scholarly journals A Novel Steroidogenic Factor-1 Antagonist, OR-449, as a Targeted Therapy for Adrenocortical Cancer

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1010-A1010
Author(s):  
Paul Crowe ◽  
Ray Fox ◽  
Haiyan Tao ◽  
Emily Eastwood ◽  
Neil Raheja ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Surgical Resection ◽  
Locally Advanced ◽  
Unmet Need ◽  
Primary Treatment ◽  
Tumor Xenograft ◽  
Orphan Nuclear Receptor ◽  
Adrenocortical Cancer ◽  
Steroidogenic Factor 1 ◽  
Immunocompromised Mice

Abstract Adrenocortical carcinoma (ACC) is a rare cancer with an annual incidence of 0.7-2.0 cases per million in the US and EU. Surgical resection combined with adjuvant chemotherapy remains the primary treatment for patients with advanced disease. Although surgery is an option for most patients, oftentimes cases presenting with locally advanced or metastatic disease are not candidates for surgical resection. Furthermore, the non-specific adrenolytic and highly toxic FDA-approved chemotherapy drug, mitotane, is only marginally effective in adult and pediatric ACC. Steroidogenic factor-1 (SF-1 or NR5A1), an orphan nuclear receptor that is essential for the growth and development of the adrenal gland, is highly expressed in adult and pediatric ACC. Moreover, SF- is the major, active transcription factor in ACC (1,2). To address the unmet need for a targeted therapy in ACC, we identified potent small molecule SF-1 antagonists that block SF-1 transcriptional activity through the SF-1 ligand-binding domain (IC50 = 15-20 nM in a CHO cell reporter assay). In short-term dissociated cell cultures established from SJ-ACC3 (3), a pediatric ACC patient-derived tumor xenograft (PDX), OR-449 and a related SF-1 antagonist, OR-907S, blocked DNA synthesis as measured by inhibition of EdU incorporation in SF-1+ cells (IC50 = 500-600 nM, >80% efficacy at 10 μM) whereas OR-907R, the 100-fold less potent enantiomer of OR-907S, is nearly inactive. OR-449, which has >20% oral bioavailability and a long plasma half-life (> 9 h) in mouse, rat and dog, inhibited growth of SJ-ACC3 tumors grown in immunocompromised mice following daily oral dosing (30 mg/kg) for 4 weeks. SF-1-responsive genes, both down- and up-regulated, identified by RNAseq (by comparison of OR-907S and OR-907R in SJ-ACC3 dissociated cell culture), also responded to OR-449 in SJ-ACC3 xenografts following 7 days of dosing, indicating transcriptional regulation of SF-1 by OR-449. Importantly, in an exploratory 2-week mouse safety study, OR-449 showed no adverse effects when dosed up to 100 mg/kg. Taken together, these findings suggest that SF-1 antagonists could provide a safe and effective targeted therapy for ACC. References: (1) Mohan, et al., Curr. Opin. Endocrinol. Metab. Res., 2019; 8:72; (2) Corces, et al., Science, 2018; 362:eaav1898; (3) Pinto, et al., Clin. Cancer. Res., 2013; 19:1740.

scholarly journals SUN-LB23 Translational Feasibility of Steroidogenic Factor-1 Antagonists as a Novel Targeted Therapy for Adrenocortical Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Paul D Crowe ◽  
Haiyan Tao ◽  
Ray Fox ◽  
Neil Raheja ◽  
Scott McNear Thacher
Keyword(s):  
Targeted Therapy ◽  
Cell Cultures ◽  
Locally Advanced ◽  
Tumor Resection ◽  
Tumor Cell Line ◽  
High Rate ◽  
Tumor Xenograft ◽  
Orphan Nuclear Receptor ◽  
Steroidogenic Factor 1 ◽  
Structural Class

