Po Hien Ear’s research while affiliated with Mercy Iowa City and other places

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Publications (34)


GLP-1R agonist promotes proliferation of neuroendocrine neoplasm cells expressing GLP-1 receptors
  • Article

December 2024

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6 Reads

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1 Citation

Surgery

Jonathan S. Shilyansky

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Casandro J. Chan

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Sophia Xiao

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[...]

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Po Hien Ear


Peptide Receptor Radionuclide Therapy Improves Survival in Patients Who Progress After Resection of Gastroenteropancreatic Neuroendocrine Tumors

November 2024

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14 Reads

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1 Citation

Annals of Surgical Oncology

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for advanced gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). We investigated a 2-decade experience with PRRT to determine whether PRRT confers a survival advantage to patients who progress after surgery versus other therapies. We identified patients from our clinic who had resection/cytoreduction of GEP-NETs, then disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The Kaplan–Meier method assessed progression-free survival (PFS) and overall survival (OS), calculated from progression after surgery (no-PRRT group) or the start of PRRT. Cox regression with time-dependent covariates controlled for immortal time bias and other confounders. Overall, 237 patients progressed after surgery; 95 received PRRT and 142 did not. No differences existed in sex, T or N stage, tumor grade/differentiation, primary site, or time to progression; 94% of PRRT patients had metastases at diagnosis versus 77% in the no-PRRT group. Median PFS was longer in the PRRT group versus the no-PRRT group (32.4 vs. 11.0 months, p < 0.001), as was median OS (49.8 vs. 38.4 months; p = 0.009). In subgroup analysis, the PRRT group had improved PFS in small bowel NETs and pancreatic NETs. Time-dependent covariate analysis revealed a lower risk of death associated with PRRT (hazard ratio 0.61, p = 0.028) after adjusting for sex, age, M stage, tumor grade, and primary site. Surgical resection and cytoreduction is an effective treatment for patients with GEP-NETs, but most patients with metastatic disease develop recurrent disease. Surgery followed by PRRT after progression conferred superior PFS and OS over no PRRT/other therapies, and is an effective strategy for managing patients with GEP-NETs.


NET models meeting 2024: the current state of neuroendocrine tumour research models and our future aspirations
  • Literature Review
  • Full-text available

November 2024

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24 Reads

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1 Citation

Endocrine Oncology

Current models for the study of neuroendocrine tumours (NETs) are severely limited. While in vitro (e.g. cell lines), ex vivo (e.g. organoids), and in vivo (e.g. mice) models all exist, each has limitations. To address these limitations and collectively identify strategies to move the NET models field forward, we held an inaugural NET Models meeting, hosted by our founding group: Dr. Lines (Oxford); Prof. Quelle (Iowa); Dr. Dayton (Barcelona); Dr. Ear (Iowa); Dr. Marinoni (Bern); and Dr. Guenter (Alabama). This 2-day meeting in Oxford (UK) was organised and supported by Bioscientifica Ltd and was solely dedicated to the discussion of NET models. The meeting was attended by 30 international researchers (from UK, EU, Israel, USA and Canada). Plenary talks were given by Prof. Thakker who summarised NET research over the last few decades, and Dr. Schrader who described the process and pitfalls of generating new cell lines. Eight researchers also presented their work on topics ranging from human cell 3D bioprinting, to zebrafish models, and included novel ideas as well as improvements on current concepts. This was followed by an interactive workshop where discussion topics included, a summary of currently available NET models, limitations of these models, barriers to developing new models, and how we can address these issues going forward. This white paper summarises the key points raised in these discussions, as well as the future aspirations of the NET Models Consortium. The next meeting will take place in Oxford (UK) in 2025, contact contact@netcancerfoundation.com for more information.

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Abstract 3578: A systematic NEN spheroid drug screen reveals a novel drug resistance mechanism in small bowel NETs

