and N-methyl-D-aspartate (NMDA)-induced LH release and on the abundance of NMDA receptor subunits Nr1 and Nr2b and Kiss1r transcript and protein in the hypothalamus of young and middle-aged female rats. We infused vehicle, IGF-I, or JB-1, a selective antagonist of IGF-Ir, into the third ventricle of ovariectomized female rats primed with estradiol or vehicle and injected with vehicle, kisspeptin (3 or 30 nmol/kg), or NMDA (15 or 30 mg/kg). Regardless of dose, NMDA and kisspeptin resulted in significantly more LH release, GnRH/c-Fos colabeling, and c-Fos immunoreative cells in young than in middle-aged females. Estradiol priming significantly increased Kiss1r, Nr1, and Nr2b receptor transcript and protein abundance in young but not middle-aged female hypothalamus. JB-1 attenuated kisspeptin and NMDA-induced LH release, numbers of GnRH/c-Fos and c-Fos cells, and Kiss1r, Nr1, and Nr2b transcript and protein abundance in young females to levels observed in middle-aged females. IGF-I significantly enhanced NMDA and kisspeptin-induced LH release in middle-aged females without increasing numbers of GnRH/c-Fos or c-Fos immunoreactive cells. IGF-I infusion in middle-aged females also increased Kiss1r, Nr1, and Nr2b protein and transcript to levels that were equivalent to young estradiol-primed females. These findings indicate that age-related changes in estradiol-regulated responsiveness to excitatory input from glutamate and kisspeptin reflect reduced IGF-Ir signaling.

Insulin-like growth factor receptor-1 (IGF-IR) as a target for prostate cancer therapy.

Prostate cancer is the most commonly diagnosed cancer in men and is the second leading cause of cancer-related deaths in men each year. Androgen deprivation therapy is and has been the gold standard of care for advanced or metastatic prostate cancer for decades. While this treatment strategy initially shows benefit, eventually tumors recur as castration-resistant prostate cancer for which there are limited treatment options with only modest survival benefit. Upregulation of the insulin-like growth factor receptor type I (IGF-IR) signaling axis has been shown to drive the survival of prostate cancer cells in many studies. As many IGF-IR blockades have been developed, few have been tested preclinically and even fewer have entered clinical trials for prostate cancer therapy. In this review, we will update the most recent preclinical and clinical studies of IGF-IR therapy for prostate cancer. We will also discuss the challenges for IGF-IR targeted therapies to achieve clinical benefit for prostate cancer.

Resveratrol regulates the cell viability promoted by 17ß-estradiol or bisphenol A via down-regulation of the cross-talk between estrogen receptor α and insulin growth factor-1 receptor in BG-1 ovarian cancer cells.

Endocrine disrupting chemicals (EDCs) and estrogens appear to promote development of estrogen-dependent cancers, including breast and ovarian carcinomas. In this study, we evaluated the cell viability effect of BPA on BG-1 human ovarian cancer cells, along with the growth inhibitory effect of resveratrol (trans-3,4,5-trihydroxystilbene; RES), a naturally occurring phytoestrogen. In addition, we investigated the underlying mechanism(s) of BPA and RES in regulating the interaction between estrogen receptor alpha (ERα) and insulin-like growth factor-1 receptor (IGF-1R) signals, a non- genomic pathway induced by 17ß-estradiol (E2). BPA induced a significant increase in BG-1 cell growth and up-regulated mRNA levels of ERα and IGF-1R. In parallel with its mRNA level, the protein expression of ERα was induced, and phosphorylated insulin receptor substrate-1 (p-IRS-1), phosphorylated Akt1/2/3, and cyclin D1 were increased by BPA or E2. However, RES effectively reversed the BG-1 cell proliferation induced by E2 or BPA by inversely down-regulating the expressions of ERα, IGF-1R, p-IRS-1, and p-Akt1/2/3, and cyclin D1 at both transcriptional and translational levels. Taken together, these results suggest that RES is a novel candidate for prevention of tumor progression caused by EDCs, including BPA via effective inhibition of the cross-talk of ERα and IGF-1R signaling pathways.