Abstract Adrenocortical carcinoma (ACC) is an aggressive cancer with devastating outcomes. ACC is usually locally advanced or metastatic at diagnosis and, despite tumor resection plus chemotherapy, has a high rate of recurrence. The 5-year survival rate among metastatic ACC patients is less than 15%. ACC responds poorly to the single FDA-approved drug, mitotane, which is non-specifically adrenolytic and highly toxic. Other chemotherapy regimens tested have been unsuccessful in improving overall survival. Steroidogenic factor-1 (SF-1 or NR5A1) is an orphan nuclear receptor essential for growth and development of the adrenal gland and is the major, active transcription factor in ACC (1,2). To address the need for a targeted therapy in ACC, we have identified potent small molecule SF-1 antagonists that block SF-1 transcriptional activity through the ligand-binding domain (IC50 = 15-20 nM in a CHO cell reporter assay). In short-term dissociated cell cultures established from SJ-ACC3 (3), a pediatric ACC patient-derived tumor xenograft (PDX), the SF-1 antagonists OR-907S and OR-070 blocked DNA synthesis as measured by inhibition of EdU incorporation in SF-1+ cells (IC50 = 500-600 nM, >80% efficacy at 10 μM) whereas OR-907R, the 100-fold less potent enantiomer of OR-907S, is nearly inactive. Because the SF-1 antagonist sensitivity of the dissociated SJ-ACC3 cells declines markedly with repeated passage of the PDX in immunocompromised (C.B-17 SCID) mice, we have utilized an alternative model system for evaluating tumor target engagement and growth inhibition: the rat Leydig tumor cell line (R2C), which is growth-inhibited by the SF-1 antagonists OR-907S and OR-070 in vitro (IC50 = 60-100 nM) and as a xenograft in immunocompromised mice (CD-1 nude). The SF-1-responsive gene signature identified by RNAseq in R2C cell cultures by comparison of OR-907S and OR-907R was replicated by OR-070 and other orally-bioavailable lead antagonists in R2C xenografts following 3 days of dosing, indicating engagement of SF-1 by these compounds. Significantly, R2C tumors were growth-inhibited following daily oral dosing for 4 weeks with OR-070 (10-30 mg/kg). These findings suggest that SF-1 antagonists could be a targeted therapy for ACC. OR-070 has >30% oral bioavailability in rat and dog, indicating that this structural class of SF-1 antagonists has potential for clinical development.References: (1) Mohan, et al., Curr. Opin. Endocrinol. Metab. Res., 2019; 8:72; (2) Corces, et al., Science, 2018; 362:eaav1898; (3) Pinto, et al., Clin. Cancer. Res., 2013; 19:1740.

Thymoma: From Chemotherapy to Targeted Therapy

2012 ◽  
pp. 475-479
Author(s):  
Nicolas Girard
Keyword(s):  
Targeted Therapy ◽  
Personalized Medicine ◽  
Molecular Characterization ◽  
Surgical Resection ◽  
Locally Advanced ◽  
Tumor Burden ◽  
Advanced Tumor ◽  
Druggable Targets ◽  
Locally Advanced Tumor

Overview: Thymic malignancies are rare epithelial tumors that may be aggressive and difficult to treat. Thymomas are frequently eligible for upfront surgical resection. However, nearly 30% of patients present with locally advanced tumor at time of diagnosis, and chemotherapy is then used to reduce the tumor burden—possibly allowing subsequent surgery and/or radiotherapy. Metastatic and recurrent thymic malignancies may be similarly treated with chemotherapy. More recently, the molecular characterization of thymoma led to the identification of potentially druggable targets, laying the foundation to implement personalized medicine for patients.

Differential tumor and normal mucosa biomarker modulation by epidermal growth factor receptor (EGFR) inhibition using erlotinib in oral cavity squamous cell carcinoma (OCSCC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 6077-6077
Author(s):  
C. Tsien ◽  
M. Nyati ◽  
D. Chepeha ◽  
F. Worden ◽  
J. Helman ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Surgical Resection ◽  
Locally Advanced ◽  
Immunohistochemical Analysis ◽  
Normal Mucosa ◽  
Preclinical Model ◽  
Published Data ◽  
Head Neck Cancer ◽  
Egfr Inhibition ◽  
Tumor Biopsies

6077 Background: Targeted therapy may improve the therapeutic index in locally advanced head neck cancer if differential EGFR inhibition in tumors compared to the normal mucosa is demonstrated. Based on prior published data, EGFR degradation is an important biomarker of cytotoxicity in a preclinical model. The aim of this pilot study was to determine if there are differences in biomarker modulation between tumor and the normal mucosa and confirm our initial preclinical findings regarding EGFR degradation. Methods: Patients with primary OCSCC requiring surgical resection had normal mucosa and tumor biopsies prior to a test course of erlotinib. Patients received one week of erlotinib 150 mg qd. Repeat tumor and normal mucosal biopsies were obtained at the time of surgical resection to evaluate the effect of the EGFR inhibitor on both tumor and the normal mucosa. Changes in known preclinical markers of EGFR activity (phospho, total EGFR, AKT, STAT3) were measured by immunoblotting assays. In addition, changes in distribution of these biomarkers were analyzed by immunohistochemical analysis. Results: 12 pts were enrolled; 7 pts with paired tumor and normal mucosa biopsies. Tumor specimens showed over-expression of EGFR compared to the normal mucosa (p = 0.005). Erlotinib treatment led to marked inhibition of both pEGFR and EGFR protein (p = 0.004 and p = 0.007, respectively) in tumor biopsies. In contrast, we found heterogeneity in EGFR inhibition in the normal mucosa following erlotinib. (p = 0.1 [pEGFR], and p = 0.07 [EGFR)]) We noted dramatic reduced levels of pSrc and pSTAT3 following erlotinib in tumors compared to untreated matched tumor samples. In addition, levels of p27 were enhanced. Conclusions: Differential EGFR inhibition in tumors compared to the normal mucosa, may suggest that the addition of EGFR inhibitors to chemo-RT or accelerated RT, whose dose limiting toxicity is acute mucositis, may select patients who will benefit from targeted therapy. Our results demonstrate that EGFR inhibition by erlotinib led to marked reduction in EGFR protein levels. EGFR degradation may be an important biomarker in selecting patients predicted to have a response to TKI. These results need further validation. No significant financial relationships to disclose.

