Pancreatic cancer (PDAC) is the most lethal malignancy. New treatment options for it are urgently required. The aim was to develop an antibody-drug conjugate (ADC) targeting glypican-1 (GPC-1) as a ...new therapy for PDAC.
We evaluated GPC-1 expression in resected PDAC specimens and PDAC cell lines. We then measured the antitumour effect of anti-GPC-1 monoclonal antibody conjugated with the cytotoxic agent monomethyl auristatin F (MMAF) in vitro and in vivo.
GPC-1 was overexpressed in most primary PDAC cells and tissues. The PDAC cell lines BxPC-3 and T3M-4 strongly expressed GPC-1 relative to SUIT-2 cells. Compared with control ADC, GPC-1-ADC showed a potent antitumour effect against BxPC-3 and T3M-4, but little activity against SUIT-2 cells. In the xenograft and patient-derived tumour models, GPC-1-ADC significantly and potently inhibited tumour growth in a dose-dependent manner. GPC-1-ADC-mediated G2/M-phase cell cycle arrest was detected in the tumour tissues of GPC-1-ADC-treated mice relative to those of control-ADC-treated mice.
GPC-1-ADC showed significant tumour growth inhibition against GPC-1-positive pancreatic cell lines and patient-derived, GPC-1-positive pancreatic cancer tissues. Our preclinical data demonstrated that targeting GPC-1 with ADC is a promising therapy for patients with GPC-1-positive pancreatic cancer.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Pancreatic ductal adenocarcinoma (PDAC) is a stroma-rich cancer. Extracellular matrix proteins produced by cancer-associated fibroblasts (CAFs) found in tumor stroma that impedes effective delivery ...of chemotherapeutic agents results in poor response in patients with PDAC. Previously, our group reported that glypican-1 (GPC1) was overexpressed in human PDAC and negatively correlated with patient survival. Immunohistochemical analysis of 25 patients with PDAC tumor specimens revealed elevated expression of GPC1 in stromal cells and pancreatic cancer cells in 80% of patients. Interestingly, GPC1 was expressed on CAFs in PDAC. We generated a GPC1 antibody-drug conjugate conjugated with monomethyl auristatin E GPC1-ADC(MMAE) and evaluated its preclinical antitumor activity by targeting GPC1-positive CAF and cancer cells in PDAC. GPC1-ADC(MMAE) inhibited the growth of GPC1-positive PDAC cell lines
Furthermore, GPC1-ADC(MMAE) showed a potent antitumor effect in the PDAC patient-derived tumor xenograft (PDX) model against GPC1-positive CAF and heterogeneous GPC1-expressing cancer cells. Notably, GPC1-ADC(MMAE) showed robust preclinical efficacy against GPC1 in a stroma-positive/cancer-negative PDAC PDX model. GPC1-ADC(MMAE) was delivered and internalized to CAFs. Although apoptosis was not observed in CAFs, the released MMAE from CAFs via MDR-1 induced apoptosis of cancer cells neighboring CAFs and efficiently inhibited PDAC tumor growth. GPC1-ADC(MMAE) exhibited potent and unique antitumor activity in GPC1-positive PDAC PDX models, which suggests that GPC1 is a novel therapeutic target in PDAC and other stromal GPC1-positive solid tumors. These findings show that targeting GPC1 on CAF using GPC1-ADC(MMAE) is a useful approach in case of stroma-rich tumors such as PDAC.
Background
This study evaluated the prognostic value of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) together with host-related factors in patients with unresectable advanced gastric ...cancer.
Methods
The study enrolled 262 patients who received chemotherapy for unresectable advanced gastric cancer at Kochi Medical School from 2007 to 2015. Clinicopathological information and systemic inflammatory response data were analyzed for associations between baseline cancer-related prognostic variables and survival outcomes.
