The identification and molecular profiling of early metastases remains a major challenge in cancer diagnostics and therapy. Most in vivo imaging methods fail to detect small cancerous lesions, a problem that is compounded by the distinct physical and biological barriers associated with different metastatic niches. Here, we show that intravenously injected rare-earth-doped albumin-encapsulated nanoparticles emitting short-wave infrared light (SWIR) can detect targeted metastatic lesions in vivo, allowing for the longitudinal tracking of multi-organ metastases. In a murine model of basal human breast cancer, the nanoprobes enabled whole-body SWIR detection of adrenal gland microlesions and bone lesions that were undetectable via contrast-enhanced magnetic resonance imaging (CE-MRI) as early as, respectively, three weeks and five weeks post-inoculation. Whole-body SWIR imaging of nanoprobes functionalized to differentially target distinct metastatic sites and administered to a biomimetic murine model of human breast cancer resolved multi-organ metastases that showed varied molecular profiles at the lungs, adrenal glands and bones. Real-time surveillance of lesions in multiple organs should facilitate pre-therapy and post-therapy monitoring in preclinical settings.
Asthma is a chronic inflammatory disorder delineated by a heightened immunological response due to environmental or genetic factors. Single nucleotide polymorphism studies have shown that FOXO3a plays a pivotal role in maintaining immunoregulation. Polymorphism in FOXO3a has been linked to inflammatory diseases such as chronic obstructive pulmonary disease (COPD), Rheumatoid Arthritis, and Crohn's disease suggesting that FOXO3a may be associated with asthma. Airway inflammation in asthma is characterized by activation of T helper type 2 (Th2) T cells and Foxo family members are reported to play critical roles in the suppression of T cell activation. Thus this study was undertaken to investigate an association between single nucleotide polymorphism of the FOXO3a (rs13217795, C>T transition) gene and asthma in Indian population. To our knowledge we are the first ones reporting an association between FOXO3a and asthma.
Background The ability to detect tumor-specific biomarkers in real-time using optical imaging plays a critical role in preclinical studies aimed at evaluating drug safety and treatment response. In this study, we engineered an imaging platform capable of targeting different tumor biomarkers using a multi-colored library of nanoprobes. These probes contain rare-earth elements that emit light in the short-wave infrared (SWIR) wavelength region (900–1700 nm), which exhibits reduced absorption and scattering compared to visible and NIR, and are rendered biocompatible by encapsulation in human serum albumin. The spectrally distinct emissions of the holmium (Ho), erbium (Er), and thulium (Tm) cations that constitute the cores of these nanoprobes make them attractive candidates for optical molecular imaging of multiple disease biomarkers. Methods SWIR-emitting rare-earth-doped albumin nanocomposites (ReANCs) were synthesized using controlled coacervation, with visible light-emitting fluorophores additionally incorporated during the crosslinking phase for validation purposes. Specifically, HoANCs, ErANCs, and TmANCs were co-labeled with rhodamine-B, FITC, and Alexa Fluor 647 dyes respectively. These Rh-HoANCs, FITC-ErANCs, and 647-TmANCs were further conjugated with the targeting ligands daidzein, AMD3100, and folic acid respectively. Binding specificities of each nanoprobe to distinct cellular subsets were established by in vitro uptake studies. Quantitative whole-body SWIR imaging of subcutaneous tumor bearing mice was used to validate the in vivo targeting ability of these nanoprobes. Results Each of the three ligand-functionalized nanoprobes showed significantly higher uptake in the targeted cell line compared to untargeted probes. Increased accumulation of tumor-specific nanoprobes was also measured relative to untargeted probes in subcutaneous tumor models of breast (4175 and MCF-7) and ovarian cancer (SKOV3). Preferential accumulation of tumor-specific nanoprobes was also observed in tumors overexpressing targeted biomarkers in mice bearing molecularly-distinct bilateral subcutaneous tumors, as evidenced by significantly higher signal intensities on SWIR imaging. Conclusions The results from this study show that tumors can be detected in vivo using a set of targeted multispectral SWIR-emitting nanoprobes. Significantly, these nanoprobes enabled imaging of biomarkers in mice bearing bilateral tumors with distinct molecular phenotypes. The findings from this study provide a foundation for optical molecular imaging of heterogeneous tumors and for studying the response of these complex lesions to targeted therapy.
