Browsing by Author "Cheng, Monica"

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    Combined targeting of TGF-beta, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model
    (Elsevier, 2016-08-28) Gore, Jesse; Imasuen-Williams, Imade E.; Conteh, Abass M.; Craven, Kelly E.; Cheng, Monica; Korc, Murray; Medicine, School of Medicine
    Pancreatic ductal adenocarcinomas (PDAC) are aggressive with frequent lymphatic spread. By analysis of data from The Cancer Genome Atlas, we determined that ∼35% of PDACs have a pro-angiogenic gene signature. We now show that the same PDACs exhibit increased expression of lymphangiogenic genes and lymphatic endothelial cell (LEC) markers, and that LEC abundance in human PDACs correlates with endothelial cell microvessel density. Lymphangiogenic genes and LECs are also elevated in murine PDACs arising in the KRC (mutated Kras; deleted RB) and KIC (mutated Kras; deleted INK4a) genetic models. Moreover, pancreatic cancer cells (PCCs) derived from KRC tumors express and secrete high levels of lymphangiogenic factors, including the EGF receptor ligand, amphiregulin. Importantly, TGF-β1 increases lymphangiogenic genes and amphiregulin expression in KRC PCCs but not in murine PCCs that lack SMAD4, and combinatorial targeting of the TGF-β type I receptor (TβRI) with LY2157299 and EGFR/HER2 with lapatanib suppresses tumor growth and metastasis in a syngeneic orthotopic model, and attenuates tumor lymphangiogenesis and angiogenesis while reducing lymphangiogenic genes and amphiregulin and enhancing apoptosis. Therefore, this combination could be beneficial in PDACs with lymphangiogenic or angiogenic gene signatures.
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    Genetic Variations in the Transforming Growth Factor-β1 Pathway May Improve Predictive Power for Overall Survival in Non-small Cell Lung Cancer
    (Frontiers Media, 2021-07-07) Zhang, Hong; Wang, Weili; Pi, Wenhu; Bi, Nan; DesRosiers, Colleen; Kong, Fengchong; Cheng, Monica; Monica, Li; Yang, Li; Lautenschlaeger, Tim; Jolly, Shruti; Jin, Jianyue; Kong, Feng-Ming (Spring); Radiation Oncology, School of Medicine
    Purpose: Transforming growth factor-β1 (TGF-β1), a known immune suppressor, plays an important role in tumor progression and overall survival (OS) in many types of cancers. We hypothesized that genetic variations of single nucleotide polymorphisms (SNPs) in the TGF-β1 pathway can predict survival in patients with non-small cell lung cancer (NSCLC) after radiation therapy. Materials and Methods: Fourteen functional SNPs in the TGF-β1 pathway were measured in 166 patients with NSCLC enrolled in a multi-center clinical trial. Clinical factors, including age, gender, ethnicity, smoking status, stage group, histology, Karnofsky Performance Status, equivalent dose at 2 Gy fractions (EQD2), and the use of chemotherapy, were first tested under the univariate Cox's proportional hazards model. All significant clinical predictors were combined as a group of predictors named "Clinical." The significant SNPs under the Cox proportional hazards model were combined as a group of predictors named "SNP." The predictive powers of models using Clinical and Clinical + SNP were compared with the cross-validation concordance index (C-index) of random forest models. Results: Age, gender, stage group, smoking, histology, and EQD2 were identified as significant clinical predictors: Clinical. Among 14 SNPs, BMP2:rs235756 (HR = 0.63; 95% CI:0.42-0.93; p = 0.022), SMAD9:rs7333607 (HR = 2.79; 95% CI 1.22-6.41; p = 0.015), SMAD3:rs12102171 (HR = 0.68; 95% CI: 0.46-1.00; p = 0.050), and SMAD4: rs12456284 (HR = 0.63; 95% CI: 0.43-0.92; p = 0.016) were identified as powerful predictors of SNP. After adding SNP, the C-index of the model increased from 84.1 to 87.6% at 24 months and from 79.4 to 84.4% at 36 months. Conclusion: Genetic variations in the TGF-β1 pathway have the potential to improve the prediction accuracy for OS in patients with NSCLC.