Results
The median survival time was significantly lower for patients with high ALP, high LDH, high total bilirubin, high aspartate aminotransferase, high alanine transaminase, high gamma-glutamyltransferase, high creatinine, a Glasgow prognostic score (GPS) of 1 or 2 score compared to GPS 0, higher compared to lower neutrophil to lymphocyte ratio (NLR) 3.9, lower compared to higher prognostic nutrition index 36.1, T3–4 compared to T1–2 tumor and diffuse-type compared to intestinal-type histology. Multivariate survival analysis identified high ALP 322 (HR 1.808; 95% CI 1.015–3.220;
P
= 0.044), T2–3 (HR 2.622; 95% CI 1.224–5.618;
P
= 0.013), and diffuse-type gastric cancer (HR 2.325; 95% CI 1.341–4.032;
P
= 0.003) as significant independent predictors of worse prognosis in the studied group of cancer patients.
Conclusions
High level of ALP is an independent, worse prognosis factor for patients receiving chemotherapy for unresectable and recurrent gastric cancer.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cholangiocarcinoma is a highly malignant cancer. Many patients need systemic chemotherapy to prevent tumor development and recurrence; however, their prognosis is poor due to the lack of effective ...therapy. Therefore, a new treatment option is urgently required. We recently identified glypican-1 (GPC1) as a novel cancer antigen of esophageal squamous cell carcinoma. We also demonstrated the efficacy and safety of GPC1-targeted ADC (GPC1-ADC) conjugating anti-GPC1 mAb possessing high internalization activity with monomethyl auristatin F (MMAF), which is a potent tubulin polymerizing inhibitor. In this study, we confirmed that GPC1 was highly expressed in cholangiocarcinoma cells and tissues. IHC analysis of 49 extrahepatic cholangiocarcinoma patient tumor specimens revealed high expression of GPC1 in 47% of patients. These patients demonstrated significantly poorer prognosis compared with the low-expression group in terms of disease-free survival and overall survival (
< 0.05). GPC1 was also expressed in tumor vessels of cholangiocarcinoma, but not on the vessels of nontumor tissues. MMAF-conjugated GPC1-ADC showed potent tumor growth inhibition against GPC1-positive cholangiocarcinoma cells
and
In a GPC1 knockout xenograft model, GPC1-ADC partially inhibited tumor growth. Vascular endothelial cells in tumor tissues of GPC1-negative xenograft mice expressed GPC1 and were arrested in the G
-M phase of cell cycle by GPC1-ADC. GPC1-ADC exhibits direct as well as indirect antitumor effects via inhibition of tumor angiogenesis. Our preclinical data highlight GPC1-ADC as a promising therapy for GPC1-positive cholangiocarcinoma.
•The authors developed a humanized anti-glypican-1 (GPC1) monoclonal antibody (clone T2) and produced an antibody-drug conjugate (ADC) linked to monomethyl auristatin E (MMAE). The ADC potently ...inhibited the growth of GPC1-positive pancreatic ductal adenocarcinoma and esophageal squamous cell carcinoma in vitro and in vivo, and exhibited bystander killing activity. Humanized GPC1-ADC(MMAE) was effective against BxPC-3-Luc#2 pancreatic cancer liver metastases in mice. Humanized GPC1-ADC(MMAE) may provide a promising therapeutic strategy for GPC1-positive tumors.
