Identification of a novel germ-line mutation in the TP53 gene in a Mexican family with Li-Fraumeni syndrome

Background

Intra-peritoneal (i.p.) chemotherapy is an encouraging treatment option for ovarian cancer with peritoneum involvement in addition with intravenous (i.v.) chemotherapy. Intra-operative i.p. chemotherapy is an interesting method of administration by enhancing the diffusion of chemotherapy. This study had assessed the feasibility of intra-operative i.p. chemotherapy in patients with peritoneal carcinoma of ovarian cancer.

Methods

From January 2003 to February 2006, 47 patients with stage III ovarian cancer were treated with standard paclitaxel carboplatin intravenous chemotherapy and debulking surgery with intra-operative i.p. chemotherapy. After optimal cytoreductive surgery, defined by no unresectable residual disease > 1 cm, i.p. chemotherapy was performed during surgery. The peritoneal cavity was filled by 3 litres of isotonic saline pre-heated at 37 degrees and 90 mg of cisplatin. The sequence was repeated twice during 2 hours based on previous published studies which optimized the cisplatin dosage and exposure duration. Optimal diffusion was obtained by stirring by hands during the 2 hours.

Results

Median age was 59.6 years. No severe haematological or non-haematological toxicity induced by intra operative i.p. chemotherapy was reported. No patient died due to the complications of surgery or the i.p. chemotherapy. No neurotoxicity occurred, and one patients had renal impairment.

Conclusion

This study demonstrates the feasibility of intra-operative i.p. chemotherapy with cisplatin after optimal resection of peritoneal tumor nodules. Further randomized trials are planned to investigate the clinical benefit of this therapeutic modality.     

Cancerous ovarian stem cells: Obscure targets for therapy but relevant to chemoresistance

Chemotherapy with platinum and taxanes is the first line of treatment for all epithelial ovarian cancer (EOC) patients after debulking surgery. Even though the treatment is initially effective in 80% of patients, recurrent cancer is inevitable in the vast majority of cases. Emerging evidence suggests that some tumor cells can survive chemotherapy by activating the self‐renewal pathways resulting in tumor progression and clinical recurrence. These defined population of cells commonly termed as “cancer stem cells” (CSC) may generate the bulk of the tumor by using differentiating pathways. These cells have been shown to be resistant to chemotherapy and, to have enhanced tumor initiating abilities, suggesting CSCs as potential targets for treatment. Recent studies have introduced a new paradigm in ovarian carcinogenesis which proposes in situ carcinoma at the fimbrial end of the fallopian tube to generate high‐grade serous ovarian carcinomas, in contrast to ovarian cortical inclusion cysts (CIC) which produce borderline and low grade serous, mucinous, endometrioid, and clear cell carcinomas. This review summarizes recent advances in our understanding of the cellular origin of EOC and the molecular mechanisms defining the basis of CSC in EOC progression and chemoresistance. Using a model ovarian cancer cell line, we highlight the role of CSC in response to chemotherapy, and relate how CSCs may impact on chemoresistance and ultimately recurrence. We also propose the molecular targeting of CSCs and suggest ways that may improve the efficacy of current chemotherapeutic regimens needed for the management of this disease. J. Cell. Biochem. 114: 21–34, 2012. © 2012 Wiley Periodicals, Inc.     

Enhancing chemotherapy response with Bmi-1 silencing in ovarian cancer

Undoubtedly ovarian cancer is a vexing, incurable disease for patients with recurrent cancer and therapeutic options are limited. Although the polycomb group gene, Bmi-1 that regulates the self-renewal of normal stem and progenitor cells has been implicated in the pathogenesis of many human malignancies, yet a role for Bmi-1 in influencing chemotherapy response has not been addressed before. Here we demonstrate that silencing Bmi-1 reduces intracellular GSH levels and thereby sensitizes chemoresistant ovarian cancer cells to chemotherapeutics such as cisplatin. By exacerbating ROS production in response to cisplatin, Bmi-1 silencing activates the DNA damage response pathway, caspases and cleaves PARP resulting in the induction apoptosis in ovarian cancer cells. In an in vivo orthotopic mouse model of chemoresistant ovarian cancer, knockdown of Bmi-1 by nanoliposomal delivery significantly inhibits tumor growth. While cisplatin monotherapy was inactive, combination of Bmi-1 silencing along with cisplatin almost completely abrogated ovarian tumor growth. Collectively these findings establish Bmi-1 as an important new target for therapy in chemoresistant ovarian cancer.     