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    Greater Reduction in Mid-treatment FDG-PET Volume May Be Associated with Worse Survival in Non-Small Cell Lung Cancer
    (Elsevier, 2019-03) Kong, Feng-Ming (Spring); Li, Ling; Wang, Weili; Campbell, Jeff; Waller, Jennifer L.; Piert, Morand; Gross, Milton; Cheng, Monica; Owen, Dawn; Stenmark, Matthew; Huang, Colin; Frey, Kirk A.; Ten Haken, Randall K.; Lawrence, Theodore S.; Radiation Oncology, School of Medicine
    Background and purpose: This study tested the hypotheses that 1) changes in mid-treatment fluorodeoxyglucose (FDG)-positron emission tomography (PET) parameters are predictive of overall survival (OS) and 2) mid-treatment FDG-PET-adapted treatment has the potential to improve survival in patients with non-small cell lung cancer (NSCLC). Material and methods: Patients with stage I-III NSCLC requiring daily fractionated radiation were eligible. FDG-PET-CT scans were obtained prior to and mid-treatment with radiotherapy at 40-50 Gy. The normalized maximum standardized uptake value (NSUVmax), normalized mean SUV (NSUVmean), PET-metabolic tumor volume (MTV), total lesion glycolysis (TLG), and computed tomography-based gross tumor volume (CT-GTV) were consistently measured for all patients. The primary study endpoint was OS. Results: The study is comprised of 102 patients who received 3-dimensional conformal radiotherapy, among whom 30 patients who received mid-treatment PET-adapted dose escalation radiotherapy. All PET-CT parameters decreased significantly (P < 0.001) mid-treatment, with greater reductions in FDG-volumetric parameters compared to FDG-activity factors. Mid-treatment changes in MTV (P = 0.053) and TLG (P = 0.021) were associated with OS, while changes in NSUVmax, NSUVmean, and CT-GTV were not (all Ps>0.1). Patients receiving conventional radiation (60-70 Gy) with MTV reductions greater than the mean had a median survival of 14 months, compared to those with MTV reductions less than the mean who had a median survival of 22 months. By contrast, patients receiving mid-treatment PET-adapted radiation with MTV reductions greater than the mean had a median survival of 33 months, compared to those with MTV reductions less than the mean who had a median survival of 19 months. Overall, PET-adapted treatment resulted in a 19% better 5-year survival than conventional radiation. Conclusion: Changes in mid-treatment PET-volumetric parameters were significantly associated with survival in NSCLC. A greater reduction in the mid-treatment MTV was associated with worse survival in patients treated with standard radiation, but with better survival in patients who received mid-treatment PET-adapted treatment.
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    Highly variable biodistribution of 68Ga labeled somatostatin analogues 68Ga-DOTA-NOC and 68Ga-DOTA-TATE in neuroendocrine tumors: clinical implications for somatostatin receptor directed PET/CT
    (AME, 2022) Cheng, Monica; Tann, Mark; Radiology and Imaging Sciences, School of Medicine
    Background: Somatostatin receptor (SSTR)-targeted positron emission tomography/computed tomography (PET/CT) imaging has risen to the forefront for neuroendocrine tumor (NET) detection and management, yet the variability of significant uptake variability (SUV) as a semiquantitative measure of disease detection and tumor response to treatment has not been fully explored. Methods: We assess the reproducibility and interscan variability of SUV metrics of normal tissue and NET in serial 68Ga-DOTA-NOC and 68Ga-DOTA-TATE PET imaging to clinically monitor disease state. Eighty-one patients were enrolled in this retrospective study. Results: Both primary and metastatic hepatic lesions demonstrated SUV (SUVmean 16.5±8.0). The median SUVmean was 16 for the spleen, 9.7 for the pituitary, 12.6 for the adrenal glands, and 4.8 for the liver. The normal pituitary gland demonstrates focal homogenous uptake with SUVmax range of 4.5-23. The adrenal gland showed uptake with SUVmax range of 4.1-29.4, which is more than two times greater than liver uptake (SUVmean range, 2.3-12.4). Highest physiological uptake seen in the spleen (average SUVmean of 17.3, range of 5.4-34.4). Conclusions: The highly variable nature of regional SUVmean and SUVmax in both physiologic tissue and lesions suggests the need for incorporation of more reliable quantitative measures for clinical decision making.