An antibody-drug conjugate (ADC) is a promising therapeutic modality because selective and effective delivery of an anti-cancer drug is achieved by drug-conjugated antibody-targeting cancer antigen. Glypican 1 (GPC1) is highly expressed in malignant tumors, including pancreatic ductal adenocarcinoma (PDAC) and esophageal squamous cell carcinoma (ESCC). Herein, we describe the usefulness of GPC1-targeting ADC. Humanized anti-GPC1 antibody (clone T2) was developed and conjugated with monomethyl auristatin E (MMAE) via maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PABC) linkers (humanized GPC1-ADCMMAE). Humanized GPC1-ADC(MMAE) inhibited the growth of GPC1-positive PDAC and ESCC cell lines via inducing cycle arrest in the G2/M phase and apoptosis in vitro. The binding activity of humanized GPC1-ADC(MMAE) with GPC1 was comparable with that of the unconjugated anti-GPC1 antibody. The humanized GPC1-ADC(MMAE) was effective in GPC1-positive BxPC-3 subcutaneously xenografted mice but not in GPC1-negative BxPC-3-GPC1-KO xenografted mice. To assess the bystander killing activity of the humanized GPC1-ADC(MMAE), a mixture of GPC1-positive BxPC-3 and GPC1-negative BxPC-3-GPC1-KO-Luc cells were subcutaneously inoculated, and a heterogenous GPC1-expressing tumor model was developed. The humanized GPC1-ADC(MMAE) inhibited the tumor growth and decreased the luciferase signal, measured with an in vivo imaging system (IVIS), which suggests that the suppression of the BxPC-3-GPC1-KO-Luc population. The humanized GPC1-ADC(MMAE) also inhibited the established liver metastases of BxPC-3 cells and significantly improved the overall survival of the mice. It exhibited a potent antitumor effect on the GPC1-positive PDAC and ESCC patient-derived xenograft (PDX) models. Our preclinical data demonstrate that GPC1 is a promising therapeutic target for ADC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The natural amino acid 5-aminolevulinic acid (ALA) is a protoporphyrin IX (PpIX) precursor and a new-generation photosensitive substance that accumulates specifically in cancer cells. When ...indocyanine green (ICG) is irradiated with near-infrared (NIR) light, it shifts to a higher energy state and emits infrared light with a longer wavelength than the irradiated NIR light. Photodynamic diagnosis (PDD) using ALA and ICG-based NIR fluorescence imaging has emerged as a new diagnostic technique. Specifically, in laparoscopic examinations for serosa-invading advanced gastric cancer, peritoneal metastases could be detected by ALA-PDD, but not by conventional visible-light imaging. The HyperEye Medical System (HEMS) can visualize ICG fluorescence as color images simultaneously projected with visible light in real time. This ICG fluorescence method is widely applicable, including for intraoperative identification of sentinel lymph nodes, visualization of blood vessels in organ resection, and blood flow evaluation during surgery. Fluorescence navigation by ALA-PDD and NIR using ICG imaging provides good visualization and detection of the target lesions that is not possible with the naked eye. We propose that this technique should be used in fundamental research on the relationship among cellular dynamics, metabolic enzymes, and tumor tissues, and to evaluate clinical efficacy and safety in multicenter cooperative clinical trials.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Glomus tumor of the stomach is a rare submucosal mesenchymal tumor. The present study reports a patient with gastric glomus tumor treated by laparoscopic distal gastrectomy. A 39-year-old male was ...referred to Kochi Medical School Hospital for examination of a gastric submucosal tumor (SMT) initially diagnosed following a medical check-up. Esophagogastroduodenoscopy revealed a solitary, well-defined, submucosal lesion in the antrum of the stomach. Endoscopic ultrasonography (EUS) revealed a hypoechoic solid mass primarily connected to the gastric muscular layer. Abdominal contrast-enhanced computed tomography confirmed a 1.5 cm, well-defined mass lesion demonstrating homogeneous strong enhancement in the gastric antrum. Subsequent EUS-guided fine-needle aspiration produced a clinical diagnosis of neuroendocrine neoplasm and the patient underwent laparoscopic distal gastrectomy with regional lymph node dissection. Histopathology revealed solid proliferation of round, α-smooth muscle actin-immunopositive tumor cells with dilated vessels lined by endothelial cells without atypia, prompting a diagnosis of gastric glomus tumor. To the best of our knowledge, this is the seventh case of gastric glomus tumor treated by laparoscopy reported in English literature. The present case suggested that glomus tumor should be considered in the differential diagnosis for SMT of the stomach.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A 71-year-old woman with epigastric pain and fever visited our hospital. She had elevated levels of serum amylase and C-reactive protein, and computed tomography revealed a large, 20 cm diameter, ...pancreatic cyst. A low-density nodule was also identified in the head of the pancreas with mild dilation of the distal main pancreatic duct (MPD). The patient was diagnosed with pancreatic ductal carcinoma complicated by a pancreatic pseudocyst (PPC). After drainage of the cyst, a pancreaticoduodenectomy was safely performed. Histological examination revealed anaplastic pancreatic carcinoma (APC) composed of spindle cells and osteoclast-like giant cells. The tumor occupied the lumen of the MPD and acute and chronic obstructive pancreatitis was evident. Although her postoperative course was uneventful, the tumor recurred as multiple liver metastases three months after surgery, and she died of disease progression four months after surgery. PPCs are often caused by alcohol use, biliary tract disease, or blunt trauma. However, PPCs caused by APC is rarely seen. Although extremely rare, pancreatic cancer or APC should be considered as a cause of PPCs. A spindle cell component to the tumor seems to be associated with a dismal prognosis, while growth within the pancreatic duct is reported to carry a better prognosis.