Potentiating the efficacy of molecular targeted therapy for hepatocellular carcinoma by inhibiting the insulin-like growth factor pathway.

Insulin-like growth factor (IGF) signaling pathway is an important regulatory mechanism of tumorigenesis and drug resistance in many cancers. The present study explored the potential synergistic effects between IGF receptor (IGFR) inhibition and other molecular targeted agents (MTA) in HCC cells. HCC cell lines (Hep3B, PLC5, and SK-Hep1) and HUVECs were tested. The MTA tested included sorafenib, sunitinib, and the IGFR kinase inhibitor NVP-AEW541. The potential synergistic antitumor effects were tested by median dose effect analysis and apoptosis assay in vitro and by xenograft models in vivo. The activity and functional significance of pertinent signaling pathways and expression of apoptosis-related proteins were measured by RNA interference and Western blotting. We found that IGF can activate IGFR and downstream AKT signaling activities in all the HCC cells tested, but the growth-stimulating effect of IGF was most prominent in Hep3B cells. NVP-AEW541 can abrogate IGF-induced activation of IGFR and AKT signaling in HCC cells. IGF can increase the resistance of HCC cells to sunitinib. The apoptosis-inducing effects of sunitinib, but not sorafenib, were enhanced when IGFR signaling activity was inhibited by NVP-AEW541 or IGFR knockdown. Chk2 kinase activation was found contributory to the synergistic anti-tumor effects between sunitinib and IGFR inhibition. Our data indicate that the apoptosis-potentiating effects of IGFR inhibition for HCC may be drug-specific. Combination therapy of IGFR inhibitors with other MTA may improve the therapeutic efficacy in HCC.

[Current status of molecular targeted therapies in hepatocellular carcinoma].

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death in Korea. Curative treatment is only possible when the disease is diagnosed at the early stage. The prognosis of patients with HCC is even dismal in advanced stages. No systemic cytotoxic chemotherapy has proven to be beneficial in overall survival. Recently, the understanding of the molecular pathogenesis led to the development of new therapies. With the evidence of dysregulation of critical genes associated with cellular proliferation, growth factor signaling, cell cycling, apoptosis, and angiogenesis in HCC, a number of molecular target agents are under clinical trials. Sorafenib is the first systemic anticancer drug which has proven to gain survival benefit in the global as well as Asia-Pacific trials. However, the survival gain is still modest, and further efforts to improve outcomes in patients with HCC are necessary by developing novel drugs or combining other forms of therapies. This article will review signaling pathways in HCC and introduce molecular target agents under investigation currently.

Safety and pharmacokinetics of ganitumab (AMG 479) combined with sorafenib, panitumumab, erlotinib, or gemcitabine in patients with advanced solid tumors.

PURPOSE: This phase 1b dose-escalation study assessed safety, tolerability, and pharmacokinetics of ganitumab, a fully human monoclonal antibody against the insulin-like growth factor 1 (IGF1) receptor, combined with targeted agents or cytotoxic chemotherapy in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients with treatment-refractory advanced solid tumors were sequentially enrolled at 2 ganitumab dose levels (6 or 12 mg/kg i.v. every 2 weeks) combined with either sorafenib 400 mg twice daily, panitumumab 6 mg/kg every 2 weeks, erlotinib 150 mg once daily, or gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 of each 4-week cycle. The primary end points were safety and pharmacokinetics of ganitumab. RESULTS: Ganitumab up to 12 mg/kg appeared well tolerated combined with sorafenib, panitumumab, erlotinib, or gemcitabine. Treatment-emergent adverse events were generally mild and included fatigue, nausea, vomiting, and chills. Three patients had dose-limiting toxicities: grade 3 hyperglycemia (ganitumab 6 mg/kg and panitumumab), grade 4 neutropenia (ganitumab 6 mg/kg and gemcitabine), and grade 4 thrombocytopenia (ganitumab 12 mg/kg and erlotinib). Ganitumab-binding and panitumumab-binding antibodies were detected in 5 and 2 patients, respectively; neutralizing antibodies were not detected. The pharmacokinetics of ganitumab and each cotherapy did not appear affected by coadministration. Circulating total IGF1 and IGF binding protein 3 increased from baseline following treatment. Four patients (9%) had partial responses. CONCLUSIONS: Ganitumab up to 12 mg/kg was well tolerated, without adverse effects on pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents.

