Cancer Patient-derived Orthotopic Xenograft Research Articles

MODL-29. Molecular Landscape of a comprehensive panel of pediatric brain cancer Patient-derived orthotopic xenograft (PDOX) models inform unique targets for drug responsiveness

Abstract Brain tumor is a leading cause of cancer related death in children. In addition to replicating histopathology, animal models faithfully replicating genetic/epigenetic abnormalities, molecular subtypes and broad inter-tumoral heterogeneities are needed. Through direct implantation of patient surgical or autopsied tumor tissues into matching locations in the brains of SCID mice, we developed a panel of 150 PDOX mouse models. Here, we report the analysis of 74 of the 150 PDOX models, 45 matching patient tissues and 60 non-tumorigenic samples to a well-annotated reference cohort of 2,801 methylation profiles of primary brain tumors. Our data showed that the lack of tumorigenicity was neither correlated with molecular subtypes nor predicted by low cell viabilities of the patient samples. Methylation profiling identified PDOX models representing nearly a full spectrum of molecular subtypes of pediatric brain tumors including GBM, medulloblastoma, ependymoma and ATRT. Direct comparison with the original patient tumors confirmed the replication of molecular subtypes. ONCOplot [FB1] analysis of PDOX models derived from matching pairs of primary and recurrent tumors (n=8) revealed close clustering with the patient tumors. Investigation of metastatic properties was performed in 13 MB models by harvesting and sub-transplanting matching PDOX primary tumors in the cerebella and metastatic tumors in the spinal cords. To confirm the potential and power of PDOX models in preclinical drug testing, we applied fractionated radiation (2 Gy/day x 5 days) and optimized multi-agent combinatory chemotherapies in MB models of the four major subgroups. High-throughput combination drug screening with ~ 8,000 drugs in PDOX-derived GBM cell lines and primary cultures of MB PDOX cells identified a library of ~ 3,500 drugs that were active in pediatric brain tumors. In summary, this study provides detailed information on molecular subclassification of a uniquely large cohort of PDOX models to serve as essential tools for brain tumor research.

Brucea javanica Increases Survival and Enhances Gemcitabine Efficacy in a Patient-derived Orthotopic Xenograft (PDOX) Mouse Model of Pancreatic Cancer

Traditional Chinese medicine (TCM) Brucea javanica (BJO) has shown anti-proliferation efficacy on human carcinoma cells in vitro. The aim of the present study was to evaluate for the first time the efficacy of BJO combined with the first-line chemotherapeutic drug gemcitabine (GEM) on tumor growth-inhibition and survival in a pancreatic cancer patient-derived orthotopic xenograft (PDOX) mouse model. The pancreatic cancer tumor fragment originated from a patient at the Hefei First People's Hospital (Anhui, PR China). The surgical specimen was transplanted orthotopically in nude mice using surgical orthotopic implantation (SOI). All mice were randomized and assigned to 5 groups: G1: saline vehicle (0.1ml per mouse, oral, once per day); G2: GEM [100 mg/kg, intraperitoneal (i.p), twice per week]; G3: GEM+BJO [100 mg/kg GEM, i.p, twice per week+1g/kg BJO, oral, once per day (qd)]; G4: BJO (1g/kg, oral, qd). Group 5 and Group 6 were used to observe survival [G5: saline vehicle (0.1ml per mouse, oral, qd), G6: BJO (1g/kg, oral, qd)]. Body weight and tumor volume were measured twice per week. TUNEL staining was used to determine apoptosis. The combination of GEM + BJO resulted in a reduced tumor growth rate (p<0.05) and greater apoptosis (p<0.05) compared to the vehicle control and GEM monotherapy. In addition, the BJO-treated group showed a statistically significant increase in survival compared to the vehicle control (p<0.05). BJO is a promising non-toxic TCM to effectively treat pancreatic cancer, both as monotherapy and in combination with first-line GEM therapy.

