Japanese Journal of Cancer and Chemotherapy最新文献

The standard first-line treatment for unresectable advanced or recurrent gastric cancer(GC)and gastroesophageal junction cancer(GEJC)has been a platinum doublet chemotherapy. Trastuzumab with chemotherapy is the standard regimen for HER2-positive GC/GEJC. While, for HER2-negative cases, chemotherapy with or without immune checkpoint inhibitors (ICIs)such as nivolumab or pembrolizumab are regarded as the standard therapy. However, many patients do not derive benefit from anti-HER2 targeted therapies or ICIs, and new therapeutic targets have been explored. CLDN18.2 has emerged as a tissue-specific therapeutic target in gastric cancer. Zolbetuximab, a first-in-class chimeric IgG1 monoclonal antibody targeting CLDN18.2, has been developed. Zolbetuximab induces cancer cell death through antibody-dependent cellular cytotoxicity(ADCC)and complement-dependent cytotoxicity(CDC). Recently, zolbetuximab with chemotherapy improved survival rates in HER2-negative CLDN18.2-positive previously untreated patients with unresectable advanced or recurrent GC/GEJC, leading to its approval in Japan and its establishment as a standard treatment. GC/GEJC with early onset, scirrhous type or peritoneum dissemination commonly express CLDN18.2. The emergence of this novel therapeutic option is of great significance in clinical practice. We will highlight the previous clinical trials of zolbetuximab and provide future perspective of CLDN18.2 targeted therapy. In addition, we will introduce the ongoing development of various CLDN18.2 targeting therapies such as newer monoclonal antibodies, antibody-drug conjugates(ADCs), chimeric antigen receptor T-cell(CAR- T)therapy, and bispecific antibodies.

An elevated expression of claudins(CLDNs), tight junctional proteins, are reported in various solid tumors. However, the expression mechanisms and pathophysiological roles of CLDNs have not been well clarified. So far, we found that CLDN2 and CLDN14 are highly expressed in lung adenocarcinoma and colorectal cancer cells, respectively. These CLDNs augmented proliferation of cancer cells. Furthermore, these CLDNs enhanced chemoresistance of cancer spheroids mediated by the elevation of oxidative stress and activation of Nrf2 signal pathway. The restriction of glucose supply, shift of glucose metabolism from aerobic glycolysis towards oxidative phosphorylation, and elevation of mitochondria activity were suggested to be involved in the CLDN2-dependent activation of Nrf2 signal pathway. The CLDN expression inhibitors are expected to have functions of proliferation inhibition and anticancer drug resistance improvement effects. We have to search for the optimal CLDN subtype as therapeutic target because the expression pattern of CLDN subtypes is different in the type of cancer.

67-year-old woman underwent definitive chemoradiotherapy( dCRT) with cisplatin( CDDP) and 5-fluorouraci(l 5-FU)(FP) for locally advanced unresectable squamous cell carcinoma of the thoracic esophagus. During treatment, the patient developed grade 3 pharyngitis and esophagitis as adverse events. She was administered maintenance chemotherapy with 2 courses of FP and achieved complete response. Currently, she experiences esophageal stenosis; however, she remains alive and recurrence-free 9 years after initial treatment. While dCRT is effective for locally advanced esophageal cancer, its adverse effects may persist. Herein, we report our case and have included relevant literature considerations.

Locally advanced breast cancer can lead to self-destruction, necrosis, and malodor, which may reduce the patients' quality of life. We encountered a case where the combination of Mohs' paste and systemic drug therapy for locally advanced breast cancer improved quality of life and achieved marked disease control. The patient, a woman in her 70s, was referred to our department with suspected right breast cancer. After thorough examination, she was diagnosed with cT4bN3aM1(PUL), cStage Ⅳ, invasive ductal carcinoma, HER2 type. Mohs' paste treatment began on the 8th day, and systemic drug therapy was initiated on the 22nd day. Mohs' paste was applied once a week for a total of 4 times, resulting in significant tumor shrinkage. More than 6 months have passed since the start of treatment, and a complete response has been maintained, including pulmonary metastasis. Mohs' paste is a useful treatment for locally advanced breast cancer with self-destruction and necrosis.

The patient was a man in his 60s who complained of gastric reflux and was diagnosed with advanced gastric cancer (tub1, por1)involving pyloric stenosis. Computed tomography revealed an enlarged para-aortic lymph node(PALN, #16a2). His preoperative diagnosis was cT4aN2M1(LYM), cStage Ⅳb. The patient underwent laparoscopic gastric jejunal bypass surgery to treat the pyloric obstruction and was administered 2 courses of preoperative chemotherapy with S-1+L-OHP(SOX). Significant shrinkage was observed in both the primary tumor and surrounding lymph node metastases, and the PALN did not exhibit further enlargement. Therefore, the patient was eligible for surgery. Intraoperative diagnosis of PALN#16a2 was positive for metastasis, and distal gastrectomy with radical para-aorticlymph node dissection(#16a2+b1)was performed. The gastric jejunal bypass was preserved for reconstruction, and the pathological diagnosis was ypT2N3(15/60). Following discharge, adjuvant chemotherapy with S-1+DTX(DS)was performed for 1 year, and no recurrence has been observed for 1 year and 6 months. This study showed that advanced gastric cancer with pyloric stenosis and PALN enlargement can be treated with radical para-aortic lymph node dissection through prompt introduction of preoperative chemotherapy following gastric jejunostomy bypass surgery.

Epigenetic regulation mechanisms such as DNA methylation and histone acetylation are important for controlling various biological phenomena by regulating gene expression at the genome level. They are reversible systems that change depending on environmental factors. Epigenetic abnormalities are associated with the onset of various diseases, including developmental and aging abnormalities, neurological disorders, and malignant tumors. Aberrant DNA methylation is an important epigenetic change in the development and progression of colorectal cancer. DNA methylation in tumor tissues occurs mainly in CpG islands in the promoter regions of genes and inactivates gene functions by negatively suppressing transcription. CpG island methylator phenotype(CIMP)is an important carcinogenic mechanism of colorectal cancer related to DNA methylation and is involved in approximately 20% of all colorectal cancers. CIMP is generally judged to be positive when a certain percentage or more of the marker gene set is methylated, and many CIMP markers have been reported so far. However, no established marker has been set to classify colorectal cancer by genome-wide DNA methylation. We developed a new method to assess genome-wide DNA methylation status and obtained pharmaceutical approval as a new in vitro diagnostic drug to predict sensitivity to anti-EGFR antibody drugs in colorectal cancer.

Dendritic cell(DC)vaccine therapy has been widely studied as cancer immunotherapy that potently induces cytotoxic T lymphocytes. However, their efficacy in clinical practice has not yet been established. We have developed an oncolytic adenovirus OBP-702 carrying the tumor suppressor gene p53 and have demonstrated its therapeutic potential to induce cytopathic effect and activate antitumor immunity via p53 induction. In this study, we investigated the combined effect of p53-transduced DC vaccine and OBP-702 in colorectal cancer.