Antibiotics May Interfere with Nivolumab Efficacy in Patients with Head and Neck Squamous Cell Carcinoma.

INTRODUCTION: Patients with the head and neck squamous cell carcinoma (SCC) are often treated with immune checkpoint inhibitors (ICIs). Recently, antibiotic intake was reported to lower the efficacy of ICIs in patients with several types of cancers. However, it is unclear if antibiotics affect the efficacy of ICIs in patients with head and neck SCC. We retrospectively assessed the influence of antibiotics on the treatment efficacy of nivolumab, an ICI, in patients with head and neck SCC. METHODS: We reviewed the medical records of patients with head and neck SCC treated with nivolumab at the Department of Medical Oncology, Tohoku University Hospital, between 2017 and 2021. Patients who received oral or intravenous antibiotics from a month before the day of nivolumab initiation to the day of the first imaging evaluation of ICI efficacy were assigned to the antibiotic-treated group. The remaining patients were assigned to the antibiotic-untreated group. The response rate (RR), progression-free survival (PFS), and overall survival time (OS) of both groups were compared. RESULTS: Forty-five patients were assigned to the antibiotic-treated group and 19 to the antibiotic-untreated group. The RR, median PFS, and median OS of the antibiotic-treated group were 23.7%, 3.2 months (95% confidential interval [CI]: 2.0-4.1), and 8.4 months (95% CI: 5.3-15.1) and those of the antibiotic-untreated group were 42.1%, 5.8 months (95% CI: 2.3-16.7), and 18.4 months (95% CI: 6.2-23.1), respectively. The PFS of the antibiotic-untreated group was significantly longer than that of the antibiotic-treated group. CONCLUSION: Our findings indicate that antibiotic treatment significantly shortens the PFS with nivolumab therapy in patients with head and neck SCC.

Efficacy of adding levofloxacin to gemcitabine and nanoparticle-albumin-binding paclitaxel combination therapy in patients with advanced pancreatic cancer: study protocol for a multicenter, randomized phase 2 trial (T-CORE2201).

BACKGROUND: Advanced pancreatic cancer is one of the leading causes of cancer-related deaths. For patients with advanced pancreatic cancer, gemcitabine and nanoparticle albumin-binding paclitaxel (nabPTX) combination (GEM/nabPTX) therapy is one of the recommended first-line treatments. Several retrospective studies have suggested that the addition of levofloxacin improves the efficacy of GEM/nabPTX therapy in patients with advanced pancreatic cancer. This prospective study aims to evaluate whether the addition of antibiotics improves the treatment efficacy of GEM/nabPTX as a first-line chemotherapy in patients with advanced pancreatic cancer. METHODS: This multicenter, prospective, randomized, phase 2 trial will included 140 patients. Patients with advanced pancreatic cancer will be randomized in a 1:1 ratio to either the GEM/nabPTX therapy group or the GEM/nabPTX plus levofloxacin group. The primary endpoint for the two groups is median progression-free survival time (mPFS) for the full analysis set (FAS). The secondary endpoints for the two groups are median overall survival (mOS), response rate (RR), disease control rate (DCR), and adverse event (AE) for the FAS and mPFS, mOS, RR, DCR, and AE for the per-protocol set. This study will enroll patients treated with GEM/nabPTX as the first-line chemotherapy for stage IV pancreatic adenocarcinoma. DISCUSSION: GEM/nabPTX is a standard first-line chemotherapy regimen for patients with advanced pancreatic cancer. Recently, the superiority of 5-fluorouracil, liposomal irinotecan, and oxaliplatin combination therapy (NALIRIFOX) to GEM/nabPTX as first-line therapy for pancreatic cancer has been reported. However, the efficacy of NALIRIFOX is inadequate. Based on previous retrospective studies, it is hypothesized that treatment efficacy will improve when levofloxacin is added to GEM/nabPTX therapy. If the AEs (such as leukopenia, neutropenia, and peripheral neuropathy) that occur at an increased rate with levofloxacin and GEM/nabPTX combination therapy can be carefully monitored and properly managed, this simple intervention can be expected to improve the prognosis of patients with advanced pancreatic cancer. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials (jRCT; registry number: jRCTs021230005).