Ovarian cancer stem cells: Can targeted therapy lead to improved progression-free survival?

Despite significant effort and research funds, epithelial ovarian cancer remains a very deadly disease. There are no effective screening methods that discover early stage disease; the majority of patients are diagnosed with advanced disease. Treatment modalities consist primarily of radical debulking surgery followed by taxane and platinum-based chemotherapy. Newer therapies including limited targeted agents and intraperitoneal delivery of chemotherapeutic drugs have improved disease-free intervals, but failed to yield longlasting cures in most patients. Chemotherapeutic resistance, particularly in the recurrent setting, plagues the disease. Targeting the pathways and mechanisms behind the development of chemoresistance in ovarian cancer could lead to significant improvement in patient outcomes. In many malignancies, including blood and other solid tumors, there is a subgroup of tumor cells, separate from the bulk population, called cancer stem cells(CSCs). These CSCs are thought to be the cause of metastasis, recurrence and resistance. However, todate, ovarian CSCs have been difficult to identify, isolate, and target. It is felt by many investigators that finding a putative ovarian CSC and a chemotherapeutic agent to target it could be the key to a cure for this deadly disease. This review will focus on recent advances in this arena and discuss some of the controversies surrounding the concept.     

A new chemosensitivity test using a thermo-reversible gelation polymer for recurrent gynecologic cancer patients and a preliminary study of mechanisms of anticancer drug resistance

OBJECTIVES: TGP (thermo-reversible gelation polymer) is a high molecular compound that has so-gel transmitting temperature of 221C Since solid cancer tissue grows in this polymer three-dimensionally, and fibroblasts scarcely grow in it, TGP is suitable for chemosensitivity assays for solid tumors. In this study, a chemosensitivity test using TGP was applied to recurrent gynecologic cancer patients in order to evaluate its utility and efficacy. In some ovarian cancer cases, expression of anticancer drug resistance-related proteins was also analyzed. METHODS: Recurrent tumor tissues were surgically obtained with informed consent. After these tissues were minced and incubated for 4 days with CDDP, mitomycin C, 5-fluorouracil, paclitaxel, and CPT-11, the sensitivity against these drugs was estimated. Western blotting was performed in 8 recurrent ovarian cancer tissues in order to analyze the expression of Bcl-2, MRP2, BCRP, and GST-pi. RESULTS: The total evaluability rate of this assay was 90.6% (29/32). Sensitive drugs could be determined in 5 of 7 ascites samples (71.4%) and in 2 of 3 intra-tumoral fluid samples (66.7%). The overall clinical response rate of chemotherapy determined by these results was 50.0%. There were significant correlations between the IC50 of CDDP and Bcl-2, BCRP, GST-pi, and between that of 5-FU and MRP 2. CONCLUSIONS: Although this was a preliminary study, the chemosensitivity test using this new material appears to be useful for designing 'made-to order' salvage chemotherapy for pretreated recurrent gynecologic patients. In order to overcome multidrug resistance, the mechanisms of multidrug resistance should be further investigated.     

多西他赛联合卡铂治疗复发性卵巢癌的疗效观察

目的:分析多西他赛联合卡铂用于治疗复发性卵巢癌的临床疗效及用药安全性。方法:对28例复发性卵巢癌患者采用多西他赛联合卡铂方案治疗。结果:全组2例CR(7.14%),11例PR(39.28%),6例SD(21.42%),9例PD(32.14%),RR为46.42%。不良反应主要为血液系统毒性、胃肠道反应和神经系统毒性,但均未影响继续治疗,总体疗效满意。结论:多西他赛联合卡铂治疗复发性卵巢癌疗效较好,且使用过程简单,耐受性好。     