A Single Low Dose of Eribulin Regressed a Highly Aggressive Triple-negative Breast Cancer in a Patient-derived Orthotopic Xenograft Model.

In the present study, the breast cancer patient-derived orthotopic xenograft (PDOX) model was used to identify an effective drug for a highly aggressive triple negative breast cancer (TNBC). The TNBC tumor from a patient was implanted in the right 4th inguinal mammary fat pad of nude mice to establish a PDOX model. Three weeks later, 19 mice were randomized into the untreated-control group (n=10) and the eribulin treatment group (n=9, eribulin, 0.3 mg/kg, i.p., day 1). On day 8, eribulin significantly inhibited tumor volume compared to the control group (p<0.01). Eribulin regressed tumors in 3 mice (33.3%) and apparently eradicated them in 6 mice (66.7%). At day 14, tumor regrowth was observed in 2 mice of the eribulin group, which was undetectable on day 8. However, 44.4% (4 out of 9) of the mice in the eribulin group were tumor-free on day 14. A single low-dose eribulin was efficacious on a highly aggressive TNBC. The breast cancer PDOX model can be used to identify highly effective drugs for TNBC.

Temozolomide and Pazopanib Combined with FOLFOX Regressed a Primary Colorectal Cancer in a Patient-derived Orthotopic Xenograft Mouse Model

Purpose: The goal of the present study was to determine the efficacy of temozolomide (TEM) and pazopanib (PAZ) combined with FOLFOX (oxaliplatin, leucovorin and 5-fluorouracil) on a colorectal cancer patient-derived orthotopic xenograft (PDOX) mouse model. Materials and Methods: A colorectal cancer tumor from a patient previously established in non-transgenic nude mice was implanted subcutaneously in transgenic green fluorescence protein (GFP)-expressing nude mice in order to label the tumor stromal cells with GFP. Then labeled tumors were orthotopically implanted into the cecum of nude mice. Mice were randomized into four groups: Group 1, untreated control; group 2, TEM + PAZ; group 3, FOLFOX; group 4, TEM + PAZ plus FOLFOX. Tumor width, length, and mouse body weight were measured weekly. The Fluor Vivo imaging System was used to image the GFP-lableled tumor stromal cells in vivo. H&E staining and immunohistochemical staining were used for histological analysis. Results: All three treatments inhibited tumor growth as compared to the untreated control group. The combination of TEM + PAZ + FOLFOX regressed tumor growth significantly more effectively than TEM + PAZ or FOLFOX. Only the combination of TEM + PAZ + FOLFOX group caused a decrease in body weight. PAZ suppressed lymph vessels density in the colorectal cancer PDOX mouse model suggesting inhibition of lymphangiogenesis. Conclusion: Our results suggest that the combination of TEM + PAZ + FOLFOX has clinical potential for colorectal cancer patient.

Oral Methioninase Inhibits Recurrence in a PDOX Mouse Model of Aggressive Triple-negative Breast Cancer.

The aim of the study was to use a triple-negative breast cancer (TNBC) patient-derived orthotopic xenograft (PDOX) model to examine the efficacy of oral recombinant methioninase (o-rMETase) against this recalcitrant disease. The TNBC tumor from a patient was implanted in the right 4th inguinal mammary fat pad of nude mice. Two weeks later, the mice underwent tumorectomy with grossly-negative surgical margins. Two days after tumorectomy the mice were divided in two groups: one control and one treated with o-rMETase. Tumors recurred in all mice. On day 11, the mean recurrent tumor volumes were 936.7 mm3 in the control group and 450.9 mm3 in the o-rMETase group (p<0.05). On day 15, the mean recurrent tumor volumes were 3392.5 mm3 in the control group and 1603.5 mm3 in the o-rMETase group. The mean recurrent tumor weights were 2.1 g in the control group and 1.1 g in the o-rMETase group on day 15. o-rMETase is an effective adjuvant treatment for aggressive TNBC.