Combination testing (Stage 2) of the Anti-IGF-1 receptor antibody IMC-A12 with rapamycin by the pediatric preclinical testing program.

BACKGROUND: IMC-A12, a fully human antibody that blocks ligand binding to the Type 1 insulin-like growth factor receptor, and rapamycin, a selective inhibitor of mTORC1 signaling, have both demonstrated significant antitumor activity against PPTP solid tumor models. Here we have evaluated antitumor activity of each agent individually and in combination against nine tumor models. PROCEDURES: IMC-A12 was administered twice weekly and rapamycin was administered daily for 5 days per week for a planned 4 weeks. The impact of combining IMC-A12 with rapamycin was evaluated using two measures: (1) the "therapeutic enhancement" measure, and (2) a linear regression model for time-to-event to formally evaluate for sub- and supra-additivity for the combination compared to the agents used alone. RESULTS: Two osteosarcomas, and one Ewing sarcoma of the nine xenografts tested showed therapeutic enhancement. The combination effect was most dramatic for EW-5 for which PD2 responses of short duration were observed for both single agents and a prolonged PR response was observed for the combination. Both OS-2 and OS-9 showed significantly longer times to progression with the combination compared to either of the single agents, although objective response criteria were not met. CONCLUSIONS: The combination of IMC-A12 with rapamycin was well tolerated, and induced tumor responses that were superior to either single agent alone in several models. These studies confirm reports using other antibodies that inhibit IGF-1 receptor-mediated signaling that indicate enhanced therapeutic effect for this combination, and extend the range of histotypes to encompass additional tumors expressing IGF-1R where this approach may be effective.

Bitter melon (Momordica charantia) extract suppresses adrenocortical cancer cell proliferation through modulation of the apoptotic pathway, steroidogenesis, and insulin-like growth factor type 1 receptor/RAC-α serine/threonine-protein kinase signaling.

Adrenocortical carcinomas are rare but present with extremely poor prognosis. One of the approaches to control cancer progression and reduce cancer risk is prevention through diet. Bitter melon is widely consumed as a vegetable and especially as a traditional medicine in many countries. In this study, we have used human and mouse adrenocortical cancer cells as an in vitro model to assess the efficacy of bitter melon extract (BME) as an anticancer agent. The protein concentrations of BME and other extracts were measured before use. First, BME treatment of adrenocortical cancer cells resulted in a significantly dose-dependent decrease in cell proliferation. However, we did not observe an antiproliferative effect in adrenocortical cancer cells treated with extracts from blueberry, zucchini, and acorn squash. Second, apoptosis of adrenocortical cancer cells was accompanied by increased caspase-3 activation and poly(ADP-ribose) polymerase cleavage. BME treatment enhanced cellular tumor antigen p53, cyclin-dependent kinase inhibitor 1A (also called p21), and cyclic AMP-dependent transcription factor-3 levels and inhibited G1/S-specific cyclin D1, D2, and D3, and mitogen-activated protein kinase 8 (also called Janus kinase) expression, suggesting an additional mechanism involving cell cycle regulation and cell survival. Third, BME treatment decreased the key proteins involved in steroidogenesis in adrenocortical cancer cells. BME treatment decreased the level of phosphorylation of cyclin-dependent kinase 7, which is required, at least in part, for steroidogenic factor 1 activation. Finally, we observed that BME treatment significantly reduced the level of insulin-like growth factor 1 receptor and its downstream signaling pathway as evidenced by lower levels of phosphorylated RAC-α serine/threonine-protein kinase. Taken together, these data illustrate the inhibitory effect of bitter melon on cell proliferation of adrenocortical cancer through modulation of diverse mechanisms.

