抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Summary Background Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. Methods We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (>18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m 2 on day 1 plus docetaxel (75 mg/m 2 on day 1) or gemcitabine (1250 mg/m 2 on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m 2 or AUC 5 with gemcitabine 1000 mg/m 2 ) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225. Findings Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5–5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25–0·54; p vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. Interpretation Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. Funding Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Tematica de Investigacion Cooperativa en Cancer.

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Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.

https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

CA : A Cancer Journal for Clinicians

Background Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non–small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. Methods After screening tumor samples from approximately 1500 patients with non–small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. Results Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. Conclusions The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.)

/pdf/anaplastic-lymphoma-kinase-inhibition-in-non-small-cell-lung-4chlx92dsn.pdf

Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer

Highly Efficient Total Synthesis of (+)-Citreoviral.


 Although mitochondrial DNA (mtDNA) can stimulate innate immune response that potentiates the efficacy of cancer immunotherapy, how to maximize this innate immune system in certain cancer subtypes remains unknown. Here we show that mtDNA is enriched in KRAS-mutant tumor where the dsDNA-sensor machinery cGAS-STING signaling is autonomously activated at the baseline. Intriguingly, MEK inhibitor induces cytosolic mtDNA release to potently activate cGAS-STING pathway, that is counteracted by PRKN-mediated mitophagy to eliminate mtDNA within damaged mitochondria in KRAS-mutant tumor. Combined MEK and mitophagy inhibitors synergistically boost type I IFNs through mitochondrial stress and promote lymphocyte infiltration into the TME in a mtDNA efflux-dependent manner. Moreover, this combination enhances the efficacy of PD-1 blockade in KRAS-mutant tumor. PRKN clinically associates with KRAS/LKB1-mutant subtype, lower antigen-presenting signature, and ICB resistance. Together, targeting mtDNA renders promising strategy to enable cancer immunotherapy in KRAS-mutant cancers.
 Citation Format: Kosuke Tanaka, Tomoko Yamamori Morita, Yumi Hakozaki, Miyuki Yoshiya, Chiaki Mashima, Jie Liu, Shun-ichiro Kageyama, Akihiro Ohashi, Susumu Kobayashi. Combined MEK and mitophagy inhibition promotes mtDNA-mediated innate immunity in KRAS-mutant cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5635.

Abstract 5635: Combined MEK and mitophagy inhibition promotes mtDNA-mediated innate immunity in KRAS-mutant cancer


 Histone modifications play crucial roles in transcriptional activation, and aberrant epigenetic changes are associated with oncogenesis. Lysine (K) acetyltransferases 5 (KAT5) is reportedly implicated in cancer development and maintenance, although the role of KAT5 in lung cancer largely remain unclear. Here we demonstrate that KAT5 expression was lower in lung adenocarcinoma than normal lung cells. Overexpression of KAT5 had no effect on tumor proliferation and migration, whereas knockdown of KAT5 paradoxically decreased those activities. To assess KAT5 function in lung tumorigenesis in adults, we generated a lung cancer mouse model in which Kat5 is conditionally deleted in lung. We achieved this by crossing lung-specific EGFR-L858R-T790M transgenic mice with conditional Kat5 knockout mice, and found that complete deletion of Kat5 resulted in suppression of tumor formation. To investigate downstream genes of KAT5, we performed RNA sequencing and chromatin immunoprecipitation sequencing analysis using H1975 KAT5 inducible knockdown cells and control cells. We identified a transglutaminase enzyme, TGM5, as one of downstream of KAT5. We furthermore identified artemisinin, an anti-malarial drug, as a potent KAT5 inhibitor by using the connectivity map database, and treatment with artemisinin suppressed tumor growth and induced apoptosis in vitro an in vivo. Taken together, suppression of KAT5 activity shows a tumor-specific efficacy against lung cancer in which KAT5 expression is lower, with no definite influence on normal tissues. Thereby, targeting KAT5 is a potent candidate for the treatment of lung cancer.
 Citation Format: Daisuke Jefferson Shibahara, Naoki Akanuma, Eunyoung Heo, Mariko Ando, Ikei S. Kobayashi, Masanori Fujii, Prin Paul, Gilbert Pan, Danniel G. Tenen, Hideo Watanabe, Susumu S. Kobayashi. Role of KAT5 in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3723.

Abstract 3723: Role of KAT5 in non-small cell lung cancer

Stereoselective construction of aldol adducts having tertiary alcohol at the α position was achieved via a titanium(IV) enolate derived from a lactate derivative with an Evans chiral auxiliary. The stereochemistry at α-tertiary alcohol could be controlled by selecting the protective group of the starting lactate.

Susumu Kobayashi

Papers

Highly Efficient Total Synthesis of (+)-Citreoviral.

Abstract 5635: Combined MEK and mitophagy inhibition promotes mtDNA-mediated innate immunity in KRAS-mutant cancer

Abstract 3723: Role of KAT5 in non-small cell lung cancer

Stereochemical Control of Tertiary Alcohol: Aldol Condensation of Lactate Derivatives.

Total Synthesis of (‐)‐Norzoanthamine (I).