Background
The effects of sivelestat on endotoxin-induced lung injury, postperfusion lung injury, and ischemia–reperfusion are known, yet the benefits of sivelestat during liver surgery have yet to ...be elucidated. The aim of the present study was to assess the effects of sivelestat, with a focus on postoperative chemical data, in hepatectomized patients.
Patients and methods
A prospective clinical study was conducted in 50 patients undergoing hepatic resection. Patients were randomly assigned to receive Elaspol, sivelestat (ELP group,
n
= 25) or placebo (control group,
n
= 25). Perioperative blood chemistry values in both groups, including high-mobility group box 1 (HMGB1) and interleukin (IL)-6, were monitored.
Results
The HMGB1 levels increased immediately after the operation (from the intraoperative period to the second postoperative day POD) in the control group. Compared to the control group, the levels of HMGB1 in the ELP group were significantly suppressed by the perioperative administration of sivelestat. At POD 1, the levels of IL-6 in the ELP group decreased more rapidly than those before the operation compared to the control group.
Conclusions
A human clinical study demonstrated the effect of polymorphonuclear leukocyte elastase inhibitor on the earliest markers of liver injury. The present study showed that patients who received sivelestat had reduced release of HMGB1, and that IL-6 levels decreased more rapidly in patients treated with sivelestat than in those who received the placebo. The most appropriate dose, timing, and duration of sivelestat in humans remain unclear; however, it may have therapeutic potential for various liver injuries.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Conversion therapy for gastric cancer is a new therapeutic concept. We report a case of a patient with advanced gastric cancer who underwent conversion surgery due to a remarkable regression of ...multiple liver metastases following chemotherapy. A 71-year-old man was referred to our hospital with gastric cancer. Esophagogastroduodenoscopy (EGD) revealed an irregular, nodular, ulcerated lesion in the lower third of the stomach. Analysis of biopsy specimens revealed a poorly differentiated adenocarcinoma. Abdominal contrast-enhanced computed tomography (CT) showed multiple liver mass lesions. The patient was clinically diagnosed with advanced gastric cancer with liver metastases and received S-1 plus oxaliplatin chemotherapy. After 6 cycles of chemotherapy, CT and magnetic resonance imaging showed complete resolution of the liver metastases, and EGD detected mucosal irregularities only. Since there was no evidence of further metastatic lesions in other organs, the patient underwent distal gastrectomy with D2 lymphadenectomy. The gross appearance of the surgically resected specimen showed a slightly elevated tumor measuring 4.5 × 3.5 cm. Pathological examination confirmed the diagnosis of a moderately differentiated gastric adenocarcinoma invading the muscularis propria with no lymph node metastases. The postoperative course was uneventful. The patient has continued to receive S-1 and oxaliplatin chemotherapy, and there has been no evidence of recurrence for 3 months following the operation. We propose that conversion therapy might be an effective treatment for patients with advanced gastric cancer; however, further studies and assessments are needed to confirm and establish this treatment strategy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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