Genome-wide DNA methylation status is a predictor of the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer: Translational research of the EPIC trial.

PURPOSE: The genome-wide DNA methylation status (GWMS) predicts of therapeutic response to anti-epidermal growth factor receptor (EGFR) antibodies in treating metastatic colorectal cancer. We verified the significance of GWMS as a predictive factor for the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer. METHODS: Clinical data were obtained from a prospective trial database, and a genome-wide DNA methylation analysis was performed. GWMS was classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC). The patients were divided into subgroups according to the treatment arm (cetuximab plus irinotecan or irinotecan alone) and GWMS, and the clinical outcomes were compared between the subgroups. RESULTS: Of the 112 patients, 58 (51.8%) were in the cetuximab plus irinotecan arm, and 54 (48.2%) were in the irinotecan arm; 47 (42.0%) were in the HMCC, and 65 (58.0%) were in the LMCC group regarding GWMS. Compared with the LMCC group, the progression-free survival (PFS) was significantly shortened in the HMCC group in the cetuximab plus irinotecan arm (median 1.4 vs. 4.1 months, p = 0.001, hazard ratio = 2.56), whereas no significant differences were observed in the irinotecan arm. A multivariate analysis showed that GWMS was an independent predictor of PFS and overall survival (OS) in the cetuximab plus irinotecan arm (p = 0.002, p = 0.005, respectively), whereas GWMS did not contribute to either PFS or OS in the irinotecan arm. CONCLUSIONS: GWMS was a predictive factor for the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer.

[History of the Japanese Society of Medical Oncology].

The Japanese Society of Medical Oncology(JSMO)was founded in 1993 by the Research Society of Clinical Oncology, the predecessor of the Society. Twenty years have passed since the transition to JSMO in 2003. During this time, JSMO has contributed to the establishment of the academic field of medical oncology in Japan for many years. On the other hand, over the last 20 years, cancer treatment by anti-cancer agents, which forms the basis of medical oncology, has made significant progress, prolonging the survival period of many advanced cancers. In the last 5 years in particular, there have been remarkable advances in the development and clinical introduction of immune checkpoint inhibitors, cancer molecular targeted agents based on genetic abnormalities, and cancer genomic medicine. Furthermore, in addition to conventional multidisciplinary treatment with surgery, radiology, and palliative medicine, collaboration with cancer-related interdisciplinary fields has become extremely important in recent years. For this reason, there is an increasing need for medical oncologists who specialize in organ(cancer type)cross-sectional treatment including cancer genomic medicine, and treat advanced cancer as a systemic disease as a specialist in internal medicine. In this article, we review the history of the Japanese Society of Medical Oncology and the history of medical oncology in Japan and look forward to the future of medical oncology.

Distinct role of CD8 cells and CD4 cells in antitumor immunity triggered by cell apoptosis using a Herpes simplex virus thymidine kinase/ganciclovir system.

Immune cells can recognize tumor-associated antigens released from dead tumor cells, which elicit immune responses, potentially resulting in tumor regression. Tumor cell death induced by chemotherapy has also been reported to activate immunity. However, various studies have reported drug-induced immunosuppression or suppression of inflammation by apoptotic cells. Thus, this study aimed to investigate whether apoptotic tumor cells trigger antitumor immunity independent of anticancer treatment. Local immune responses were evaluated after direct induction of tumor cell apoptosis using a Herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system. The inflammatory response was significantly altered at the tumor site after apoptosis induction. The expression of cytokines and molecules that activate and suppress inflammation simultaneously increased. The HSV-tk/GCV-induced tumor cell apoptosis resulted in tumor growth suppression and promoted T lymphocyte infiltration into tumors. Therefore, the role of T cells after inducing tumor cell death was explored. CD8 T cell depletion abrogated the antitumor efficacy of apoptosis induction, indicating that tumor regression was mainly dependent on CD8 T cells. Furthermore, CD4 T cell depletion inhibited tumor growth, suggesting the potential role of CD4 T cells in suppressive tumor immunity. Tumor tissues were evaluated after tumor cell apoptosis and CD4 T cell depletion to elucidate this immunological mechanism. Foxp3 and CTLA4, regulatory T-cell markers, decreased. Furthermore, arginase 1, an immune-suppressive mediator induced by myeloid cells, was significantly downregulated. These findings indicate that tumors accelerate CD8 T cell-dependent antitumor immunity and CD4 T cell-mediated suppressive immunity. These findings could be a therapeutic target for immunotherapy in combination with cytotoxic chemotherapy.