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    Modern Radiation Further Improves Survival in Non-Small Cell Lung Cancer: An Analysis of 288,670 Patients
    (Ivyspring, 2019-01-01) Cheng, Monica; Jolly, Shruti; Quarshie, William O.; Kapadia, Nirav; Vigneau, Fawn D.; Kong, Feng-Ming Spring; Radiation Oncology, School of Medicine
    Background: Radiation therapy plays an increasingly important role in the treatment of patients with non-small-cell lung cancer (NSCLC). The purpose of the present study is to assess the survival outcomes of radiotherapy treatment compared to other treatment modalities and to determine the potential role of advanced technologies in radiotherapy on improving survival. Methods: We used cancer incidence and survival data from the Surveillance, Epidemiology, and End Results database linked to U.S. Census data to compare survival outcomes of 288,670 patients with stage I-IV NSCLC treated between 1999 and 2008. The primary endpoint was overall survival. Results: Among the 288,670 patients diagnosed with stage I-IV NSCLC, 92,374 (32%) patients received radiotherapy-almost double the number receiving surgery (51,961, 18%). Compared to other treatment groups and across all stages of NSCLC, patients treated with radiotherapy showed greater median and overall survival than patients without radiation treatment (p < 0.0001). Radiotherapy had effectively improved overall survival regardless of age, gender, and histological categorization. Radiotherapy treatment received during the recent time period 2004 - 2008 is correlated with enhanced survival compared to the earlier time period 1999 - 2003. Conclusion: Radiation therapy was correlated with increased overall survival for all patients with primary NSCLC across stages. Combined surgery and radiotherapy treatment also correlates with improved survival, signaling the value of bimodal or multimodal treatments. Population-based increases in overall survival were seen in the recent time period, suggesting the potential role of advanced radiotherapeutic technologies in enhancing survival outcomes for lung cancer patients.
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    New Prostate Cancer Targets for Diagnosis, Imaging, and Therapy: Focus on Prostate-Specific Membrane Antigen
    (Frontiers, 2018-12-21) Cimadamore, Alessia; Cheng, Monica; Santoni, Matteo; Lopez-Beltran, Antonio; Battelli, Nicola; Massari, Francesco; Galosi, Andrea B.; Scarpelli, Marina; Montironi, Rodolfo; Radiology and Imaging Sciences, School of Medicine
    The rising incidence rate of the cancer in the prostate gland has increased the demand for improved diagnostic, imaging, and therapeutic approaches. Prostate-specific membrane antigen (PSMA), with folate hydrolase and carboxypeptidase and, internalization activities, is highly expressed in the epithelial cells of the prostate gland and is strongly upregulated in prostatic adenocarcinoma, with elevated expression correlating with, metastasis, progression, and androgen independence. Recently, PSMA has been an active target of investigation by several approaches, including the successful utilization of small molecule inhibitors, RNA aptamer conjugates, PSMA-based immunotherapy, and PSMA-targeted prodrug therapy. Future investigations of PSMA in prostate cancer (PCa) should focus in particular on its intracellular activities and functions. The objective of this contribution is to review the current role of PSMA as a marker for PCa diagnosis, imaging, and therapy.