Combination of Trabectedin With Irinotecan, Leucovorin and 5-Fluorouracil Arrests Primary Colorectal Cancer in an Imageable Patient-derived Orthotopic Xenograft Mouse Model.

The aim of the present study was to determine the efficacy of trabectedin combined with FOLFIRI (irinotecan, leucovorin and 5-fluorouracil) on a colorectal cancer (CRC) patient-derived orthotopic xenograft (iPDOX) mouse model. A CRC tumor from a patient previously established in nude mice was implanted subcutaneously in transgenic green fluorescence protein (GFP)-expressing nude mice in order to label the tumor stromal cells with GFP. Mice were randomized into four groups: Group 1, untreated control; group 2, FOLFIRI; group 3, trabectedin alone; group 4, trabectedin plus FOLFIRI. Tumor width, length, and mouse body weight was measured twice every week. All three treatment groups showed inhibited tumor growth compared to the untreated control group. Only the combination of FOLFIRI and trabectedin arrested tumor growth. No significant changes was observed in body weight in any group. These findings suggest that the combination of trabectedin plus FOLFIRI has clinical potential for patients with CRC.

Combination of Trabectedin With Oxaliplatinum and 5-Fluorouracil Arrests a Primary Colorectal Cancer in a Patient-derived Orthotopic Xenograft Mouse Model.

In the present study, we aimed to determine the efficacy of trabectedin (TRAB) combined with oxaliplatinum (OXA)+5-fluorouracil (5-FU) on a colorectal cancer (CRC) patient-derived orthotopic xenograft (PDOX) mouse model. A patient CRC tumor previously established in nude mice was implanted subcutaneously in transgenic green fluorescence protein (GFP)-expressing nude mice. Harvested tumor fragments were transplanted orthotopically in non-transgenic nude mice. Mice were randomized into three groups: Group 1 (G1), untreated-control; Group 2 (G2), OXA+5-FU; Group 3 (G3), TRAB+OXA+5-FU. Tumor width, length, and mouse body weight were measured twice a week. Both treatment groups inhibited tumor growth compared to the untreated control group. The combination of TRAB, OXA and 5-FU was significantly more efficacious than OXA+5-FU and arrested tumor growth. No significant changes were observed in body-weight in any of the three groups. TRAB, OXA and 5-FU combination has clinical potential for this and other CRC patients.

Efficacy of Recombinant Methioninase (rMETase) on Recalcitrant Cancer Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models: A Review.

An excessive requirement for methionine (MET), termed MET dependence, appears to be a general metabolic defect in cancer and has been shown to be a very effective therapeutic target. MET restriction (MR) has inhibited the growth of all major cancer types by selectively arresting cancer cells in the late-S/G2 phase, when they also become highly sensitive to cytotoxic agents. Recombinant methioninase (rMETase) has been developed to effect MR. The present review describes the efficacy of rMETase on patient-derived orthotopic xenograft (PDOX) models of recalcitrant cancer, including the surprising result that rMETase administrated orally can be highly effective.

Mo1382 – Successful Establishment of Pancreatic Cancer Patient-Derived Orthotopic Xenograft Models Using Eus-Guided Fine-Needle Biopsy Samples

Mo1382 – Successful Establishment of Pancreatic Cancer Patient-Derived Orthotopic Xenograft Models Using Eus-Guided Fine-Needle Biopsy Samples

Tumor targeting Salmonella typhimurium A1-R in combination with gemcitabine (GEM) regresses partially GEM-resistant pancreatic cancer patient-derived orthotopic xenograft (PDOX) nude mouse models