Management of patients with presumed germline pathogenic variant from tumor-only genomic sequencing: A retrospective analysis at a single facility.

Cancer treatment is increasingly evolving toward personalized medicine, which sequences numerous cancer-related genes and identifies therapeutic targets. On the other hand, patients with germline pathogenic variants (GPV) have been identified as secondary findings (SF) and oncologists have been urged to handle them. All SF disclosure considerations for patients are addressed and decided at the molecular tumor boards (MTB) in the facility. In this study, we retrospectively summarized the results of all cases in which comprehensive genomic profiling (CGP) test was conducted at our hospital, and discussed the possibility of presumed germline pathogenic variants (PGPV) at MTB. MTB recommended confirmatory testing for 64 patients. Informed consent was obtained from attending physicians for 53 of them, 30 patients requested testing, and 17 patients tested positive for a confirmatory test. Together with already known variants, 4.5 % of the total confirmed in this cohort. Variants verified in this study were BRCA1 (n = 12), BRCA2 (n = 6), MSH2 (n = 2), MSH6 (n = 2), WT1 (n = 2), TP53, MEN1, CHEK2, MLH1, TSC2, PTEN, RB1, and SMARCB1. There was no difference in the tumor's VAF between confirmed positive and negative cases for variants determined as PGPV by MTB. Current results demonstrate the actual number of cases until confirmatory germline test for patients with PGPV from tumor-only CGP test through the discussion at the MTB. The practical results at this single facility will serve as a guide for the management of the selection and distribution of SF in the genome analysis.

Comparison of efficacy and safety between carboplatin-etoposide and cisplatin-etoposide combination therapy in patients with advanced neuroendocrine carcinoma, retrospective study.

INTRODUCTION: Neuroendocrine carcinoma (NEC) is characterized by a poor prognosis and is generally treated with platinum and etoposide combination therapy as first-line chemotherapy. However, it remains uncertain whether carboplatin and etoposide combination therapy (CE) and cisplatin and etoposide combination therapy (PE) have comparable treatment efficacy. In this retrospective analysis, we compared the efficacy and safety of CE and PE in patients with NEC. METHODS: We retrospectively reviewed the patient's clinical record from 2005 to 2022 at the Department of Medical Oncology, Tohoku University Hospital. Patients who received either CE or PE were included in the study. Statistical analyses were performed using JMP Pro 16.0 (SAS Institute Inc., Cary, N.C., USA). RESULTS: A total of 104 patients were enrolled, with 73 patients assigned to the CE group and 31 patients assigned to the PE group. Statistically, the response rate, progression-free survival (PFS) time and overall survival (OS) time were 42.6%, 5.1 months (95%CI: 3.5-6.3) and 13.6 months (95%CI: 8.9-17.4), respectively, in the CE groups and 44.4%, 5.6 months (95%CI: 3.1-7.0) and 12.5 months (95%CI: 11.2-14.6), respectively, in the PE groups. There was no significant difference in treatment efficacy between the CE and the PE groups. However, the number of patients with elevated creatinine (3.35 mg/dl and 3.88 mg/dl in two patients, respectively) was significantly higher in the PE group than in the CE group. CONCLUSION: The efficacy of CE and PE in patients with NEC is comparable. However, the incidence of renal dysfunction was found to be significantly higher in the PE group than in the CE group.

Prognostic awareness in Japanese patients with advanced cancer: a follow-up cohort study.