细胞凋亡抑制蛋白cIAP 与卵巢癌耐药性的研究进展

卵巢恶性肿瘤是女性生殖系统三大恶性肿瘤之一,其发病率在女性生殖系统肿瘤中占第三位,而死亡率却高居首位。目前对于晚期卵巢癌(Ⅲ或Ⅳ期)多倾向于用新辅助化疗+肿瘤细胞减灭术+术后周期性化疗的治疗方法。但是,尽管多数患者在最初对化疗药物较敏感,但仍有60%~80%最终死于卵巢癌,这些患者大部分都对化疗药物产生了耐药性,在更换新的化疗方案初期是有效的,但最终仍会耐药。近年来,有关细胞凋亡抑制蛋白(cIAP,cellular inhibitors of apoptosis proteins)在卵巢癌复发耐药中的作用机制的研究越来越受到重视。研究证实,cIAP在耐药肿瘤细胞中呈高表达,并与多种因子共同参与形成了上皮性卵巢癌的耐药机制,抑制了化疗药物引起的肿瘤细胞的凋亡。这些发现为攻克卵巢癌的耐药机制提供了重要线索,也为卵巢癌化疗药物的应用指出了新的方向。     

Carboplatin with Decitabine Therapy,in Recurrent Platinum Resistant Ovarian Cancer,Alters Circulating miRNAs Concentrations: A Pilot Study

Objective

Plasma miRNAs represent potential minimally invasive biomarkers to monitor and predict outcomes from chemotherapy. The primary goal of the current study—consisting of patients with recurrent, platinum-resistant ovarian cancer—was to identify the changes in circulating miRNA concentrations associated with decitabine followed by carboplatin chemotherapy treatment. A secondary goal was to associate clinical response with changes in circulating miRNA concentration.

Methods

We measured miRNA concentrations in plasma samples from 14 patients with platinum-resistant, recurrent ovarian cancer enrolled in a phase II clinical trial that were treated with a low dose of the hypomethylating agent (HMA) decitabine for 5 days followed by carboplatin on day 8. The primary endpoint was to determine chemotherapy-associated changes in plasma miRNA concentrations. The secondary endpoint was to correlate miRNA changes with clinical response as measured by progression free survival (PFS).

Results

Seventy-eight miRNA plasma concentrations were measured at baseline (before treatment) and at the end of the first cycle of treatment (day 29). Of these, 10 miRNAs (miR-193a-5p, miR-375, miR-339-3p, miR-340-5p, miR-532-3p, miR-133a-3p, miR-25-3p, miR-10a-5p, miR-616-5p, and miR-148b-5p) displayed fold changes in concentration ranging from -2.9 to 4 (p<0.05), in recurrent platinum resistant ovarian cancer patients, that were associated with response to decitabine followed by carboplatin chemotherapy. Furthermore, lower concentrations of miR-148b-5p after this chemotherapy regimen were associated (P<0.05) with the PFS.

Conclusions

This is the first report demonstrating altered circulating miRNA concentrations following a combination platinum plus HMA chemotherapy regiment. In addition, circulating miR-148b-5p concentrations were associated with PFS and may represent a novel biomarker of therapeutic response, with this chemotherapy regimen, in women with recurrent, drug-resistant ovarian cancer.     

Pancreatic cancer stem cells and relevance to cancer treatments

Pancreatic cancer continues to be a malignancy with few therapeutic options. The majority of patients that present for an evaluation have locally advanced or metastatic disease that is incurable by surgical approaches. Chemotherapy and radiotherapy resistance of pancreatic adenocarcinomas limits the efficacy of these therapeutic approaches. Recent evidence supports the existence of human pancreatic cancer stem cells, which appear to drive tumor initiation and progression and are particularly resistant to cell death induced by radiation or chemotherapy. Understanding the mechanisms of pancreatic cancer stem cell self‐renewal and resistance to standard therapies may lead to new, more effective therapies to treat this dismal disease. J. Cell. Biochem. 107: 40–45, 2009. © 2009 Wiley‐Liss, Inc.     

The mechanism of cisplatin-resistance in ovarian cancer

Cisplatin and its analogues have been most frequently used for treatment of human cancer including ovarian cancer. Most advanced ovarian cancer which was fatal before introduction of cisplatin have become to be treated for cure by combination chemotherapy containing cisplatin and its analogues. Thus, combination chemotherapy containing cisplatin and carboplatin have become a standard chemotherapy for treatment of ovarian cancer. Initially, platinum-based combination chemotherapy is associated with a 60-70% clinical response rate. However, the overall 5-year survival rate for advanced ovarian cancer patients is still around 20-30%. This low survival rate is due to the fact that some primary tumors and most recurrent tumors develop drug resistance that leads to treatment failure. Thus, overcoming drug resistance is the key to successful treatment of ovarian cancer. The mechanism of cisplatin-resistance in ovarian cancer is multifactorial, and accumulation of multiple genetic changes may lead to the drug-resistant phenotype. In this review, we report several genetic factors conferring cisplatin-resistance which have been elucidated in our laboratory.     