ABSTRACTGemcitabine (GEM) is first-line therapy for pancreatic cancer but has limited efficacy in most cases. Nanoparticle-albumin bound (nab)-paclitaxel is becoming first-line therapy for pancreatic cancer, but also has limited efficacy for pancreatic cancer. Our goal was to improve the treatment outcome in patient-like models of pancreatic cancer. We previously established patient-derived orthotopic xenografts (PDOX) pancreatic cancers from two patients. The pancreatic tumor was implanted orthotopically in the pancreatic tail of nude mice to establish the PDOX models. Five weeks after implantation, 50 PDOX mouse models were randomized into five groups of 10 mice for each pancreatic cancer PDOX: untreated control; GEM (100 mg/kg, i.p., once a week for 2 weeks); GEM + nab-PTX (GEM: 100 mg/kg, i.p., once a week for 2 weeks, nab-PTX: 10 mg/kg, i.v., twice a week for 2 weeks); S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., once a week for 2 weeks); GEM + S. typhimurium A1-R (GEM: 100 mg/kg, i.p., once a week for 2 weeks, S. typhimurium A1-R; 5 × 107 CFU/100 μl, i.v., once a week for 2 weeks). GEM + nab-PTX was significantly more effective than GEM alone in one PDOX model (p = 0.0004), but there was no significant difference in the other PDOX model. The combination of GEM + S. typhimurium A1-R regressed both PDOX models. These results show S. typhimurium A1-R can overcome the ineffectiveness or partial effectiveness of GEM in patient-like models of pancreatic cancer and demonstrate clinical potential for this combination.

MEK inhibitor trametinib in combination with gemcitabine regresses a patient-derived orthotopic xenograft (PDOX) pancreatic cancer nude mouse model.

Pancreatic cancer is resistant to treatment and needs precision individualized therapy to improve the outcome of this disease. Previously, we demonstrated that trametinib (TRA), a MEK inhibitor, could inhibit a pancreatic cancer patient-derived orthotopic xenograft (PDOX). In the present study, we show that gemcitabine (GEM) in combination with TRA was more effective than TRA alone. We implanted a patient pancreatic cancer orthotopically in the pancreatic tail of nude mice to establish the PDOX model. After seven weeks of tumor growth, we divided 32 pancreatic-cancer PDOX nude mice into 4 groups of eight: untreated control; GEM (once a week for 2 weeks); TRA (14 consecutive days); GEM + TRA (GEM: once a week for 2 weeks, TRA:14 consecutive days). We found that treated mice on day 14 had significantly reduced tumor volume in comparison to untreated control. TRA and the combination of GEM + TRA therapy significantly inhibited tumor development in comparison to GEM alone. However, GEM + TRA inhibited the PDOX tumor growth significantly greater than TRA alone. These results suggest the clinical potential of the combination of TRA and GEM for pancreatic cancer.

Intra-tumor L-methionine level highly correlates with tumor size in both pancreatic cancer and melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse models.

An excessive requirement for methionine (MET) for growth, termed MET dependence, appears to be a general metabolic defect in cancer. We have previously shown that cancer-cell growth can be selectively arrested by MET restriction such as with recombinant methioninase (rMETase). In the present study, we utilized patient-derived orthotopic xenograft (PDOX) nude mouse models with pancreatic cancer or melanoma to determine the relationship between intra-tumor MET level and tumor size. After the tumors grew to 100 mm3, the PDOX nude mice were divided into two groups: untreated control and treated with rMETase (100 units, i.p., 14 consecutive days). On day 14 from initiation of treatment, intra-tumor MET levels were measured and found to highly correlate with tumor volume, both in the pancreatic cancer PDOX (p<0.0001, R2=0.89016) and melanoma PDOX (p<0.0001, R2=0.88114). Tumors with low concentration of MET were smaller. The present results demonstrates that patient tumors are highly dependent on MET for growth and that rMETase effectively lowers tumor MET.