Zyflamend reduces the expression of androgen receptor in a model of castrate-resistant prostate cancer.

Prostate cancer is the most commonly diagnosed solid malignancy, and tumor cells eventually transform to castrate resistance through multiple pathways including activation of the androgen receptor via insulin-like growth factor receptor (IGF-1R) signaling involving phospho-AKT (pAKT). In this study, a mixture of herbal extracts, Zyflamend®, was used as a treatment in a model of castrate-resistant prostate cancer using CWR22Rv1 cells. Zyflamend reduced androgen receptor and IGF-1R expression along with a reduction of IGF-1-mediated proliferation of CWR22Rv1 cells. IGF-1 induced downstream AKT phosphorylation; however, the induction of pAKT was not associated with androgen receptor expression. Further, constitutively active form of AKT had no effect on nuclear expression of androgen receptor, indicating that upregulation of pAKT did not promote androgen receptor expression or nuclear translocation in castrate-resistant CWR22Rv1 cells. Conversely, Zyflamend reduced androgen receptor expression following IGF-1 stimulation and in cells overexpressing pAKT. These results demonstrated that Zyflamend inhibited IGF-1-stimulated cell growth, IGF-1R expression, and androgen receptor expression and its nuclear localization, but these effects were not dependent upon phosphatidylinositol 3-kinase/pAKT signaling. In conclusion, Zyflamend decreased cell proliferation and inhibited IGF-1R and androgen receptor expression in a phosphatidylinositol 3-kinase/pAKT independent manner.

IGF1/insulin receptor kinase inhibition by BMS-536924 is better tolerated than alloxan-induced hypoinsulinemia and more effective than metformin in the treatment of experimental insulin-responsive breast cancer.

Epidemiologic and experimental evidence suggest that a subset of breast cancer is insulin responsive, but it is unclear whether safe and effective therapies that target the insulin receptor (IR), which is homologous to oncogenes of the tyrosine kinase class, can be developed. We demonstrate that both pharmacologic inhibition of IR family tyrosine kinase activity and insulin deficiency have anti-neoplastic activity in a model of insulin-responsive breast cancer. Unexpectedly, in contrast to insulin deficiency, pharmacologic IR family inhibition does not lead to significant hyperglycemia and is well tolerated. We show that pharmacokinetic factors explain the tolerability of receptor inhibition relative to insulin deficiency, as the small molecule receptor kinase inhibitor BMS-536924 does not accumulate in muscle at levels sufficient to block insulin-stimulated glucose uptake. Metformin, which lowers insulin levels only in settings of hyperinsulinemia, had minimal activity in this normoinsulinemic model. These findings highlight the importance of tissue-specific drug accumulation as a determinant of efficacy and toxicity of tyrosine kinase inhibitors and suggest that therapeutic targeting of the IR family for cancer treatment is practical.

Differential effects of hypothalamic IGF-I on gonadotropin releasing hormone neuronal activation during steroid-induced LH surges in young and middle-aged female rats.

