Patient‐derived xenograft (PDX) models are a useful tool in cancer biology research. However, the number of lung cancer PDX is limited. In the present study, we successfully established 10 PDX, ...including three adenocarcinoma (AD), six squamous cell carcinoma (SQ) and one large cell carcinoma (LA), from 30 patients with non‐small cell lung cancer (NSCLC) (18 AD, 10 SQ, and 2 LA), mainly in SCID hairless outbred (SHO) mice (Crlj:SHO‐PrkdcscidHrhr). Histology of SQ, advanced clinical stage (III‐IV), status of lymph node metastasis (N2‐3), and maximum standardized uptake value ≥10 when evaluated using a delayed 18F‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography (FDG‐PET) scan was associated with successful PDX establishment. Histological analyses showed that PDX had histology similar to that of patients’ surgically resected tumors (SRT), whereas components of the microenvironment were replaced with murine cells after several passages. Next‐generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors (EGFR‐TKI), such as gefitinib and osimertinib. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced that was associated with epithelial‐to‐mesenchymal transition. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR‐TKI resistance.
We successfully established 10 PDX. Next‐generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had EGFR mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR‐TKI resistance.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Primary malignant melanoma (MM) of the mediastinum is rare, and there is a lack of consensus regarding the preferred treatment because non-cutaneous MM demonstrates an inferior response to systemic ...therapy. Herein, we describe the case of a 73-year-old man with MM of the anterior mediastinum with multiple liver metastases. Even though the size of lesions increased rapidly following diagnosis, nivolumab monotherapy caused remarkable tumor shrinkage. This is the first report of mediastinal MM showing a significant response to nivolumab. We, therefore, suggest that immunotherapy may be one of the treatment options for primary mediastinal MM.
Tropomyosin receptor kinase (TRK) inhibitors have demonstrated histology‐agnostic efficacy in patients with neurotrophic receptor tyrosine kinase (NTRK) gene fusion. Although responses to TRK ...inhibitors can be dramatic and durable, duration of response may eventually be limited by acquired resistance via several mechanisms, including resistance mutations such as NTRK1‐G595R. Repotrectinib is a second‐generation TRK inhibitor, which is active against NTRK1‐G595R. However, its efficacy against entrectinib‐resistant tumors has not been fully elucidated. In the present study, we established entrectinib‐resistant tumor cells (M3B) in a brain metastasis model inoculated with NTRK1‐rearranged KM12SM cells and examined the sensitivity of M3B cells to repotrectinib. While M3B cells harbored the NTRK1‐G595R mutation, they were unexpectedly resistant to repotrectinib. The resistance was due to extracellular signal–regulated kinase (ERK) reactivation partially mediated by epidermal growth factor receptor (EGFR) activation. We further demonstrate that the triplet combination of repotrectinib, EGFR inhibitor, and MEK inhibitor could sensitize M3B cells in vitro as well as in a brain metastasis model. These results indicate that resistant mutations, such as NTRK1‐G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib‐resistant tumors, thereby causing resistance to second‐generation inhibitor repotrectinib. These findings highlight the importance of intensive examinations to identify resistance mechanisms and application of the appropriate combination treatment to circumvent the resistance.
We explored the resistance mechanism to tropomyosin receptor kinase (TRK) inhibitors. We demonstrated that resistant mutations, such as NTRK1‐G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib‐resistant tumors, thereby causing resistance to entrectinib as well as repotrectinib, and that this resistance could be surmounted by triple inhibitions to TRK, EGFR, and ERK.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A BRAF V600E mutation is found as driver oncogene in patients with non-small cell lung cancer. Although combined treatment with dabrafenib and trametinib is highly effective, the efficacy of reduced ...doses of the drugs in combination therapy has not yet been reported.
A Japanese man in his mid-sixties was diagnosed with unresectable lung adenocarcinoma and was unresponsive to cytotoxic chemotherapy and immune checkpoint inhibitors. The BRAF V600E mutation was detected by next generation sequencing, and the patient was subjected to treatment with dabrafenib and trametinib in combination. Although the treatment reduced the tumor size, he experienced myalgia and muscle weakness with elevated serum creatine kinase and was diagnosed with rhabdomyolysis induced by dabrafenib and trametinib. After the patient recovered from rhabdomyolysis, the treatment doses of dabrafenib and trametinib were reduced, which prevented further rhabdomyolysis and maintained tumor shrinkage.
The reduction of the doses of dabrafenib and trametinib was effective in the treatment of BRAF V600E-mutant NSCLC, and also prevented the incidence of rhabdomyolysis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We herein report a 67-year-old woman with malignant lymphomas of the bile duct that developed after regression of a pancreatic head mass. Computed tomography suggested the mass was pancreatic head ...cancer. Endoscopic ultrasonography showed a low-echoic mass with hyperechoic strands resembling autoimmune pancreatitis. Her serum IgG4 concentration was elevated to 674 mg/dL. After the pancreatic head mass spontaneously diminished, three masses were detected in the common bile duct. A biopsy of the major papilla revealed high-grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangement. Systemic chemotherapy with rituximab plus etoposide, prednisolone, vincristine, cyclophosphamide and doxorubicin resulted in complete remission.