BACKGROUND: Patients with advanced cancer have been reported to be more likely to receive goal-concordant care if they have accurate prognostic awareness. However, many patients do not have this awareness. This study aimed to examine the prognostic awareness among Japanese patients with advanced cancer. METHODS: This single-center, follow-up cohort study included Japanese patients with advanced cancer who received chemotherapy at Tohoku University Hospital between January 2015 and January 2016. Patients were surveyed at enrollment and followed up for clinical events for 5 years thereafter. We compared (i) the patients' prognostic awareness with both actual survival time and physician's prediction of survival and (ii) physician's prediction of survival time with actual survival. Factors associated with accurate prognostic awareness were identified by univariate analysis. RESULTS: Of the 133 patients eligible for the study, 57 patients were analyzed. Only 10 (17.5%) patients had accurate prognostic awareness. Forty-three patients (75.4%) were optimistic about their prognosis; >80% of patients were more optimistic than their physicians about their prognosis. The physicians' predictions were accurate in for patients (37.5%). Accurate prognostic awareness was associated with physician's explanation of the prognosis and patients' perception of a good death. CONCLUSIONS: A majority of the patients with advanced cancer in this study had prognostic awareness that was more optimistic in comparison with their actual survival, and most were more optimistic than their physicians about their prognosis. Further research is needed to develop programs to facilitate the discussion of life expectancy with patients in a manner that is consistent with their preferences.

Altered gene expression due to aberrant DNA methylation correlates with responsiveness to anti-EGFR antibody treatment.

The cetuximab gene expression signature and DNA methylation status of colorectal cancer (CRC) are predictive of the therapeutic effects of anti-epidermal growth factor receptor (EGFR) antibody therapy. As DNA methylation is a means of regulating gene expression, it may play an important role in the expression of cetuximab signature genes. This study aims to determine the effects of aberrant DNA methylation on the regulation of cetuximab signature gene expression. Comprehensive DNA methylation and gene expression data were retrieved from CRC patients in three tumor tissue (TT) cohorts and three normal colorectal mucosa/tumor tissue paired (NCM-TT) cohorts. Of the 231 cetuximab signature genes, 57 exhibited an inverse correlation between the methylation of promoter CpG sites and gene expression level in multiple cohorts. About two-thirds of the promoter CpG sites associated with the 57 genes exhibited this correlation. In all 57 gene promoter regions, the methylation levels in NCMs did not differ according to comparisons based on cetuximab signature or DNA methylation status classification of matched TTs. Thus, the altered expression of 57 genes was caused by aberrant DNA methylation during carcinogenesis. Analysis of the association between cetuximab signature or DNA methylation status and progression-free survival (PFS) of anti-EGFR antibody agents in the same cohort showed that DNA methylation status was most associated with PFS. In conclusion, we found that aberrant DNA methylation regulates specific gene expression in cetuximab signature during carcinogenesis, suggesting that it is one of the important determinants of sensitivity to anti-EGFR antibody agents.

A modified MethyLight assay predicts the clinical outcomes of anti-epidermal growth factor receptor treatment in metastatic colorectal cancer.

DNA methylation status correlates with clinical outcomes of anti-epidermal growth factor receptor (EGFR) treatment. There is a strong need to develop a simple assay for measuring DNA methylation status for the clinical application of drug selection based on it. In this study, we collected data from 186 patients with metastatic colorectal cancer (mCRC) who had previously received anti-EGFR treatment. We modified MethyLite to develop a novel assay to classify patients as having highly methylated colorectal cancer (HMCC) or low-methylated colorectal cancer (LMCC) based on the methylation status of 16 CpG sites of tumor-derived genomic DNA in the development cohort (n = 30). Clinical outcomes were then compared between the HMCC and LMCC groups in the validation cohort (n = 156). The results showed that HMCC had a significantly worse response rate (4.2% vs 33.3%; P = .004), progression-free survival (median: 2.5 vs 6.6 mo, P < .001, hazard ratio [HR] = 0.22), and overall survival (median: 5.6 vs 15.5 mo, P < .001, HR = 0.23) than did LMCC in patients with RAS wild-type mCRC who were refractory or intolerable to oxaliplatin- and irinotecan-based chemotherapy (n = 101). The DNA methylation status was an independent predictive factor and a more accurate biomarker than was the primary site of anti-EGFR treatment. In conclusion, our novel DNA methylation measurement assay based on MethyLight was simple and useful, suggesting its implementation as a complementary diagnostic tool in a clinical setting.