Cervical Cancer Patient-Derived Orthotopic Xenograft (PDOX) is Sensitive to Cisplatinum and Resistant to Nab-paclitaxel

Cervical cancer is a world-wide problem that requires transformative therapeutic strategies. We have previously developed patient-derived orthotopic xenograft (PDOX) nude-mouse models of this disease. In the present report, we demonstrate that the standard drug, cisplatinum (CDDP), is highly-effective while the new, highly-touted agent, nab-paclitaxel (NAB-PTX) is ineffective. Cervical PDOX tumors were grown on the cervix of nude mice for 4 weeks after surgical orthotopic implantation (SOI). Tumors were treated with CDDP or NAB-PTX. H&E staining demonstrated that the PDOX tumor recapitulated the original patient tumor. CDDP was highly-effective. One tumor that was treated with CDDP completely regressed. CDDP-treated tumors were smaller (tumor volume ratio: 0.42±0.36) than the control group (tumor volume ratio: 3.47±1.66) (p<0.01). In contrast, NAB-PTX did not show significant efficacy on the cervical cancer PDOX model (tumor volume ratio: 2.85±1.45) (p=0.47). CDDP-treated tumor weight (50±50 mg) was significantly less than control (238±114 mg) (p<0.01). NAB-PTX-treated tumors were not reduced in weight (246±136 mg) compared to control (p=0.91). There were no significant differences in mouse body weight between groups. Histological evaluation demonstrated that CDDP-treated tumors were fibrotic with scattered squamous cell nests compared to control or NAB-PTX-treated tumors. The results of the present study demonstrate the power of PDOX models of cervical cancer to distinguish efficacy of potential therapeutics for individual patients with this disease.

Tumor-Targeting Salmonella typhimurium A1-R: An Overview.

The present chapter reviews the development of the tumor-targeting amino-acid auxotrophic strain S. typhimurium A1 and the in vivo selection and characterization of the high-tumor-targeting strain S. typhimurium A1-R. Efficacy of S. typhimurium A1-R in nude-mouse models of prostate, breast, pancreatic, and ovarian cancer, as well as sarcoma and glioma in orthotopic mouse models is described. Also reviewed is efficacy of S. typhimurium A1-R targeting of primary bone tumor and lung metastasis of high-grade osteosarcoma, breast-cancer brain metastasis, and experimental breast-cancer bone metastasis in orthotopic mouse models. The efficacy of S. typhimurium A1-R on pancreatic cancer stem cells, on pancreatic cancer in combination with anti-angiogenic agents, as well as on cervical cancer, soft-tissue sarcoma, and pancreatic cancer patient-derived orthotopic xenograft (PDOX) mouse models, is also described.

Imaging the microenvironment of pancreatic cancer patient-derived orthotopic xenografts (PDOX) growing in transgenic nude mice expressing GFP, RFP, or CFP

We have developed a multi-color, imageable, orthotopic mouse model for individual patients with pancreatic cancer. The tumors are labeled by first passaging them orthotopically through transgenic nude mice expressing green fluorescent protein (GFP), red fluorescent protein (RFP), or cyan fluorescent protein (CFP). Passage of the tumors in these colored transgenic mice labels the stromal cells of the tumor. The cancer cells in the PDOX are labeled in situ with GFP by telomerase-dependent adenovirus OBP-401. The models are termed imageable patient-derived orthotopic xenografts (iPDOX). The tumors acquired brightly-fluorescent stromal cells from the transgenic host mice, which were stably associated with the tumors through multiple passages. The colored fluorescent protein-expressing stromal cells included cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). This model enables powerful color-coded imaging of the interaction of cancer and stromal cells during tumor progression and treatment.