Patients with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who are prescribed ALK-tyrosine kinase inhibitors (ALK-TKIs) rarely have complete responses, with ...residual tumors relapsing as heterogeneous resistant phenotypes. Herein, we investigated new therapeutic strategies to reduce and eliminate residual tumors in the early treatment phase. Functional genomic screening using small guide RNA libraries showed that treatment-induced adaptive survival of ALK-rearranged lung cancer cells was predominantly dependent on STAT3 activity upon ALK inhibition. STAT3 inhibition effectively suppressed the adaptive survival of ALK-rearranged lung cancer cells by enhancing ALK inhibition-induced apoptosis. The combined effects were characterized by treatment-induced STAT3 dependence and transcriptional regulation of anti-apoptotic factor BCL-X
. In xenograft study, the combination of YHO-1701 (STAT3 inhibitor) and alectinib significantly suppressed tumor regrowth after treatment cessation with near tumor remission compared with alectinib alone. Hence, this study provides new insights into combined therapeutic strategies for patients with ALK-rearranged lung cancer.
Background
Potential disparities between cancer patients with and without disabilities remained to be validate in Japan.
Methods
We surveyed retrospective data on hospital cancer registration as well ...as information on disability certificates obtained through the Hokushin Ganpro database. In total, 93,545 cancer patients in 10 principal hospitals covering the region of northwestern Japan were registered with the Hokushin Ganpro database between 2010 and 2015. The database included the following data: diagnosis date, cancer type, staging, treatment, cancer detection process, and possession of a disability certificate.
Results
We found that 2983 patients, which accounted for 3.2% of the total patients, had disabilities. No significant differences in gender, age at diagnosis, cancer stage distribution, and cancer incidence rates were observed between the disabled and non-disabled patients. Even though the proportion of early-stage cancer among disabled patients differed only slightly from that in non-disabled patients, early-stage cancer was more frequently diagnosed in patients with disabilities during their regular hospital visits than in those without disabilities, who had more opportunity for early cancer detection during cancer screening. According to in-house data reflecting treatment period and process from a single hospital, all 16 disabled patients treated with chemotherapy completed the treatment until disease progression or end of predetermined cycles.
Conclusion
These results indicate that deep disparities between cancer patients with and without disabilities are not apparent and that the disabled patients in the region of northwestern Japan receive appropriate hospital follow-up.
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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
Anaplastic lymphoma kinase (
)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine ...kinase inhibitor in
-positive NSCLCs, most patients experience resistance. We conducted a phase II study to investigate the combination of alectinib with bevacizumab in
-positive NSCLC patients after failure of alectinib. In this study,
-positive nonsquamous NSCLC patients previously treated with alectinib received bevacizumab 15 mg/kg on day 1 every 3 weeks and alectinib 600 mg/day until disease progression. The primary endpoints were progression-free survival (PFS) and the safety of alectinib and bevacizumab. The secondary endpoints included overall survival (OS) and correlation of circulating tumor DNA and plasma proteins with PFS. Of the 12 patients treated, the median PFS was 3.1 months (95% CI 1.2-16.1), and the median OS was 24.1 months (95% CI 8.3-not estimable). The
fusion gene in circulating tumor DNA was significantly correlated with shorter PFS (1.2 months vs. 11.4 months, HR 5.2,
= 0.0153). Two patients experienced grade 3 adverse events; however, none of the patients required dose reduction. Although the primary endpoint was not met, alectinib combined with bevacizumab showed clinical efficacy in
-positive patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
In recent years, cancer immunotherapy has been emerged as a major therapeutic modality in several malignancies. Immune-checkpoint inhibitors (ICI), such as anti-programmed death 1 (PD-1) / ...programmed death -ligand 1 (PD-L1) antibodies and anti-cytotoxic-T-lymphocyte associated protein-4 (CTLA-4) antibodies have demonstrated durable antitumor effects. In phase III trials, PD-1 / PD-L1 blockade therapies have shown better survival benefits compared to standard chemotherapies in patients with non-small lung cancer. However, the mechanisms of anti-PD-1 treatments have not been fully understood. Immune-checkpoint molecules play an important role to regulate autoimmune reactions by T cells. Thus, PD-1 / PD-L1 blockade therapy and anti-CTLA-4 treatment can cause immune-related adverse events including interstitial-lung disease (ILD). ILD is a serious and life threatening adverse event. On the other hand, better outcomes have been reported in lung cancer patients who developed ILD during anti-PD-1 treatment. These findings suggest that effector T cells attack similar antigens presented on both tumor cells and normal lung tissues. In order to elucidate the mechanisms of development of ILD and augmentation of anti-tumor effect by ICI, we established mouse model of ILD. In this study, C57BL/6J mice were injected intravenously with MCA 205 fibrosarcoma or B16 melanoma to make lung metastases. These mice were administered intraperitoneally with anti-PD-1 antibodies and/or anti-CTLA-4 antibodies. EGFR-TKI-ILD mice, which have been previously reported elsewhere, were also established to compare the pathological findings with those of ICI-induced ILD. Also, we administered lipopolysaccharide (LPS) intratracheally before injection of ICIs to test whether lung inflammation exacerbate ILD caused by ICIs. The infiltration of inflammatory cells and thickening of interstitial wall in the lung tissue were observed in mice treated with the combination of anti-CTLA-4 antibodies and anti-PD-1 antibodies. The antitumor effects of anti-PD-1 treatment against lung metastases were enhanced in mice which had ILD caused by anti-PD-1 antibodies and injury of bronchial epithelium. High density of infiltration of lymphocytes in tumor tissues was observed in ILD mice. Further study is warranted to determine effector cells which are responsible for establishment of ILD and augmentation of antitumor effects.
Citation Format: Masashi Arita, Satoshi Watanabe, Naohiro Yanagimura, Yuko Mishina, Miyuki Sato, Satoshi Shoji, Kosuke Ichikawa, Rie Kondo, Junta Tanaka, Takuro Sakagami, Toshiyuki Koya, Toshiaki Kikuchi. Antitumor effects are augmented in mouse models of interstitial-lung disease caused by immune-checkpoint inhibitors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2717.
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