BRCA1 transports the DNA damage signal for CDDP-induced centrosome amplification through the centrosomal Aurora A.

Breast cancer gene 1 (BRCA1) plays roles in DNA repair and centrosome regulation and is involved in DNA damage-induced centrosome amplification (DDICA). Here, the centrosomal localization of BRCA1 and the kinases involved in centrosome duplication were analyzed in each cell cycle phase after treatment with DNA crosslinker cisplatin (CDDP). CDDP treatment increased the centrosomal localization of BRCA1 in early S-G2 phase. BRCA1 contributed to the increased centrosomal localization of Aurora A in S phase and that of phosphorylated Polo-like kinase 1 (PLK1) in late S phase after CDDP treatment, resulting in centriole disengagement and overduplication. The increased centrosomal localization of BRCA1 and Aurora A induced by CDDP treatment involved the nuclear export of BRCA1 and BRCA1 phosphorylation by ataxia telangiectasia mutated (ATM). Patient-derived variants and mutations at phosphorylated residues of BRCA1 suppressed the interaction between BRCA1 and Aurora A, as well as the CDDP-induced increase in the centrosomal localization of BRCA1 and Aurora A. These results suggest that CDDP induces the phosphorylation of BRCA1 by ATM in the nucleus and its transport to the cytoplasm, thereby promoting the centrosomal localization Aurora A, which phosphorylates PLK1. The function of BRCA1 in the translocation of the DNA damage signal from the nucleus to the centrosome to induce centrosome amplification after CDDP treatment might support its role as a tumor suppressor.

Effect of DNA methylation status on first-line anti-epidermal growth factor receptor treatment in patients with metastatic colorectal cancer.

PURPOSE: The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer (CRC). However, there is a lack of consensus on CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with metastatic CRC (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors. METHODS: We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment. We analyzed the incidence and clinicopathological characteristics of highly methylated CRC (HMCC) and associations between genome-wide DNA methylation status and response rate (RR), progression-free survival (PFS), and overall survival (OS). RESULTS: In total, 169 patients were included in the final analyses. The frequency of HMCC was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAF V600E mutation (P < 0.0001). Patients with HMCC showed worse clinical outcomes than those with low-methylated CRC in terms of RR (P = 0.017), PFS (P = 0.004), and OS (P = 0.019). In the multivariate analysis, peritoneal metastasis (P = 0.017), methylation status (P = 0.037), and BRAF V600E mutations (P = 0.0001) were independent factors for shorter PFS. CONCLUSIONS: Genome-wide DNA methylation status is an independent factor associated with PFS in patients with mCRC treated with first-line EGFR inhibitors.

The BRCA1/BARD1-interacting protein OLA1 functions in centrosome regulation.

The breast and ovarian cancer-specific tumor suppressor BRCA1, along with its heterodimer partner BRCA1-associated RING domain protein (BARD1), plays important roles in DNA repair, centrosome regulation, and transcription. To explore further functions of BRCA1/BARD1, we performed mass spectrometry analysis and identified Obg-like ATPase 1 (OLA1) as a protein that interacts with the carboxy-terminal region of BARD1. OLA1 directly bound to the amino-terminal region of BRCA1 and γ-tubulin. OLA1 localized to centrosomes in interphase and to the spindle pole in mitotic phase, and its knockdown resulted in centrosome amplification and the activation of microtubule aster formation. OLA1 with a mutation observed in breast cancer cell line, E168Q, failed to bind BRCA1 and rescue the OLA1 knockdown-induced centrosome amplification. BRCA1 variant I42V also abrogated the binding of BRCA1 to OLA1. These findings suggest that OLA1 plays an important role in centrosome regulation together with BRCA1.

[The Tohoku Next-Generation Cancer Professional Training Plan-Results, Problems and the Future Prospects].