scholarly journals Results of surgical treatment of localized and locally advanced adrenocortical cancer in children

2021 ◽  
Vol 8 (2) ◽  
pp. 42-49
Author(s):  
A. S. Temniy ◽  
A. P. Kazantsev ◽  
P. A. Kerimov ◽  
N. Yu. Kalinchenko ◽  
M. V. Rubanskaya ◽  
...  
Keyword(s):  
Surgical Treatment ◽  
Surgical Resection ◽  
Locally Advanced ◽  
Surgical Excision ◽  
Stage I ◽  
Adrenocortical Cancer ◽  
Ki 67 ◽  
Results Of Treatment ◽  
Low Incidence ◽  
Radical Surgical Resection

Introduction. Adrenal cortical carcinoma (ACC) is a rare cancer but is the most common primary cancer in the adrenal gland. Despite the low incidence of ACC the mortality rate ranges from 0.04 to 0.2 %, in the overall structure of cancer mortality. Treatment of ACC is mainly surgical and radical surgical excision is the treatment of choice for local disease stages.Aim of the study — to present our results of surgical treatment of localized and locally advanced ACC in children and to determine the risk factors of relapse.Materials and methods. Twenty-eight patients (median age of 47.8 (06—216) mo.) with localized and locally advanced ACC underwent a retrospectively analysis. Stage I, II, and III revealed in 12 (45 %), 7 (25 %), and 9 (30 %), respectively. In 19 (68 %) cases the secretion of one or more hormone observed. Macroscopically and microscopically complete resection were performed in 26 (93 %) and 23 (82 %) patients, respectively. The median tumor volume was 183 (3.6—1608) cm3 and the median tumor weight was 207.9 (48—710) g.Results. Five-year overall (OS) and relapse-free (RFS) survival were 71 % and 69 %, respectively. OS and RFS according to stage I, II, and III were 100 % vs. 71 % vs. 17 % and 100 % vs. 71 % vs. 14 % respectively. The radical surgical resection and the level of Ki-67 expression influenced significantly the rates of OS and RFS (p < 0.001).Conclusion. The main factor affecting the survival rate of ACC in children with stages I—III is the radical surgical resection. It should be taken into account when planning postoperative therapy. Some of biological characteristics of the tumor could also significantly affect the results of treatment.

scholarly journals SUMOylation Inhibits SF-1 Activity by Reducing CDK7-Mediated Serine 203 Phosphorylation

2008 ◽  
Vol 29 (3) ◽  
pp. 613-625 ◽  
Author(s):  
Wei-Hsiung Yang ◽  
Joanne H. Heaton ◽  
Holly Brevig ◽  
Sarmistha Mukherjee ◽  
Jorge A. Iñiguez-Lluhí ◽  
...  
Keyword(s):  
Target Genes ◽  
Orphan Nuclear Receptor ◽  
Adrenocortical Cancer ◽  
Steroidogenic Enzyme ◽  
Hormonal Stimulation ◽  
Steroidogenic Factor 1 ◽  
Protein Levels ◽  
Endogenous Genes ◽  
Hormone Biosynthesis ◽  
Promoter Occupancy

ABSTRACT Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor selectively expressed in the adrenal cortex and gonads, where it mediates the hormonal stimulation of multiple genes involved in steroid hormone biosynthesis. SF-1 is the target of both phosphorylation and SUMOylation, but how these modifications interact or contribute to SF-1 regulation of endogenous genes remains poorly defined. We found that SF-1 is selectively SUMOylated at K194 in Y1 adrenocarcinoma cells and that although SUMOylation does not alter the subcellular localization of SF-1, the modification inhibits the ability of SF-1 to activate target genes. Notably, whereas SF-1 SUMOylation is independent of S203 phosphorylation and is unaffected by adrenocorticotropin (ACTH) treatment, loss of SUMOylation leads to enhanced SF-1 phosphorylation at serine 203. Furthermore, preventing SF-1 SUMOylation increases the mRNA and protein levels of multiple steroidogenic enzyme genes. Analysis of the StAR promoter indicates that blockade of SF-1 SUMOylation leads to an increase in overall promoter occupancy but does not alter the oscillatory recruitment dynamics in response to ACTH. Notably, we find that CDK7 binds preferentially to the SUMOylation-deficient form of SF-1 and that CDK7 inhibition reduces phosphorylation of SF-1. Based on these observations, we propose a coordinated modification model in which inhibition of SF-1-mediated transcription by SUMOylation in adrenocortical cancer cells is mediated through reduced CDK7-induced phosphorylation of SF-1.

