Ching-Wei D Tzeng

Publications of Ching-Wei D Tzeng

• ErbB3 expression promotes tumorigenesis in pancreatic adenocarcinoma.

  Authors: J Spencer Liles, Juan Pablo Arnoletti, Ching-Wei D Tzeng, J Harrison Howard, Andrew V Kossenkov, Peter Kulesza, Martin J Heslin, Andrey Frolov

  Cancer biology & therapy. 09/2010; 10(6):555-63.

  Historically, ErbB3 has been overlooked within the ErbB receptor family due to its perceived lack of tyrosine kinase activity. We have previously demonstrated that in pancreatic cancer ErbB3 is theHistorically, ErbB3 has been overlooked within the ErbB receptor family due to its perceived lack of tyrosine kinase activity. We have previously demonstrated that in pancreatic cancer ErbB3 is the preferred dimerization partner of EGFR, ErbB3 protein expression level directly correlates with the anti-proliferative effect of erlotinib (an EGFR-specific tyrosine kinase inhibitor), and transient knockdown of ErbB3 expression results in acquired resistance to EGFR-targeted therapy. In this study, we develop a stable isogenic model of ErbB3 expression in an attempt to decipher ErbB3's true contribution to pancreatic cancer tumorigenesis and to examine how this receptor affects cellular sensitivity to EGFR-targeted therapy. Analysis of the EGFR-ErbB3 heterodimer demonstrates that ligand-induced PI3K-AKT signaling is limited to ErbB3-expressing cells and that this signaling cascade can be partially abrogated by inhibiting EGFR function with erlotinib. Using our model of exogenous ErbB3 expression we showed a direct relationship between ErbB3 protein levels and increased pancreatic cancer cell proliferation in vitro. In vivo, ErbB3(+)PANC-1 xenografts had a significantly larger tumor volume than PANC-1 control xenografts (ErbB3-PANC-1) and displayed increased sensitivity to EGFR-targeted therapy. In pancreatic cancer, ErbB3 appears to be critically involved in EGFR signaling as evidenced by its profound effect on cellular proliferation and its ability to influence response to EGFR-targeted therapy.

• Epidermal growth factor receptor (EGFR) intron 1 polymorphism and clinical outcome in pancreatic adenocarcinoma.

  Authors: Andrey Frolov, J Spencer Liles, Andrew V Kossenkov, Ching-Wei D Tzeng, Nirag Jhala, Peter Kulesza, Shyam Varadarajulu, Mohamad Eloubeidi, Martin J Heslin, J Pablo Arnoletti

  American journal of surgery. 09/2010; 200(3):398-405.

  Epidermal growth factor receptor (EGFR) intron 1 has a polymorphic region of CA repeats that is believed to be associated with increased EGFR expression, tumor aggressiveness, and worse survival inEpidermal growth factor receptor (EGFR) intron 1 has a polymorphic region of CA repeats that is believed to be associated with increased EGFR expression, tumor aggressiveness, and worse survival in cancer patients. A large population of pancreatic adenocarcinoma patients was investigated to evaluate this polymorphism as a potential prognostic marker of clinical outcome. Deoxyribonucleic acid obtained from 50 resected pancreatic adenocarcinomas and from 85 diagnostic endoscopic ultrasound-guided fine-needle aspiration procedures corresponding to patients with unresectable tumors was included. The correlation between CA repeat length and EGFR messenger ribonucleic acid levels was also examined. Analysis of the 135 patients revealed no correlation between EGFR intron 1 CA repeat length and tumor stage. There was no difference in overall patient survival when stratified by allele length. A correlation between EGFR intron 1 length and EGFR transcript and protein levels could not be established. The length of the EGFR intron 1 CA repeats does not correlate with levels of EGFR expression and cannot be used as marker of clinical prognosis in pancreatic cancer patients.

• Retroperitoneal and intra-abdominal sarcoma.

  Authors: J Spencer Liles, Ching-Wei D Tzeng, Joshua J Short, Peter Kulesza, Martin J Heslin

  Current problems in surgery. 07/2009; 46(6):445-503.

• Radiofrequency ablation for unresectable tumors of the liver.