The polycomb repressive complex 2 (PRC2) is responsible for the methylation of histone 3 at lysine 27 (H3K27) which leads to long-term transcriptional silencing. Through this epigenetic chromatin silencing mechanism, PRC2 plays a key role in regulating cellular functions such as cell growth and differentiation. PRC2 comprises three core subunits: the catalytic subunit enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development (EED) and suppressor of zeste 12 (SUZ12). EED directly interacts with histone H3K27me3 and is essential for the histone methyltransferase activity of PRC2. PRC2 dysregulation occurs in multiple solid tumors and hematological malignancies, resulting in elevated levels of PRC2 activity and H3K27 trimethylation, and has been linked to poor prognosis in patients with metastatic prostate cancer. First-generation PRC2 inhibitors which target EZH2 have demonstrated clinical activity in several cancers, yet the pharmacological and ADME properties of these compounds require high doses that only achieve partial target inhibition at clinically active levels and exhibit drug-drug interaction (DDI) liabilities. As an alternative strategy to fully inhibit the PRC2 complex, we developed ORIC-944, a potent and highly selective allosteric inhibitor of PRC2 via binding the EED subunit. This unique EED targeting strategy can more completely inhibit PRC2, for example, in the presence of innate or acquired resistance mutations in EZH2, and by addressing the potential compensatory escape mechanism of EZH1-driven tumor growth. ORIC-944 has potential best-in-class drug properties compared to first generation PRC2 inhibitors, including superior potency and improved DDI liabilities. In diffuse large B-cell lymphoma (DLBCL) xenografts in vivo, ORIC-944 significantly depleted H3K27 trimethylation and induced tumor regressions in a dose-dependent manner. ORIC-944 demonstrated strong tumor growth inhibition as a single agent with once daily oral dosing in both enzalutamide-responsive and enzalutamide-resistant prostate cancer models. ORIC-944 caused a significant reduction in tumor cell proliferation and anti-apoptotic signaling, as measured by Ki67 and survivin, respectively. Moreover, in PK/PD assessments, ORIC-944 strongly depleted H3K27me3 in treated tumors. These in vivo studies established that effective single agent inhibition of PRC2 via EED results in decreased tumor cell growth in PRC2-dependent prostate cancer models. In summary, ORIC-944 is a potent, highly selective, allosteric, orally bioavailable PRC2 inhibitor via the EED subunit that represents a differentiated strategy to block PRC2 activity in selected cancers. We are developing ORIC-944 as a best-in-class PRC2 inhibitor for the treatment of patients with advanced prostate cancer and expect to file an IND in the second half of 2021. Citation Format: Anneleen Daemen, Jessica D. Sun, Aleksandr Pankov, Frank L. Duong, Natalie Yuen, Shravani Barkund, Shelly Kaushik, Jae H. Chang, David M. Briere, Niranjan Sudhakar, Andrew Calinisan, Aaron Burns, John M. Ketcham, Matthew A. Marx, Peter Olson, James G. Christensen, Melissa R. Junttila, Lori S. Friedman. ORIC-944, a potent and selective allosteric PRC2 inhibitor, demonstrates robust in vivo activity in prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1131.
ORIC-101 is a novel and selective glucocorticoid receptor (GR) antagonist currently in Ph1 clinical evaluation in solid tumors. In preclinical models, ORIC-101 potently sensitized triple-negative breast cancer (TNBC) cells to chemotherapy by inhibiting GR-mediated resistance through the epithelial-to-mesenchymal transition and anti-apoptosis pathways, both in vitro and in vivo. To inform the clinical development of ORIC-101, we identified pharmacodynamic (PD) biomarkers and established a relationship between those biomarkers, pharmacokinetics (PK), and efficacy in preclinical models. Using genome-wide profiling, we developed a GR activation signature that includes the direct GR transcriptional targets FKBP5 and GILZ, and subsequently validated both genes as ORIC-101 PD biomarkers in a panel of cell lines. We demonstrated that FKBP5 and GILZ are transcriptionally induced by glucocorticoids in a dose-dependent manner, and that the degree of their transcriptional activation is correlated with basal levels of GR in these models. We showed that ORIC-101 robustly inhibits the transcriptional induction of FKBP5 and GILZ and fully reverses GR-mediated chemoresistance in vitro and in vivo. Furthermore, FKBP5 and GILZ are reliable PD biomarkers for ORIC-101 in human-derived peripheral blood mononuclear cells (PBMCs). Importantly, by integrating PK, PD, and efficacy results from numerous preclinical studies, we captured the relationship between ORIC-101 PK, PD biomarker modulation, and chemopotentiation. Altogether, FKBP5 and GILZ mRNA levels are robust PD biomarkers to measure GR pathway engagement and modulation which corresponds with efficacy in response to GR antagonist treatment in preclinical models. These findings will guide the clinical development of ORIC-101 in TNBC. Citation Format: Haiying Zhou, Qiuping Ye, Aleksandr Pankov, Wayne Kong, Shravani Barkund, Lori S. Friedman, Jessica D. Sun, Omar Kabbarah. ORIC-101 robustly inhibits the glucocorticoid pathway and overcomes chemoresistance in triple-negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-03-24.