Interactions between brain IGF-I receptors and estrogen receptors regulate female reproductive physiology and behavior. The present study investigated potential mechanisms by which IGF-I receptors in the neuroendocrine hypothalamus regulate GnRH neuronal activation and LH release in young and middle-aged female rats under estradiol (E2) positive feedback conditions. We infused vehicle, IGF-I, or JB-1, a selective antagonist of IGF-I receptors, into the third ventricle of ovariectomized female rats primed with E2 and progesterone or vehicle. In young females, blockade of IGF-I receptors attenuated the steroid hormone-induced LH surge, reduced the percent of GnRH neurons expressing c-fos on the day of the LH surge, and decreased the total number of neurons expressing c-fos in the preoptic area. Middle-aged females had fewer GnRH neurons expressing c-fos during the LH surge than young females, and the LH surge amplitude was attenuated. Infusion of an IGF-I dose previously shown to increase LH surge amplitude did not increase the percent of GnRH neurons expressing c-fos in middle-aged females. Brain IGF-I receptor blockade did not modify E2 induction of progestin receptor-immunoreactive neurons in the preoptic area, arcuate, or ventromedial hypothalamus of young rats. These findings indicate that brain IGF-I receptors are required for E2 activation of GnRH neurons in young rats and for robust GnRH release from axon terminals in middle-aged females. IGF-I likely exerts its effects by actions on E2-sensitive neurons that are upstream of GnRH neurons and terminals.

Dual inhibition of epidermal growth factor and insulin-like 1 growth factor receptors reduce intestinal adenoma burden in the Apc(min/+) mouse.

BACKGROUND: Identification of early molecular pathway changes may be useful as biomarkers for tumour response/resistance prediction, and here we provide direct in vivo proof of this concept. The type 1 insulin-like growth factor receptor (IGF1R) has been implicated in various aspects of adenoma development and metastasis. We show here that, in murine intestinal adenomas acutely exposed to a small molecular inhibitor of EGFR (gefitinib), there is concurrent suppression of EGFR downstream signalling and induction of IGF signalling. We therefore tested the hypothesis that blockade of EGFR signalling was being tempered by compensatory activation of the IGF pathway by examining the effect of chronic suppression of IGF1R using AZ12253801, a small molecular tyrosine kinase inhibitor of IGF1R. METHODS: Male Apc(min/+) mice with an intestinal tumour burden were exposed to a single dose of an inhibitor against EGFR (gefitinib), IGF1R (AZ12253801), 0.5% Tween 80 or combined EGFR/IGF1R inhibitor and culled 4 h post dosing. Tumour tissue was analysed to detect the early molecular pathways induced and anti-tumour phenotypic changes. Cohorts of male Apc(min/+) mice (n=15-17) were subsequently treated with gefitinib for a period of 8 weeks and subsequently exposed to single (either gefitinib or AZ12253801) or combined (gefitinib and AZ12253801) therapy. We also included a vehicle-treated cohort, which was never exposed to gefitinib and became symptomatic of the disease by day 150. RESULTS: Both single treatments delayed the onset of disease symptoms. Combined dosing with gefitinib and AZ12253801 similarly delayed the onset of symptoms, and at 200 days suppressed small intestinal tumourigenesis more effectively than either treatment alone (median small intestinal adenoma volume (47 mm(3) (comb) vs 248 mm(3) (AZ12253801), P=0.0003 and 47 mm(3) (comb) vs 123 mm(3) (gefitinib), P=0.0042, Mann-Whitney (two-sided) test). CONCLUSION: Our data provide evidence in support of the use of combinatorial therapy, and establishes the need to further define the precise benefit in vivo.

A hepatoprotective Lindera obtusiloba extract suppresses growth and attenuates insulin like growth factor-1 receptor signaling and NF-kappaB activity in human liver cancer cell lines.