  Authors: J Harrison Howard, Ching-Wei D Tzeng, J Kevin Smith, Devon E Eckhoff, J Steve Bynon, Thomas Wang, J Pablo Arnoletti, Martin J Heslin

  The American surgeon. 07/2008; 74(7):594-600; discussion 600-1.

  Surgical resection of primary or metastatic tumors of the liver offers patients the best long-term survival. Liver resections may not be appropriate in patients with bilobar metastases, liverSurgical resection of primary or metastatic tumors of the liver offers patients the best long-term survival. Liver resections may not be appropriate in patients with bilobar metastases, liver dysfunction, or severe comorbidities. Radiofrequency ablation (RFA) is a technique used to destroy unresectable hepatic tumors through thermocoagulation. We retrospectively reviewed a consecutive series of patients undergoing RFA with unresectable hepatic tumors for local recurrence and overall survival. Under an Institutional Review Board-approved protocol, all patients treated with RFA at the University of Alabama at Birmingham from September 1, 1998, to June 15, 2005, were identified. During this time period, 189 lesions in 107 patients were treated with RFA. Patients' charts were retrospectively reviewed. Data is presented as mean +/- SEM. Significance is defined as P < 0.05. Patient demographics revealed 62 per cent males and 38 per cent females with a mean age of 59 (+/- 1) years. Hepatocellular carcinoma (HCC) represented 54 per cent of the tumors treated. Metastatic colorectal cancer represented 22 per cent and the remaining 24 per cent were other metastatic tumors. Overall recurrence rates for all tumors after RFA was 53 per cent. Local recurrence rates for HCC, colorectal cancer, and other metastatic lesions were 27.6 per cent, 29.1 per cent, and 52 per cent, respectively. The morbidity rate for the procedure was 11 per cent. There was one mortality (0.9%) related to RFA. Laparoscopic RFA for HCC in Childs-Pugh Class C cirrhotics (n = 6) resulted in 50 per cent of patients being transplanted with no evidence of disease at a mean follow-up period of 14 months. RFA is a safe and effective way for treating HCC and other unresectable tumors in the liver that are not eligible for hepatic resection. More effective control of systemic recurrence will dictate survival in the majority of patients with metastatic cancers. Local ablation for HCC in cirrhotic patients may be an effective bridge to transplantation. Liver transplantation may still be the most effective long-term treatment for localized HCC.

• EGFR genomic gain and aberrant pathway signaling in pancreatic cancer patients.

  Authors: Ching-Wei D Tzeng, Andrey Frolov, Natalya Frolova, Nirag C Jhala, J Harrison Howard, Selwyn M Vickers, Donald J Buchsbaum, Martin J Heslin, J Pablo Arnoletti

  The Journal of surgical research. 12/2007; 143(1):20-6.

  BACKGROUND: Epidermal growth factor receptor (EGFR) expression does not predict response to anti-EGFR therapy with erlotinib in pancreatic cancer patients. In the absence of known pancreatic cancerBACKGROUND: Epidermal growth factor receptor (EGFR) expression does not predict response to anti-EGFR therapy with erlotinib in pancreatic cancer patients. In the absence of known pancreatic cancer EGFR activating mutations, we sought to identify alternative factors, such as increased gene copy number (genomic gain) and ligand overexpression, which could be associated with aberrant EGFR pathway activation and improved response to targeted therapy. METHODS: EGFR gene copy number was analyzed by fluorescence in situ hybridization in nine pancreatic cancer cell lines and 31 pancreatic cancer surgical specimens. In vitro effects of erlotinib on tumor cell proliferation were tested. Tumor specimen EGFR expression levels were measured by reverse transcriptase-polymerase chain reaction. Expression of stimulating ligand (EGF), phosphorylated receptor (p-EGFR), and activated downstream adaptor proteins (p-Akt and p-ERK), were evaluated by immunohistochemistry and immunoblotting. RESULTS: Pancreatic cancer EGFR genomic gain, in the form of high polysomy, was present in four of nine cell lines and in 10/24 (42%) of patients. Twenty-four patients (77%) expressed EGFR transcript, and of those, half displayed p-EGFR (35% of all patients). A majority of patients demonstrated downstream EGFR pathway activation, with 65% expressing p-Akt and 84% expressing p-ERK. EGFR-expressing tumors also expressed EGF, with exclusive tumor cell localization, suggesting autocrine stimulation of the EGFR pathway. EGF expression level was significantly greater in patients with increased EGFR gene copy number (P = 0.016). CONCLUSIONS: Increased EGFR gene copy number and elevated EGF levels are present in a significant proportion of pancreatic cancer patients, and this may reflect increased EGFR pathway dependence with improved sensitivity to EGFR-targeted therapy.