Ex vivo Live Imaging of Lung Metastasis and Their Microenvironment

Metastasis is a major cause for cancer-related morbidity and mortality. Metastasis is a multistep process and due to its complexity, the exact cellular and molecular processes that govern metastatic dissemination and growth are still elusive. Live imaging allows visualization of the dynamic and spatial interactions of cells and their microenvironment. Solid tumors commonly metastasize to the lungs. However, the anatomical location of the lungs poses a challenge to intravital imaging. This protocol provides a relatively simple and quick method for ex vivo live imaging of the dynamic interactions between tumor cells and their surrounding stroma within lung metastasis. Using this method, the motility of cancer cells as well as interactions between cancer cells and stromal cells in their microenvironment can be visualized in real time for several hours. By using transgenic fluorescent reporter mice, a fluorescent cell line, injectable fluorescently labeled molecules and/or antibodies, multiple components of the lung microenvironment can be visualized, such as blood vessels and immune cells. To image the different cell types, a spinning disk confocal microscope that allows long-term continuous imaging with rapid, four-color image acquisition has been used. Time-lapse movies compiled from images collected over multiple positions and focal planes show interactions between live metastatic and immune cells for at least 4 hr. This technique can be further used to test chemotherapy or targeted therapy. Moreover, this method could be adapted for the study of other lung-related pathologies that may affect the lung microenvironment.     

Targeted therapies in epithelial ovarian cancer: Molecular mechanisms of action

Ovarian cancer is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at an advanced stage and have a poor prognosis. Currently, surgical tumor debulking, followed by platinum- and taxane-based chemotherapy is the standard treatment for advanced ovarian cancer. However, these patients are at great risk of recurrence and emerging drug resistance. Therefore, novel treatment strategies are required to improve outcomes for women with advanced ovarian cancer. A variety of molecular targeted agents, the majority of which are monoclonal antibodies and small-molecule protein-kinase inhibitors, have been explored in the management of ovarian cancer. The targets of these agents include angiogenesis, the human epidermal growth factor receptor family, ubiquitin-proteasome pathway, epigenetic modulators, poly(ADP-ribose) polymerase (PARP), and mammalian target of rapamycin (mTOR) signaling pathway, which are aberrant in tumor tissue. The antiangiogenic agent, bevacizumab, has been reported as the most effective targeted agent and should be included in the standard chemotherapeutic regimen for advanced ovarian cancer. PARP inhibitors, which are mainly used in breast and ovarian cancer susceptibility gene-mutated patients, and mTOR inhibitors are also attractive treatment strategies, either alone or combination with chemotherapy, for ovarian cancer. Understanding the tumor molecular biology and identification of predictive biomarkers are essential steps for selection of the best treatment strategies. This article reviews the molecular mechanisms of the most promising targeted agents that are under early phase clinical evaluation for ovarian cancer.     

Mechanisms underlying acquired platinum resistance in high grade serous ovarian cancer - a mini review

Background

Advanced epithelial ovarian cancer is one of the hardest human malignancies to treat. Standard treatment involves cytoreductive surgery and platinum-based chemotherapy, however, median progression-free survival for patients diagnosed with advanced stage disease (FIGO stages III and IV) is approximately 18?months. There has been little improvement in overall survival over the past decade and less than half of women with advanced stage disease will be living 5?years after diagnosis. A majority of patients initially have a favourable response to platinum-based chemotherapy, but most will eventually relapse and their disease will become platinum resistant.