BACKGROUND: In traditional Chinese and Korean medicine, an aqueous extract derived from wood and bark of the Japanese spice bush Lindera obtusiloba (L.obtusiloba) is applied to treat inflammations and chronic liver diseases including hepatocellular carcinoma. We previously demonstrated anti-fibrotic effects of L.obtusiloba extract in hepatic stellate cells. Thus, we here consequently examine anti-neoplastic effects of L.obtusiloba extract on human hepatocellular carcinoma (HCC) cell lines and the signaling pathways involved. METHODS: Four human HCC cell lines representing diverse stages of differentiation were treated with L.obtusiloba extract, standardized according to its known suppressive effects on proliferation and TGF-ß-expression. Beside measurement of proliferation, invasion and apoptosis, effects on signal transduction and NF-κB-activity were determined. RESULTS: L.obtusiloba extract inhibited proliferation and induced apoptosis in all HCC cell lines and provoked a reduced basal and IGF-1-induced activation of the IGF-1R signaling cascade and a reduced transcriptional NF-κB-activity, particularly in the poorly differentiated SK-Hep1 cells. Pointing to anti-angiogenic effects, L.obtusiloba extract attenuated the basal and IGF-1-induced expression of hypoxia inducible factor-1α, vascular endothelial growth factor, peroxisome proliferator-activated receptor-γ, cyclooxygenase-2 and inducible nitric oxide synthase. CONCLUSIONS: The traditional application of the extract is confirmed by our experimental data. Due to its potential to inhibit critical receptor tyrosine kinases involved in HCC progression via the IGF-1 signaling pathway and NF-κB, the standardized L.obtusiloba extract should be further analysed for its active compounds and explored as (complementary) treatment option for HCC.

Discovery of 2,4-bis-arylamino-1,3-pyrimidines as insulin-like growth factor-1 receptor (IGF-1R) inhibitors.

The insulin-like growth factor-1 receptor (IGF-1R) plays an important role in the regulation of cell growth and differentiation, and in protection from apoptosis. IGF-1R has been shown to be an appealing target for the treatment of human cancer. Herein, we report the synthesis, structure-activity relationships (SAR), X-ray cocrystal structure and in vivo tumor study results for a series of 2,4-bis-arylamino-1,3-pyrimidines.

Discovery of the first non-ATP competitive IGF-1R kinase inhibitors: advantages in comparison with competitive inhibitors.

A new series of IGF-1R inhibitors related to hydantoins were identified from a lead originating from HTS. Their noncompetitive property as well as their slow binding characteristics provided a series of compounds with unique selectivity and excellent cellular activities.

18FDG-PET predicts pharmacodynamic response to OSI-906, a dual IGF-1R/IR inhibitor, in preclinical mouse models of lung cancer.

PURPOSE: To evaluate 2-deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography imaging ((18)FDG-PET) as a predictive, noninvasive, pharmacodynamic (PD) biomarker of response following administration of a small-molecule insulin-like growth factor-1 receptor and insulin receptor (IGF-1R/IR) inhibitor, OSI-906. EXPERIMENTAL DESIGN: In vitro uptake studies of (3)H-2-deoxy glucose following OSI-906 exposure were conducted evaluating correlation of dose with inhibition of IGF-1R/IR as well as markers of downstream pathways and glucose metabolism. Similarly, in vivo PD effects were evaluated in human tumor cell line xenografts propagated in athymic nude mice by (18)FDG-PET at 2, 4, and 24 hours following a single treatment of OSI-906 for the correlation of inhibition of receptor targets and downstream markers. RESULTS: Uptake of (3)H-2-deoxy glucose and (18)FDG was significantly diminished following OSI-906 exposure in sensitive tumor cells and subcutaneous xenografts (NCI-H292) but not in an insensitive model lacking IGF-1R expression (NCI-H441). Diminished PD (18)FDG-PET, collected immediately following the initial treatment agreed with inhibition of pIGF-1R/pIR, reduced PI3K (phosphoinositide 3-kinase) and MAPK (mitogen activated protein kinase) pathway activity, and predicted tumor growth arrest as measured by high-resolution ultrasound imaging. CONCLUSION: (18)FDG-PET seems to serve as a rapid, noninvasive PD marker of IGF-1R/IR inhibition following a single dose of OSI-906 and should be explored clinically as a predictive clinical biomarker in patients undergoing IGF-1R/IR-directed cancer therapy.