• Pancreatic cancer epidermal growth factor receptor (EGFR) intron 1 polymorphism influences postoperative patient survival and in vitro erlotinib response.

  Authors: Ching-Wei D Tzeng, Andrey Frolov, Natalya Frolova, Nirag C Jhala, J Harrison Howard, Selwyn M Vickers, Donald J Buchsbaum, Martin J Heslin, J Pablo Arnoletti

  Annals of surgical oncology. 07/2007; 14(7):2150-8.

  BACKGROUND: Epidermal growth factor receptor (EGFR) has a highly polymorphic CA repeat region that affects transcription efficiency and anti-EGFR drug sensitivity in carcinomas. Erlotinib is an EGFRBACKGROUND: Epidermal growth factor receptor (EGFR) has a highly polymorphic CA repeat region that affects transcription efficiency and anti-EGFR drug sensitivity in carcinomas. Erlotinib is an EGFR tyrosine kinase inhibitor approved for pancreatic cancer treatment. We analyzed the impact of EGFR intron 1 CA repeat lengths in pancreatic cancer clinical outcome and in vitro response to erlotinib. METHODS: Allele-specific EGFR intron 1 lengths were analyzed in 30 microdissected pancreatic cancer surgical specimens, matched peripheral blood samples, and 9 pancreatic cancer cell lines treated with erlotinib. CA repeat lengths were correlated with survival, tumor parameters, molecular markers of EGFR pathway activation, and in vitro antiproliferative effects of erlotinib. RESULTS: Both patient samples and cell lines displayed the full spectrum of EGFR CA repeat lengths (14-22 per allele). Patients with shorter sum of total CA repeats (<36) had worse median survival than patients with >or=36 repeats (13.7 vs 30.6 months, P = .002). Shorter patient EGFR intron 1 length correlated with EGFR expression (P = .026). Tumor intron 1 length was identical to that of matched peripheral blood specimens. There was no correlation between EGFR intron 1 length and pancreatic cancer stage, nodal status, grade, or expression of p-EGFR, p-ERK and p-Akt. Shorter EGFR intron 1 length was associated with in vitro response to erlotinib treatment (P = .02). CONCLUSIONS: Shorter EGFR intron 1 CA repeat length is associated with worse pancreatic cancer clinical prognosis and in vitro response to erlotinib. EGFR intron 1 length can be reliably measured in peripheral blood and may translate into a quantitative predictive marker of both pancreatic cancer aggressiveness and erlotinib sensitivity.

• Epidermal growth factor receptor (EGFR) is highly conserved in pancreatic cancer.

  Authors: Ching-Wei D Tzeng, Andrey Frolov, Natalya Frolova, Nirag C Jhala, J Harrison Howard, Donald J Buchsbaum, Selwyn M Vickers, Martin J Heslin, J Pablo Arnoletti

  Surgery. 05/2007; 141(4):464-9.