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    Predicting progression of in situ carcinoma in the era of precision genomics
    (AME Publishing Company, 2019-06) Cheng, Monica; Hanna, Nasser H.; Davidson, Darrell D.; Gunderman, Richard B.; Radiology and Imaging Sciences, School of Medicine
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    T1 mapping for the diagnosis of early chronic pancreatitis: correlation with Cambridge classification system
    (British Institute of Radiology, 2021) Cheng, Monica; Gromski, Mark A.; Fogel, Evan L.; DeWitt, John M.; Patel, Aashish A.; Tirkes, Temel; Radiology and Imaging Sciences, School of Medicine
    Objective: This study aims to determine if T1 relaxation time of the pancreas can detect parenchymal changes in early chronic pancreatitis (CP). Methods: This study retrospectively analyzed 42 patients grouped as no CP (Cambridge 0; n = 21), equivocal (Cambridge 1; n = 12) or mild CP (Cambridge 2; n = 9) based on magnetic resonance cholangiopancreatography findings using the Cambridge classification as the reference standard. Unenhanced T1 maps were acquired using a three-dimensional dual flip-angle gradient-echo technique on the same 1.5 T scanner with the same imaging parameters. Results: There was no significant difference between the T1 relaxation times of Cambridge 0 and 1 group (p = 0.58). There was a significant difference (p = 0.0003) in the mean T1 relaxation times of the pancreas between the combined Cambridge 0 and 1 (mean = 639 msec, 95% CI: 617, 660) and Cambridge 2 groups (mean = 726 msec, 95% CI: 692, 759). There was significant difference (p = 0.0009) in the mean T1 relaxation times of the pancreas between the Cambridge 0 (mean = 636 msec, 95% CI: 606, 666) and Cambridge 2 groups (mean = 726 msec, 95% CI: 692,759) as well as between Cambridge 1 (mean = 643 msec, 95% CI: 608, 679) and Cambridge 2 groups (mean = 726 msec, 95% CI: 692,759) (p = 0.0017). Bland-Altman analysis showed measurements of one reader to be marginally higher than the other by 15.7 msec (2.4%, p = 0.04). Conclusion: T1 mapping is a practical method capable of quantitatively reflecting morphologic changes even in the early stages of chronic pancreatitis, and demonstrates promise for future implementation in routine clinical imaging protocols. Advances in knowledge: T1 mapping can distinguish subtle parenchymal changes seen in early stage CP, and demonstrates promise for implementation in routine imaging protocols for the diagnosis of CP.
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    TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis
    (Impact Journals, LLC, 2015-04-10) Gore, Jesse; Craven, Kelly E.; Wilson, Julie L.; Cote, Gregory A.; Cheng, Monica; Nguyen, Hai V.; Cramer, Harvey M.; Sherman, Stuart; Korc, Murray; Department of Medicine, IU School of Medicine
    Pancreatic ductal adenocarcinomas (PDACs) overexpress pro-angiogenic factors but are not viewed as vascular. Using data from The Cancer Genome Atlas we demonstrate that a subset of PDACs exhibits a strong pro-angiogenic signature that includes 37 genes, such as HDAC9, that are overexpressed in PDAC arising in KRC mice, which express mutated Kras and lack RB. Moreover, patient-derived orthotopic xenografts can exhibit tumor angiogenesis, whereas conditioned media (CM) from KRC-derived pancreatic cancer cells (PCCs) enhance endothelial cell (EC) growth and migration, and activate canonical TGF-β signaling and STAT3. Inhibition of the type I TGF-β receptor with SB505124 does not alter endothelial activation in vitro, but decreases pro-angiogenic gene expression and suppresses angiogenesis in vivo. Conversely, STAT3 silencing or JAK1-2 inhibition with ruxolitinib blocks CM-enhanced EC proliferation. STAT3 disruption also suppresses endothelial HDAC9 and blocks CM-induced HDAC9 expression, whereas HDAC9 re-expression restores CM-enhanced endothelial proliferation. Moreover, ruxolitinib blocks mitogenic EC/PCC cross-talk, and suppresses endothelial p-STAT3 and HDAC9, and PDAC progression and angiogenesis in vivo, while markedly prolonging survival of KRC mice. Thus, targeting JAK1-2 with ruxolitinib blocks a final pathway that is common to multiple pro-angiogenic factors, suppresses EC-mediated PCC proliferation, and may be useful in PDACs with a strong pro-angiogenic signature.