March 2024

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23 Reads

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1 Citation

Cancer Research

Neuroendocrine neoplasms (NENs) are rare cancers that arise from neuroendocrine cells. NENs are classified as well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Small bowel NETs (SBNETs) and pancreatic NETs (PNETs) are generally slow growing but they commonly metastasize to the liver and can become aggressive cancers. NECs are rapidly growing, and patients have poor prognosis. Little is known about the drug sensitivity profile of SBNETs, PNETs and NECs due to a paucity of cellular and animal models of these malignancies. We have successfully cultured NEN cells from clinical samples as patient-derived spheroids (PDS) and showed that they express appropriate tumor markers. We systematically screened 20 NEN (12 SBNET, 5 PNET, and 3 NEC) spheroid cultures against a library of 175 compounds (147 FDA-approved anti-cancer drugs, 8 lab selected compounds, and 20 structurally diverse molecules) and compared their drug sensitivity profiles to identify the most effective drug classes and to better understand the biology of each NEN subtype. Top drug hits were validated for their anti-tumor properties in NEN PDS and patient-derived xenograft (PDX) mouse models. Our NEN PDS cultures identified common and unique drug sensitivity profiles for each type of NEN. SBNET spheroids were more resistant to many classes of anti-cancer drugs, which was due to overexpression of cytochrome P450 genes. Consistent with clinical findings, PNET spheroids showed increased sensitivity to tyrosine kinase and mTOR/PI3K inhibitors compared to SBNET & NEC spheroids. NEC spheroids showed the broadest sensitivity to many anti-neoplastic compounds. The top candidate drug identified from our screen was romidepsin, a histone deacetylase inhibitor. Romidepsin displayed anti-tumor properties in vitro and in vivo for all 3 NEN models and was highly synergistic with rapamycin, an mTOR inhibitor similar to the SBNET approved drug everolimus. Excitingly, low-dose romidepsin effectively inhibited tumor growth when combined with low-dose rapamycin in an SBNET PDX mouse model. These NEN PDS drug screens enabled direct drug testing in primary tumor cultures to identify promising drugs that could be used alone or in combination with currently approved-NEN therapies. Histone deacetylase inhibitors, such as romidepsin, may be effective against SBNETs. NEN PDS models also serve as a valuable resource for understanding the unique biology and mechanisms of drug resistance for specific NEN subtypes. Citation Format: Catherine G. Tran, Luis C. Borbon, Dane H. Tow, Jonathan Shilyansky, Guiying Li, James Egan, Scott K. Sherman, Ellen Abusada, Jing Tang, Ramaswamy govindan, Ryan C. Fields, Terry A. Braun, Carlos HF Chan, Chandrikha Chandrasekharan, Douglas Spitz, Dawn E. Quelle, Andrew M. Bellizzi, James R. Howe, Po Hien Ear. A systematic NEN spheroid drug screen reveals a novel drug resistance mechanism in small bowel NETs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3578.


Abstract 5953: DUSP6 is a novel target in neuroendocrine tumors

March 2024

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12 Reads

Cancer Research

Background: Neuroendocrine tumors (NETs) are rare malignancies derived from enterochromaffin cells of the diffuse neuroendocrine system and most frequently observed in the gastrointestinal tract and bronchopulmonary system. Surgery is the major treatment for localized NETs. In high-grade NETs, treatment opportunities include chemotherapeutic drugs such as temozolomide (TEM), and capecitabine and small-molecule targeted therapies such as everolimus or sunitinib. Despite promising initial responses, most patients develop therapy resistance by unknown mechanisms. Therefore, there is a pressing need to apprehend the mechanisms of resistance to improve the therapeutic efficacy of the current treatments. Phosphatases are emerging and novel targets in human malignancies and their modulation yields significant anti-tumor activities. Dual specificity phosphatase 6 (DUSP6) is a MAPK phosphatase and mainly binds to and dephosphorylates extracellular signal-regulated kinase (ERK)1/2. DUSP6 expression is increased in several malignancies, correlating with distant metastases and a worse clinical outcome. Moreover, DUSP6 mediates resistance to certain chemotherapeutics and small molecular tyrosine kinase inhibitors and its blockade increases therapeutic sensitivity. The current study aimed to investigate the contribution of DUSP6 to therapy resistance in the NET models. Material and Methods: Using Western blot analysis, the expression of DUSP6 was measured in 8 clinical samples of small bowel neuroendocrine tumors, the NET cell lines BON-1, H69, IMR-32, QGP and H524 and two PDX models, 1452 (rectal neuroendocrine) and 913 (pancreatic neuroendocrine). The effects of DUSP6 depletion on cell viability were explored using a pharmacological inhibitor, BCI, and its siRNA-mediated knockdown. Moreover, BCI-mediated apoptotic cell death was measured by an annexin V/PI staining assay. Results: DUSP6 expression was positive in 5 out of 8 clinical samples, 4 NET cell lines and both the PDX models. BCI treatment induced an apoptotic response in the NET models and synergistically increased sensitivity to TMZ and cisplatin in 1452 cells., RNAi-mediated depletion of DUSP6 also increased sensitivity to sunitinib and triggered TMZ-induced apoptotic cell death in 1452 cells, which was associated with changes in (O6-Methylguanine-DNA-methyltransferase) MGMT expression. These findings suggest that DUSP6 is an important therapeutic target in neuroendocrine tumors and its blockade is a promising therapeutic approach to enhance the therapeutic index of current treatments. Citation Format: Majid Momeny, Vahid Khalaj, Solmaz AghaAmiri, Po Hien Ear, Servando Hernandez Vargas, Sukhen Ghosh, Ali Azhdarinia. DUSP6 is a novel target in neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5953.