Prostate cancer is the second leading cause of cancer-related death in men. Androgen deprivation is commonly used to treat hormone-sensitive prostate cancer, while second-generation antiandrogens, including enzalutamide and abiraterone, benefit patients with castration-resistant prostate cancer (CRPC). New therapeutic strategies are needed for patients who relapse with metastatic CRPC. The glucocorticoid receptor (GR) has been implicated as a major bypass mechanism to escape androgen blockade in patients with CRPC, indicating that GR-targeted therapies may provide an avenue to overcome therapeutic resistance in this clinical setting. We discovered a novel, selective, oral GR antagonist, ORIC-101, which fully reverses GR-driven resistance to enzalutamide in a dose-dependent manner in preclinical models. Specifically, we show that GR is widely expressed in prostate cancer cell lines, organoids, and tumor tissue, and that GR levels are upregulated upon enzalutamide treatment. We demonstrate in preclinical studies that physiological levels of glucocorticoids promote tumor cell growth, stimulate androgen-regulated gene expression, and drive resistance to enzalutamide. Importantly, these effects were completely reversed by ORIC-101, suggesting ORIC-101 overcomes GR-driven resistance to enzalutamide. To inform the clinical development of ORIC-101 in combination with enzalutamide, we identified FKBP5 and KLK3 as direct transcriptional targets of both androgen receptor and GR. We subsequently validated that secreted PSA, a product of the KLK3 gene, can be induced by glucocorticoids and this induction is fully inhibited by ORIC-101. These findings confirm that targeting GR may help overcome resistance to enzalutamide in CRPC, and that FKBP5 and KLK3 are rational PD biomarkers that may be used in clinical trials of ORIC-101, along with PSA. Citation Format: Haiying Zhou, Shravani Barkund, Aleksandr Pankov, Sharvani Sinha, Dena Sutimantanapi, Lori S. Friedman, Omar Kabbarah. ORIC-101 overcomes glucocorticoid-driven resistance to enzalutamide in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A10. doi:10.1158/1535-7163.TARG-19-LB-A10
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and one of the most lethal cancers, with a 5-year survival rate of 8%. Chemotherapy remains the main treatment option for patients with advanced and metastatic tumors. However, intrinsic resistance to chemotherapeutics and lack of effective targeted therapies are major factors contributing to the dismal prognosis. Activation of glucocorticoid receptor (GR) signaling confers resistance to chemotherapy in solid tumors, making GR antagonism an attractive combination treatment strategy to overcome chemotherapeutic resistance. ORIC-101 is a novel selective GR antagonist under clinical evaluation in combination with anticancer therapies. We previously reported that ORIC-101 can sensitize triple-negative breast cancer cells to chemotherapy by reversing multiple GR-modulated pathways. Here, we investigate the effects of ORIC-101 in preclinical models of PDAC. Employing in vitro functional assays and gene expression analysis, ORIC-101 exhibited chemo-potentiation in a panel of PDAC cell lines. Biomarker analysis of transcription activity following ORIC-101 treatment in vitro confirmed pharmacodynamic (PD) modulation of core GR target genes, indicative of suppressed GR signaling. Extending these findings in vivo across several PDAC xenograft models (SW1990, BxPC3, and HPAC) revealed that ORIC-101 blocks GR transcriptional activity induced by dexamethasone in a dose-dependent manner. The PD modulation observed in vivo correlated with ORIC-101 plasma exposure. Consistent with ORIC-101's ability to suppress GR activity, in vivo efficacy studies in combination with paclitaxel significantly inhibited PDAC tumor growth compared to the paclitaxel control group. These results in PDAC preclinical models support the clinical development of ORIC-101 in overcoming GR-driven chemoresistance. A phase 1b study of ORIC-101 in combination with nab-paclitaxel in patients with advanced or metastatic solid tumors is ongoing (NCT03928314). Citation Format: Jessica D. Sun, Haiying Zhou, Wayne Kong, Natalie Yuen, Frank L. Duong, Shravani Barkund, Aleksandr Pankov, Dan McWeeney, Qiuping Ye, Omar Kabbarah, Lori S. Friedman, Anneleen Daemen, Melissa Junttila. ORIC-101 overcomes glucocorticoid receptor-mediated chemoresistance in pancreatic cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4123.
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