奥拉帕利维持治疗对铂敏感复发性卵巢癌患者血清肿瘤标志物和凋亡因子的影响

摘要 目的：观察奥拉帕利维持治疗对铂敏感复发性卵巢癌患者血清凋亡因子、肿瘤标志物的影响。方法：按照随机数字表法,将2020年1月到2022年1月期间我院收治的80例铂敏感复发性卵巢癌患者分为对照组（n=40）和观察组（n=40）。两组患者均经二线含铂化疗后,经评估达到临床缓解或部分缓解后,对照组患者不予特殊药物处理,观察组则在化疗结束8周内开始口服奥拉帕利作为维持治疗,直至疾病进展或发生不可接受的毒性反应。对比两组的血清肿瘤标志物和凋亡因子水平情况,观察两组不良反应发生率和预后情况。结果：两组治疗后癌胚抗原（CEA）、糖类抗原（CA）125、人附睾蛋白4（HE4）均下降（P<0.05）,且观察组低于对照组（P<0.05）。两组治疗后B淋巴细胞瘤-2（Bcl-2）、可溶性细胞凋亡因子（sFas）和Bcl-2结合抗凋亡基因-1（Bag-1）均下降,Bcl-2相关X蛋白（Bax）升高（P<0.05）,观察组治疗后Bcl-2、sFas、Bag-1低于对照组,Bax高于对照组（P<0.05）。两组治疗期间各项不良反应发生率对比未见统计学差异（P>0.05）。两组治疗后认知能力、情感健康、社会功能、躯体功能、行为功能评分升高,且观察组的改善幅度大于对照组（P<0.05）。结论：奥拉帕利维持治疗铂敏感复发性卵巢癌患者,可有效改善血清肿瘤标志物和凋亡因子水平,提高患者生存质量,预后良好。     

Pre-treatment prediction of chemoresistance in second-line chemotherapy of ovarian carcinoma: value of serological tumor marker determination (tetranectin, YKL-40, CASA, CA 125)

OBJECTIVE: To examine if the determination of the levels of serological tumor markers at time of relapse had any predictive value for chemoresistance in the second-line treatment of ovarian cancer patients. METHODS: From a registry of consecutive single-institution patients with epithelial ovarian carcinoma pretreated with paclitaxel plus platinum, we selected 82 patients with (a) solid tumor recurrence, and (b) second-line chemotherapy consisting of topotecan (platinum-resistant disease) or paclitaxel plus carboplatin (platinum-sensitive disease). Stored serum samples were analyzed for the biochemical tumor markers tetranectin, YKL-40, CASA (cancer-associated serum antigen), and CA 125. The serum tumor marker levels at time of relapse were correlated with response status at landmark time after 4 cycles of second-line chemotherapy. Univariate and multivariate logistic regression analyses (chemoresistant vs non-chemoresistant disease) were performed. RESULTS: At landmark time, 26% of patients had progression according to the GCIG (Gynecologic Cancer Intergroup) progression criteria. In univariate logistic regression analysis, the tumor markers tetranectin (OR 0.4; 95% CI: 0.2-0.8; p=0.008), YKL-40 (OR 1.8; 95% CI: 1.0-3.3; p=0.045), and CASA (OR 1.8; 95% CI: 1.2-2.7; p=0.007) had predictive value for second-line chemoresistance, whereas serum CA 125 had no predictive value. In a multivariate logistic regression analysis, serum tetranectin and CASA both had independent predictive value for chemoresistance. The combined determination of tetranectin and CASA had a specificity of 90% with 33% sensitivity for the prediction of chemoresistance (area under the receiver operating characteristic curve = 0.78; 95% CI: 0.66-0.91; p=0.001). CONCLUSION: Low serum levels of tetranectin, or high serum levels of CASA or YKL-40, are associated with increased risk of second-line chemoresistance in patients with ovarian cancer.     

不同给药途径的新辅助化疗在晚期上皮性卵巢癌的疗效观察

目的:探讨新辅助化疗中不同给药方式在晚期上皮性卵巢癌的临床疗效及意义。方法:选取132例初治上皮性卵巢癌患者,临床分期为Ⅲc一Ⅳ期。随机平均分为4组(A组:单纯紫杉醇静脉化疗B组:单纯卡铂腹腔灌注C组:紫杉醇静脉联合卡铂腹腔D组:直接手术)。A、B、C三组给予1个疗程新辅助化疗后评估其疗效,行卵巢癌肿瘤细胞减灭术;D组直接手术治疗,比较各组治疗情况。结果:4组的满意肿瘤减灭率分别为78.8%、75.7%、87.9%、63.6%;化疗A、B与C组间、化疗各组与D组间在减灭术成功率、手术时间、术中出血量、术后排气时间上比较均有统计学意义(P0.05);新辅助化疗各组不良反应可耐受,均顺利完成手术,其中骨髓抑制及神经毒性以C组发生率较高(P0.01)。结论:1新辅助化疗可降低手术风险,有效提高满意的减灭术的成功率,改善生存质量。2静脉联合腹腔灌注较单途径用药的临床疗效好,毒副作用略高但可耐受。     