Abstract 146: Development of a novel pediatric patient-derived xenograft model with THPO and NDUFB3 mutations

March 2024

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15 Reads

Cancer Research

Familial myeloproliferative neoplasms (MPN) of childhood are extremely rare and have propensity towards malignant transformation such as leukemia and lymphoma. Due to the rarity of these cases, few cellular and mouse models are available for understanding the tumor biology. Therefore, the molecular mechanisms of malignant transformation remain poorly understood limiting the therapeutic progress to treat these conditions. Here, we report the development of a novel pediatric patient-derived xenograft (PDX) mouse model harboring mutations in the THPO and mitochondrial subunit NDUFB3 genes and characterization of their functions. THPO is a regulator of hematopoiesis and induces trilineage hematopoiesis through HSPC proliferation while NDUFB3 is a subunit of the mitochondrial complex 1. We isolated malignant cells from an enlarged spleen sample and blood sample from a pediatric patient with TPO mediated MPN and established a PDX model (PDX-2333) that recapitulates the patient’s disease. Short tandem repeat analyses confirmed an exact match between the PDX-2333 tumors and patient samples. Exome and Sanger sequencing analyses were performed to identify mutations. Immunohistochemistry staining was used for tumor characterization. Wildtype (WT) and mutant forms of NDUFB3 genes were cloned into expression plasmids with a puromycin selection marker and stably transfected in HEK-293 cells. Stable clones of HEK-293 overexpressing WT and NDUFB3 mutants were tested for growth and sensitivity to anti-cancer therapies. We established a novel PDX model of lymphomagenesis harboring unique mutations in THPO and NDUFB3 genes. The THPO (c.-52C>T) mutation in upstream open reading frame causes loss of inhibition of THPO mRNA expression. The NDUFB3 (c.23 A>G) mutation results in a change of amino acid from glutamine 8 (E8) to glycine 8 (G8) (Ndufb3_E8) and is highly conserved in many vertebrate species. HEK-293 cell lines stably overexpressing WT or NDUFB3 mutants were tested for growth and their sensitivity to ruxolitinib, a Jak2 inhibitor and doxorubicin, an FDA-approved treatment for leukemia and lymphoma. Our data showed that cells overexpressing Ndufb3_E8 have increased proliferation and are highly resistant to ruxolitinib and doxorubicin in comparison to the WT NDUFB3. Developing a novel pediatric PDX model and exome sequencing allow us to identify novel genes involved in malignant transformation leading to lymphoma development. Our data demonstrated that mutations in the THPO (c.-52C>T) and NDUFB3 (c.23 A>G) genes play a key role in the pathogenesis of a lymphoma and in regulating drug sensitivity. Citation Format: Jonathan Shilyansky, Casandro J. Chan, Kristen L. Coleman, Mariah Leidinger, Sharathkumar Bhagavathi, Anjali Sharathkumar, Po Hien Ear. Development of a novel pediatric patient-derived xenograft model with THPO and NDUFB3 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 146.