  BACKGROUND: Pancreatic cancer remains a deadly disease, and the vast majority of pancreatic cancer patients are not candidates for treatment with curative intent. Erlotinib, an EGFR-specific tyrosineBACKGROUND: Pancreatic cancer remains a deadly disease, and the vast majority of pancreatic cancer patients are not candidates for treatment with curative intent. Erlotinib, an EGFR-specific tyrosine kinase inhibitor, was approved recently for use in patients with pancreatic cancer. Somatic mutations in the EGFR gene appear to predict survival and response to tyrosine kinase inhibitor therapy in a subset of patients with non-small-cell lung cancer (NSCLC). METHODS: The purpose of this study was to characterize EGFR mutations in pancreatic adenocarcinoma. EGFR TK mutations were analyzed in 9 pancreatic carcinoma cell lines and 31 clinical specimens from patients with pancreatic cancer who underwent resection. Using laser capture microdissection, tumor cells from patients were harvested selectively for genomic DNA extraction. Mutations were examined by direct sequencing of exons 18-21. RESULTS: Of 9 pancreatic cancer cell lines, 6 had either 2454G>A or 2361G>A mutations in exon 20. Of 31 patients, 25 patients had 2361G>A in exon 20, and 1 patient had 2508C>T in exon 21. All were silent mutations. CONCLUSIONS: The EGFR tyrosine kinase domain is highly conserved in pancreatic cancer. The association among EGFR mutation status, clinical prognosis, and response to anti-EGFR therapy described in NSCLC may not be applicable to pancreatic cancer. This observation does not diminish the possible role of anti-EGFR therapy in pancreatic cancer because there remains a need to explore alternative explanations for pancreatic cancer aberrant EGFR pathway activation such as ligand overexpression, gene amplification, and loss of inhibitory mechanisms.

• ErbB3 expression and dimerization with EGFR influence pancreatic cancer cell sensitivity to erlotinib.

  Authors: Andrey Frolov, Kyle Schuller, Ching-Wei D Tzeng, Emily E Cannon, Brandon C Ku, J Harrison Howard, Selwyn M Vickers, Martin J Heslin, Donald J Buchsbaum, J Pablo Arnoletti

  Cancer biology & therapy. 05/2007; 6(4):548-54.

  Abnormal expression and signaling of ErbB receptors has been implicated in multiple epithelial malignancies, including pancreatic cancer. Erlotinib, an epidermal growth factor receptor tyrosineAbnormal expression and signaling of ErbB receptors has been implicated in multiple epithelial malignancies, including pancreatic cancer. Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has been recently approved for pancreatic cancer treatment, but there are no reliable predictors of patient response. Expression of additional ErbB receptors seems to influence tumor response to EGFR-targeted therapy. We analyzed the influence of ErbB3 expression on pancreatic cancer cell response to erlotinib treatment. Proliferation assays of five human pancreatic cancer cell lines were performed following treatment with erlotinib. Expression and phosphorylation profiles of ErbB receptors and downstream adaptor protein (Akt, ERK1/2, STAT3, mTOR) were evaluated following stimulation with EGF or neuregulin-beta. The formation of EGFR homodimers and EGFR-ErbB3 heterodimers, necessary to enable ErbB3 downstream signaling, was demonstrated by chemical cross-linking assays. The effects of RNA inhibition of ErbB3 on sensitivity to erlotinib treatment were evaluated in AsPC-1 pancreatic cancer cells. Erlotinib inhibited Akt phosphorylation and proliferation of all the ErbB3-expressing cell lines but did not affect mTOR activation. Cross-linking studies confirmed the presence of EGFR-ErbB3 heterodimers in pancreatic cancer cells. Only the ErbB3-deficient MIA PaCa-2 cells displayed persistent Akt activation and ongoing proliferation in spite of erlotinib treatment. siRNA-mediated inhibition of ErbB3 expression in AsPC-1 cells resulted in acquired resistance to erlotinib treatment. Pancreatic cancer cells which lack ErbB3 do not display activation of the ErbB3-PI3K-Akt cascade induced by EGFR/ErbB3 heterodimers and become less critically dependent on EGFR signaling and therefore resistant to erlotinib. Pancreatic cancer expression of ErbB3 may be useful for EGFR-targeted therapy patient selection.

• Soft tissue sarcoma: preoperative and postoperative imaging for staging.

  Authors: Ching-Wei D Tzeng, J Kevin Smith, Martin J Heslin

  Surgical oncology clinics of North America. 05/2007; 16(2):389-402.

  Soft tissue sarcoma (STS) management requires accurate tumor imaging for staging, treatment planning, and clinical follow-up. Careful preoperative planning may prevent poor primary resections thatSoft tissue sarcoma (STS) management requires accurate tumor imaging for staging, treatment planning, and clinical follow-up. Careful preoperative planning may prevent poor primary resections that place the patient at risk for more operations, local recurrence, and worse survival. Although MRI may be preferred for extremity STS, contrast-enhanced CT is an excellent alternative, with no decrease in ability to plan the operative strategy for limb-sparing resection. In retroperitoneal and other intra-abdominal STS, double (oral/intravenous) contrast-enhanced CT evaluates for liver metastases, defines surrounding vital structures that might be resected en bloc, identifies margins at risk for local recurrence, and shows surrounding organs at risk for toxicity during radiation therapy. Postoperative clinical follow-up and imaging must continue even beyond 5 years because of the continued risk of long-term relapse.