Abstract 219: Fluorescence-guided surgery with an anti-CA 19-9-conjugated fluorophore in combination with neoadjuvant chemotherapy inhibits metastatic recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) nude mouse model

Abstract The efficacy of fluorescence-guided surgery (FGS) in combination with neoadjuvant chemotherapy (NAC) with gemcitabine (GEM) on a pancreatic cancer patient derived orthotopic xenograft (PDOX) model was determined. A PDOX model was established from a CA19-9-positive, CEA-negative tumor from a patient who had undergone a pancreaticoduodenectomy for pancreatic adenocarcinoma. Mice were randomized to 4 groups: bright light surgery (BLS) only; BLS + NAC; FGS only; and FGS + NAC. An anti-CA19-9 or anti-CEA antibody conjugated to DyLight 650 was administered intravenously via the tail vein of mice with the pancreatic cancer PDOX 24 hours before surgery. The PDOX was brightly labeled with fluorophore-conjugated anti-CA19-9, but not with a fluorophore-conjugated anti-CEA antibody. FGS was performed using the fluorophore-conjugated anti-CA19-9 antibody. FGS + NAC significantly reduced the metastatic recurrence frequency to one of 8 mice, compared to FGS only after which metastasis recurred in 6 out of 8 mice, and BLS + NAC with metastatic recurrence in 7 out of 8 mice (p = 0.041). Thus NAC in combination with FGS can reduce or even eliminate metastatic recurrence of pancreatic cancer sensitive to NAC. The present study further emphasizes the power of the PDOX model which enables metastasis to occur and thereby identify the efficacy of FGS in combination with NAC on metastatic recurrence. Citation Format: Yukihiko Hiroshima, Ali Maawy, Yong Zhang, Takashi Murakami, Masashi Momiyama, Ryutaro Mori, Ryusei Matsuyama, Matthew H. Katz, Jason B. Fleming, Takashi Chishima, Kuniya Tanaka, Yasushi ichikawa, Itaru Endo, Robert M. Hoffman, Michael Bouvet. Fluorescence-guided surgery with an anti-CA 19-9-conjugated fluorophore in combination with neoadjuvant chemotherapy inhibits metastatic recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) nude mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 219. doi:10.1158/1538-7445.AM2015-219

Pancreas divisum in acute and chronic pancreatic disease

The aim of this study is to determine the efficacy of neoadjuvant chemotherapy (NAC) with gemcitabine (GEM) in combination with fluorescence-guided surgery (FGS) on a pancreatic cancer patient derived orthotopic xenograft (PDOX) model.A PDOX model was established from a CEA-positive tumor from a patient who had undergone a pancreaticoduodenectomy for pancreatic adenocarcinoma. Mice were randomized to 4 groups: bright light surgery (BLS) only; BLS + NAC; FGS only; and FGS + NAC. An anti-CEA antibody conjugated to DyLight 650 was administered intravenously via the tail vein of mice with a pancreatic cancer PDOX 24 h before surgery.The PDOX was clearly labeled with fluorophore-conjugated anti-CEA antibody. Only one out of 8 mice had local recurrence in the FGS only group and zero out of 8 mice had local recurrence in the FGS + NAC which was significantly lower than BLS only or BLS + NAC mice, where local disease recurred in 6 out of 8 mice in each treatment group (p = 0.041 and p = 0.007, respectively). NAC did not significantly reduce recurrence rates when combined with either FGS or BLS.These results indicate that FGS can significantly reduce local recurrence compared to BLS in pancreatic cancer resistant to NAC.

Fluorescence-guided surgery, but not bright-light surgery, prevents local recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) model resistant to neoadjuvant chemotherapy (NAC)

BackgroundThe aim of this study is to determine the efficacy of neoadjuvant chemotherapy (NAC) with gemcitabine (GEM) in combination with fluorescence-guided surgery (FGS) on a pancreatic cancer patient derived orthotopic xenograft (PDOX) model. MethodsA PDOX model was established from a CEA-positive tumor from a patient who had undergone a pancreaticoduodenectomy for pancreatic adenocarcinoma. Mice were randomized to 4 groups: bright light surgery (BLS) only; BLS + NAC; FGS only; and FGS + NAC. An anti-CEA antibody conjugated to DyLight 650 was administered intravenously via the tail vein of mice with a pancreatic cancer PDOX 24 h before surgery. ResultsThe PDOX was clearly labeled with fluorophore-conjugated anti-CEA antibody. Only one out of 8 mice had local recurrence in the FGS only group and zero out of 8 mice had local recurrence in the FGS + NAC which was significantly lower than BLS only or BLS + NAC mice, where local disease recurred in 6 out of 8 mice in each treatment group (p = 0.041 and p = 0.007, respectively). NAC did not significantly reduce recurrence rates when combined with either FGS or BLS. ConclusionThese results indicate that FGS can significantly reduce local recurrence compared to BLS in pancreatic cancer resistant to NAC.