Abstract 7615: Epithelial-mesenchymal-transition gene signature changes and poor oncological outcome in Candida -positive pancreatic ductal adenocarcinoma

March 2024

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20 Reads

Cancer Research

Candida are commonly found in bile collected during surgery in pancreatic ductal adenocarcinoma (PDAC) patients. However, their significance in tumor biology and oncological outcome is unclear. PDAC patients receiving neoadjuvant therapy and pancreatectomy with intraoperative bile fungal culture were identified (N=40) in a prospective single-institution cohort. Tumor regression scores (TRS) were abstracted from pathology reports and correlated with bile fungal cultures. Bulk tumor RNASeq data were obtained from the Oncology Research Information Exchange Network (ORIEN). Tumor microbiome data of non-metastatic PDAC patients with upfront surgery were extracted using the {exotic} tool (Hoyd et al. Cancer Res. Commun., 2023). Gene expression profiles were compared between Candida+ and Candida- tumors, defined by a cutoff microbial count of 0. Overall survival (OS) of resected PDAC patients with Candida+ and Candida- tumors was compared using Kaplan Meier survival analysis. From the single-institution PDAC cohort, Candida+ bile was associated with poor pathological response to neoadjuvant therapy (Table 1). Using the ORIEN cohort, Candida were detected in 67% (106/158) of the PDAC tumors. Patients with Candida+ tumors had worse OS (median 28 vs. 56 months, Log-Rank p<0.008). Gene Set Enrichment Analysis (GSEA) using Hallmark gene sets showed an enrichment of epithelial-mesenchymal-transition (EMT) gene set and a reduction of metabolic and DNA repair gene sets in Candida+ tumors. GSEA for Immune signature and Tumor Immune Microenvironment Deconvolution (TIMEx) cell types showed an enrichment of Stromal-Fibroblast and EMT signature in Candida+ tumors. Further investigations are underway to determine the causal and metabolic relationship between Candida and this tumor microenvironment with EMT and stromal fibroblasts which is a well-known contributor to poor chemotherapy response and oncological outcome of PDAC. Table 1: Pathological Response to Neoadjuvant Therapy for PDAC Bile Culture TRS0/1 TRS2 TRS3 Candida - 5 (25%) 15 (75%) 0 (0%) Candida + 1 (5%) 11 (55%) 8 (40%) TRS: Tumor Regression Score (TRS0: complete response; TRS1: near-complete response; TRS2: partial response; TRS3: no response). Chi-Square Test, P=0.0035. Citation Format: Po Hien Ear, Min Hu, Jonathan S. Shilyansky, Naomi H. Fei, Sam Coleman, Rebecca Hoyd, Caroline E. Wheeler, Kelsey L. Steckly, Michelle L. Churchman, Nicholas Denko, Rebecca D. Dodd, Sheetal Hardikar, Ning Jin, Qin Ma, Martin D. McCarter, Abdul Rafeh Naqash, Afaf E. Osman, Gregory Riedlinger, Lary A. Robinson, Bryan P. Schneider, Eric A. Singer, Ahmad A. Tarhini, Gabriel Tinoco, Cornelia M. Ulrich, Yousef Zakharia, Daniel Spakowicz, Aik Choon Tan, Carlos H. Chan. Epithelial-mesenchymal-transition gene signature changes and poor oncological outcome in Candida-positive pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7615.



Citations (17)


... The effect of glucagon-like peptide (GLP)-1 agonist, another anti-diabetic agent, on malignancy has also been reported [29]. Similar to CANA in this study, GLP-1 agonists exhibit anti-cancer effects as well as tumor-promoting effects which appear to depend on the cancer type [29,30]. No report has compared the anti-cancer effects of SGLT2 inhibitors and GLP-1 agonists. ...

Reference:

Dual Roles of Canagliflozin on Cholangiocarcinoma Cell Growth and Enhanced Growth Suppression in Combination with FK866
GLP-1R agonist promotes proliferation of neuroendocrine neoplasm cells expressing GLP-1 receptors
  • Citing Article
  • December 2024

Surgery

... Moreover, spontaneous insulinomas in dogs provide a model with intact host immunity, as well as natural tumor heterogeneity and microenvironment. However, further research into the genetic background of these tumors is needed to determine whether they share the same drivers as those found in human patients 8 . ...

NET models meeting 2024: the current state of neuroendocrine tumour research models and our future aspirations

Endocrine Oncology

... The authors, Perez-Castro in 2023 [44] believe that the role of Trp and its metabolites in growth and homeostasis is only beginning to be understood [44]. The enzymes that limit tryptophan metabolism, IDO, TDO, KMO and TPH, are current targets of therapeutic strategies for treating diseases [45][46][47][48][49]. ...