Aromatase inhibitors in gynecologic cancers

The female genital tract is hormonally responsive, and consequently some tumors, which arise within in it, may be treated at least in part, with hormonal manipulation. The range of responses in clinical trials and case reports will be reviewed. Many of these diseases are too rare for clinical trial testing, and in some cases evidence is anecdotal at best. Recurrences of ovarian cancer have been treated with tamoxifen and megesterol acetate with variable response rates from 0 to 56%. The favorable toxicity profile of aromatase inhibitors led to trials of these agents for the treatment of relapsed epithelial ovarian cancer. These agents have proved tolerable with minor response rates but a significant disease stabilization rate, which may be prolonged in a minority of cases. It is unclear if these responses may be predicted by estrogen receptor expression or aromatase expression. Anastrazole has also been tried in combination with an EGFR receptor-inhibitor, again showing minor responses but possibly an increase in TTT in some patients. Granulosa cell tumors of the ovary are rare, hormonally sensitive tumors, with reported responses to a variety of hormonal manipulations, including aromatase inhibition. In addition, combined endocrine blockade, including aromatase inhibition, has been tried with reports of success. Endometrial cancers, particularly type I lesions, are often treated with hormonal manipulation, most commonly with progestins, but also with antiestrogens such as tamoxifen. A trial of aromatase inhibition in the treatment of recurrent endometrial cancer showed minimal responses. Endometrial stromal sarcoma, an uncommon uterine malignancy, has shown response to hormonal treatments, with multiple case reports of efficacy of aromatase inhibition. Despite the rarity of some of these tumor types, rare tumor study groups, such as within the Gynecologic Oncology Group, should make an effort to prospectively define the utility of these treatments.     

放疗联合热疗治疗68例晚期卵巢癌术后复发的放疗联合热疗临床观察

目的:探讨放疗联合热疗治疗晚期卵巢癌术后复发的临床疗效。方法:选择哈医科大学第四临床医院及黑龙江省第二肿瘤医院2010年3月~2013年3月收治的68例卵巢癌术后复发患者(均为术后化疗6-8个疗程盆腔复发),将其随机分为热疗联合放疗组(实验组)和单纯化疗组(对照组)。所有患者均给予化疗6-8个周期以上,实验组在放疗结束后2小时内进行热疗,2次/周,共6-8周。通过影像学检查治疗前后肿瘤体积的变化进行疗效评估,观察两组治疗期间各种不良反应的发生情况及术后3年的生存情况。结果:观察组肿瘤完全缓解率(CR)实验组明显高于对照组(P0.05)。皮肤损伤的发生率显著高于对照组,而白细胞计数下降的发生率明显低于对照组(P0.05)。两组随访1、2年的生存率无明显差异(P0.05),实验组第3年的生存率明显高于对照组(P0.05)。结论:热疗联合放疗可提高晚期卵巢癌术后复发的临床疗效。     

Targeting altered cancer methionine metabolism with recombinant methioninase (rMETase) overcomes partial gemcitabine-resistance and regresses a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer

Pancreatic cancer is a recalcitrant disease. Gemcitabine (GEM) is the most widely-used first-line therapy for pancreatic cancer, but most patients eventually fail. Transformative therapy is necessary to significantly improve the outcome of pancreatic cancer patients. Tumors have an elevated requirement for methionine and are susceptible to methionine restriction. The present study used a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer to determine the efficacy of recombinant methioninase (rMETase) to effect methionine restriction and thereby overcome GEM-resistance. A pancreatic cancer obtained from a patient was grown orthotopically in the pancreatic tail of nude mice to establish the PDOX model. Five weeks after implantation, 40 pancreatic cancer PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n = 10); GEM (100 mg/kg, i.p., once a week for 5 weeks, n = 10); rMETase (100 units, i.p., 14 consecutive days, n = 10); GEM+rMETase (GEM: 100 mg/kg, i.p., once a week for 5 weeks, rMETase: 100 units, i.p., 14 consecutive days, n = 10). Although GEM partially inhibited PDOX tumor growth, combination therapy (GEM+rMETase) was significantly more effective than mono therapy (GEM: p = 0.0025, rMETase: p = 0.0010). The present study is the first demonstrating the efficacy of rMETase combination therapy in a pancreatic cancer PDOX model to overcome first-line therapy resistance in this recalcitrant disease.