Metastatic recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) nude mouse model is inhibited by neoadjuvant chemotherapy in combination with fluorescence-guided surgery with an anti-CA 19-9-conjugated fluorophore.

The aim of this study is to determine the efficacy of neoadjuvant chemotherapy (NAC) with gemcitabine (GEM) in combination with fluorescence-guided surgery (FGS) on a pancreatic cancer patient derived orthotopic xenograft (PDOX) model. A PDOX model was established from a CA19-9-positive, CEA-negative tumor from a patient who had undergone a pancreaticoduodenectomy for pancreatic adenocarcinoma. Mice were randomized to 4 groups: bright light surgery (BLS) only; BLS+NAC; FGS only; and FGS+NAC. An anti-CA19-9 or anti-CEA antibody conjugated to DyLight 650 was administered intravenously via the tail vein of mice with the pancreatic cancer PDOX 24 hours before surgery. The PDOX was brightly labeled with fluorophore-conjugated anti-CA19-9, but not with a fluorophore-conjugated anti-CEA antibody. FGS was performed using the fluorophore-conjugated anti-CA19-9 antibody. FGS had no benefit over BLS to prevent metastatic recurrence. NAC in combination with BLS did not convey an advantage over BLS to prevent metastatic recurrence. However, FGS+NAC significantly reduced the metastatic recurrence frequency to one of 8 mice, compared to FGS only after which metastasis recurred in 6 out of 8 mice, and BLS+NAC with metastatic recurrence in 7 out of 8 mice (p = 0.041). Thus NAC in combination with FGS can reduce or even eliminate metastatic recurrence of pancreatic cancer sensitive to NAC. The present study further emphasizes the power of the PDOX model which enables metastasis to occur and thereby identify the efficacy of NAC in combination with FGS on metastatic recurrence.

Abstract B01: A portable imaging system for fluorescence-guided surgery on a human colon cancer patient-derived orthotopic xenograft (PDOX™) nude mouse model

Abstract In this study, we determined the effectiveness of fluorescence-guided surgery (FGS) using a fluorophore-conjugated anti-carcinoembryonic antigen (CEA) antibody on a colon-cancer patient-derived orthotopic xenografts (PDOX™) nude mouse model. The patient tumor was established in NOD/SCID mice and passed orthotopically in nude mice to make PDOX™ models. Eight weeks after orthotopic implantation in nude mice, a monoclonal anti-CEA antibody conjugated with Alexa 488 was delivered to the PDOX™ models as a single intravenous dose 24 hours before laparotomy. The tumor was completely resected under fluorescence guidance using a hand-held portable fluorescence imaging system. Frozen section microscopy of the resected specimen demonstrated that the anti-CEA antibody selectively labeled cancer cells in the colon cancer PDOX™. Histologic evaluation of the resected specimen demonstrated that cancer cells were not present in the margins. The results of the present report predict that FGS using a fluorophore-conjugated anti-CEA antibody and hand-held portable imaging system should improve intraoperative staging and efficacy of resection for colorectal cancer in the clinic. Citation Format: Yukihiko Hiroshima, Ali Maawy, Sharmeela Kaushal, Yong Zhang, Fuminari Uehara, Shinji Miwa, Shuya Yano, Sho Sato, Takashi Murakami, Masashi Momiyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. A portable imaging system for fluorescence-guided surgery on a human colon cancer patient-derived orthotopic xenograft (PDOX™) nude mouse model. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B01.