A luminescent sensor for investigating serotonin metabolism in neuroendocrine cancer
  • Citing Article
  • October 2023

Surgery

... Some of these tumor cells can be grown in culture as spheroids, but they grow very slowly and are difficult to propagate as xenografts. [20][21][22] The 2 widely used cell lines, BON 23 and QGP1 24 resemble poorly differentiated NECs 25-27 , and unfortunately express low level of NEN markers such as the somatostatin receptor 2 (SSTR2). 25 Although well-differentiated GEP NET cell lines such as the P-STS, GOT1, and NT-3 cells have been described 25,26,28 , difficulties growing these cells in abundance have limited their distribution to other researchers. ...

Establishment and Characterization of Small Bowel Neuroendocrine Tumor Spheroids
  • Citing Article
  • October 2019

Journal of Visualized Experiments

... The identification of any dangerous or unwanted side effects, such as birth defects, infertility, toxicity, liver damage, or potential carcinogenic effects, is of paramount importance. The use of genetically engineered mouse models of tumor luminescence to study pituitary tumors [44], observe the development of oligodendrocyte tumors [45], and examine the growth and potential metastasis of prostate and breast cancers represents a novel approach to the study of liver and lymphoid tumors [46][47][48]. ...

Preclinical Models of Neuroendocrine Neoplasia

... Moreover, this approach may prove beneficial in peptide, protein-fragment, or particle-based targeting strategies, where the characteristics of small molecule labeling chemistry can significantly influence in vivo properties. [58][59][60] Ultimately, the BAC-based linker may facilitate the devel- opment of particularly well-tolerated drug delivery constructs, and efforts towards this goal are currently underway. ...

High-Contrast Detection of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery
  • Citing Article
  • September 2022

Molecular Pharmaceutics

... In a recent study, Borbon et al. 30 reported a median overall survival of 19 months for patients with well-differentiated grade 3 gastroenteropancreatic NETs managed nonoperatively, most of whom had distant metastatic disease, and additional studies have shown similar results. 31,32 Although patient selection must again be considered when outcomes after operative and nonoperative therapy are compared, these results suggest that high grade alone should not preclude patients from consideration for cytoreductive hepatectomy. ...

Is There a Role for Surgical Resection of Grade 3 Neuroendocrine Neoplasms?
  • Citing Article
  • July 2022

Annals of Surgical Oncology

... Direct radiolabeling via the MMC allowed us to examine the pharmacological properties of the drug conjugate in vitro using the standard methodology for PET tracer development. First, we radiolabeled MMC(TMZ)-TOC and DOTA-TOC with 67 Ga and performed saturation binding assays to measure the equilibrium dissociation constant (K d ). The K d for 67/nat Ga-MMC(TMZ)-TOC was calculated to be 5.98 ± 0.96 nmol/L, which compared favorably to that of 67/nat Ga-DOTA-TOC (4.68 ± 0.7 nmol/L) and indicated a high binding affinity for SSTR2 ( Figure 2A). ...

Establishment of Novel Neuroendocrine Carcinoma Patient-Derived Xenograft Models for Receptor Peptide-Targeted Therapy

... There are >20 genes described to be mutated in NETs, with the most common being Menin 1 (MEN1), death-domain-associated protein (DAXX), and ATRX Chromatin Remodeler (ATRX), which occur in 40-70% of sporadic G1-3 Pancreatic NETs (PanNETs) and Cyclin-dependent kinase inhibitor 1B (CDKN1B) that occurs in approximately 10% of sporadic G1-3 small intestinal NETs (siNETs) (Di Domenico, et al. 2017;Francis, et al. 2013;Jiao, et al. 2011;Scarpa, et al. 2017;van Riet, et al. 2021). Mutations in other genes, such as Phosphatase And Tensin Homolog (PTEN), and those in the mammalian target of rapamycin (mTOR) signalling pathway have also been identified, predominately in PanNETs, but at lower frequencies (Di Domenico, et al. 2017;Jiao, et al. 2011;Maharjan, et al. 2021;van Riet, et al. 2021). ...

Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

... However, D-NETs of >2 cm or of any size with lymph node involvement, or located in the ampullary of peri-ampullary region are treated via surgical resection [18]. Furthermore, Howe et al. in their series of 104 patients concluded that in 1-2 cm DNETs, there was no difference in survival between endoscopic resection and surgical resection after age adjustment [19]. Inoperable D-NET or metastatic disease are treated with peptide receptor chemo radionuclide therapy [20]. ...

Management of Duodenal Neuroendocrine Tumors: Surgical versus Endoscopic Mucosal Resection
  • Citing Article
  • September 2021

Annals of Surgical Oncology