scholarly journals Co-Clinical Trials: An Innovative Drug Development Platform for Cholangiocarcinoma

2021 ◽  
Vol 14 (1) ◽  
pp. 51
Author(s):  
Brinda Balasubramanian ◽  
Simran Venkatraman ◽  
Kyaw Zwar Myint ◽  
Tavan Janvilisri ◽  
Kanokpan Wongprasert ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Drug Development ◽  
Surgical Resection ◽  
Treatment Options ◽  
Standard Of Care ◽  
Time Data ◽  
Current Standard ◽  
Innovative Drug ◽  
Curative Intent

Cholangiocarcinoma (CCA), a group of malignancies that originate from the biliary tract, is associated with a high mortality rate and a concerning increase in worldwide incidence. In Thailand, where the incidence of CCA is the highest, the socioeconomic burden is severe. Yet, treatment options are limited, with surgical resection being the only form of treatment with curative intent. The current standard-of-care remains adjuvant and palliative chemotherapy which is ineffective in most patients. The overall survival rate is dismal, even after surgical resection and the tumor heterogeneity further complicates treatment. Together, this makes CCA a significant burden in Southeast Asia. For effective management of CCA, treatment must be tailored to each patient, individually, for which an assortment of targeted therapies must be available. Despite the increasing numbers of clinical studies in CCA, targeted therapy drugs rarely get approved for clinical use. In this review, we discuss the shortcomings of the conventional clinical trial process and propose the implementation of a novel concept, co-clinical trials to expedite drug development for CCA patients. In co-clinical trials, the preclinical studies and clinical trials are conducted simultaneously, thus enabling real-time data integration to accurately stratify and customize treatment for patients, individually. Hence, co-clinical trials are expected to improve the outcomes of clinical trials and consequently, encourage the approval of targeted therapy drugs. The increased availability of targeted therapy drugs for treatment is expected to facilitate the application of precision medicine in CCA.

scholarly journals Disulfiram Acts as a Potent Radio-Chemo Sensitizer in Head and Neck Squamous Cell Carcinoma Cell Lines and Transplanted Xenografts

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 517
Author(s):  
Wenhao Yao ◽  
Xu Qian ◽  
Sebastian Ochsenreither ◽  
Ferrone Soldano ◽  
Albert B. DeLeo ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Colony Formation ◽  
Therapeutic Potential ◽  
Synergistic Effects ◽  
Locally Advanced ◽  
Neck Squamous Cell Carcinoma ◽  
Tumor Xenograft

The poor prognosis of locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC) is primarily mediated by the functional properties of cancer stem cells (CSCs) and resistance to chemoradiotherapy. We investigated whether the aldehyde dehydrogenase (ALDH) inhibitor disulfiram (DSF) can enhance the sensitivity of therapy. Cell viability was assessed by the 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) and apoptosis assays, and the cell cycle and reactive oxygen species (ROS) levels were evaluated by fluorescence-activated cell sorting (FACS). The radio-sensitizing effect was measured by a colony formation assay. The synergistic effects were calculated by combination index (CI) analyses. The DSF and DSF/Cu2+ inhibited the cell proliferation (inhibitory concentration 50 (IC50) of DSF and DSF/Cu2+ were 13.96 μM and 0.24 μM). DSF and cisplatin displayed a synergistic effect (CI values were <1). DSF or DSF/Cu2+ abolished the cisplatin-induced G2/M arrest (from 52.9% to 40.7% and 41.1%), and combining irradiation (IR) with DSF or DSF/Cu2+ reduced the colony formation and attenuated the G2/M arrest (from 53.6% to 40.2% and 41.9%). The combination of cisplatin, DSF or DSF/Cu2+, and IR enhanced the radio-chemo sensitivity by inducing apoptosis (42.04% and 32.21%) and ROS activity (46.3% and 37.4%). DSF and DSF/Cu2+ enhanced the sensitivity of HNSCC to cisplatin and IR. Confirming the initial data from patient-derived tumor xenograft (PDX) supported a strong rationale to repurpose DSF as a radio-chemosensitizer and to assess its therapeutic potential in a clinical setting.

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