• Radiation therapy for retroperitoneal sarcoma.

  Authors: Ching-Wei D Tzeng, John B Fiveash, Martin J Heslin

  Expert review of anticancer therapy. 09/2006; 6(8):1251-60.

  Retroperitoneal soft-tissue sarcoma is an uncommon cancer of mesodermal origin, which is difficult to treat owing to its location and proximity to vital structures. Complete gross resection, oftenRetroperitoneal soft-tissue sarcoma is an uncommon cancer of mesodermal origin, which is difficult to treat owing to its location and proximity to vital structures. Complete gross resection, often involving en bloc resection, is the standard of care as it represents the only treatment that improves overall survival. Unlike extremity sarcoma, retroperitoneal soft-tissue sarcoma tumor mortality is from local recurrence. Radiation therapy is the only adjuvant treatment that has improved local control in several institutional series. However, there remains no definitive prospective, randomized trial that establishes the role of adjuvant radiation versus no radiation. Owing to significant radiation morbidity with adjacent organs, especially the small bowel, there exists no consensus on radiation timing, delivery method or dosing. Recent and current protocols use preoperative external-beam radiation with or without a method of focal boost dosing. Methods of boost dosing include brachytherapy, intraoperative radiation therapy and intensity-modulated radiation therapy. Further studies are needed to definitively include radiation therapy in the standard treatment of retroperitoneal soft-tissue sarcoma and to find the optimal balance between acceptable radiation toxicity and effective local control in treatment protocols.

• Preoperative radiation therapy with selective dose escalation to the margin at risk for retroperitoneal sarcoma.

  Authors: Ching-Wei D Tzeng, John B Fiveash, Richard A Popple, J Pablo Arnoletti, Suzanne M Russo, Marshall M Urist, Kirby I Bland, Martin J Heslin

  Cancer. 08/2006; 107(2):371-9.

  BACKGROUND: Retroperitoneal sarcomas (RPSs) are rare tumors with poor survival rates due to difficult resectability and high local and distant recurrence rates. Preoperative radiation therapy appearsBACKGROUND: Retroperitoneal sarcomas (RPSs) are rare tumors with poor survival rates due to difficult resectability and high local and distant recurrence rates. Preoperative radiation therapy appears to have dosimetric advantages to utilize the tumor as a tissue expander to limit exposure of small bowel to higher radiation doses. METHODS: Between June 1999 and December 2003, 16 consecutive patients with biopsy-proven RPS were treated with preoperative radiation with selective dose escalation. This included 45 grays (Gy) in 25 fractions to the entire tumor plus margin and a boost dose of 57.5 Gy to the volume predicted as high risk for positive surgical margins. Treatment toxicity and local control were evaluated prospectively as primary endpoints. The secondary goal was the theoretical calculation of future dose escalation and feasibility. Each patient underwent laparotomy. Tumor response was judged using computed tomography (CT) scan and by necrosis on final pathology. Theoretical treatment plans evaluated the potential for additional radiation dose escalation. RESULTS: All patients completed the radiation protocol. The most common acute side effects were nausea/vomiting, which affected 4 patients (25%), with only 1 patient requiring inpatient intravenous hydration. There was no severe late postoperative morbidity or mortality. Twelve tumors (75%) decreased in maximum dimension, with a median decrease of 9.4%. Fourteen of 16 patients (88%) underwent complete macroscopic resection. With a median follow-up of 28 months (range, 7-52 months), there were only 2 local recurrences. The actuarial 2-year local control rate was 80%. Theoretical treatment plans suggest that significant dose escalation (up to 80 Gy) may be possible. CONCLUSIONS: Preoperative radiation therapy with selective dose escalation to the margin at risk is tolerable and allows higher radiation dose to the volume judged to be at greatest risk for local tumor recurrence.