"The Tohoku next-generation cancer professional training plan"that Tohoku University, as the base university, applied for and was adopted in cooperation with Yamagata University, Fukushima Medical University, Niigata University was conducted with a grant for 5 years by Ministry of Education, Culture, Sports, Science and Technology, Japan. We built postgraduate education system by the cooperation between these 4 universities and trained the cancer healthcare worker of the Tohoku district. As an education base, we established 57 courses in total in 3 courses consisting of(1)oncologist training course, (2)the cancer health professional training course for medical staffs except the physician(, 3)intensive training courses specialized in cancer. We realized the education curriculum which was necessary for specialized qualification by the original e- learning(Tohoku University Internet School)and the training in each university cooperation hospital in 4 university's original lecture systems. In 5 years, 56(36.8% of aim achievement quotients), 49(69.0% of aim achievement quotients)and 4,554 people studied in the oncologist training course, the cancer health professional training course for medical staffs except the physicians and the oncologist training course, respectively. As a result, we contributed to the improvement of the cancer medical level in this area. For measures to the new cancer medical field such as cancer genomic medicine and cancers of children and the AYA generation, the training of the healthcare worker specialized in a cancer is necessary continuously.

[Biomarkers of Anti-EGFR Antibodies in the Treatment of Metastatic Colorectal Cancer].

Anti-EGFR antibodies(cetuximab and panitumumab)are molecular targeted agents that exert their antitumor effects by binding directly to the epidermal growth factor receptor(EGFR)and inhibiting its downstream signaling. Anti-EGFR antibodies have become one of the most important agents in the treatment of metastatic colorectal cancer(CRC), showing efficacy in combination with cytotoxic chemotherapeutic agents and as single agents in first-line and second-line treatment or later. Molecular targeted agents show more potent therapeutic effects than conventional chemotherapeutic agents, but their cost-effectiveness is often an issue due to their high drug costs. Predictive biomarkers of therapeutic efficacy that enable appropriate patient selection have an important role not only in improving the cost-effectiveness of molecular targeted agents, but also from the perspective of avoiding side effects in invalid patients. In addition to RAS and BRAF genotypes as molecular biological factors, anatomical factors such as the site of primary tumor(sidedness)are described in guidelines as important biomarkers for anti-EGFR treatment in the treatment of metastatic CRC. Recently, an association between HER2 gene amplification and anti-EGFR antibody resistance in RAS/BRAF wild-type metastatic CRC was reported. Furthermore, an epigenetic factor, DNA methylation status, was reported to be associated with the therapeutic effect of anti-EGFR treatments, and our subsequent studies have suggested that DNA methylation status is predictive of therapeutic efficacy of anti- EGFR antibodies regardless of the site of the primary tumor. Novel biomarkers will continue to be developed from a variety of approaches to provide more optimal cancer treatment for each individual patient.

[Panel Discussion - Problems in the Cancer Genomic Medicine].

About 4 and a half years have passed since"Cancer Genome Medicine"was first mentioned in the Third Phase of the Basic Plan to Promote Cancer Control Programs that started in October 2017. Currently, cancer genomic medicine is being carried out by the cancer gene panel test, which is covered by public insurance, mainly at the 12 Cancer Genome Medicine Core Center Hospital designated nationwide by the Ministry of Health, Labor, and Welfare in Japan. Cancer genomic medicine has come to be positioned as a standard medical treatment. However, there are various challenges in operating an expert panel that professionally examines the results of the gene panel tests and reports treatment recommendations and secondary findings that suggest hereditary tumors. In addition, there is an urgent need to disseminate and educate healthcare professionals and patients about cancer genomic medicine. In this panel discussion on January 14, 2022, 10 panelists discussed how to solve these issues and the prospects for the future.

Inhibition of IRAK1/4 enhances the antitumor effect of lenvatinib in anaplastic thyroid cancer cells.

Anaplastic thyroid cancer (ATC) is an extremely aggressive tumor associated with poor prognosis due to a lack of efficient therapies. In Japan, lenvatinib is the only drug approved for patients with ATC; however, its efficacy is limited. Therefore, novel therapeutic strategies are urgently required for patients with ATC. The present study aimed to identify compounds that enhance the antiproliferative effects of lenvatinib in ATC cells using a compound library. IRAK1/4 Inhibitor I was identified as a candidate compound. Combined treatment with lenvatinib and IRAK1/4 Inhibitor I showed synergistic antiproliferative effects via the induction of cell cycle arrest at G2/M phase in the ATC cell lines 8305C, HTC/C3, ACT-1, and 8505C. Furthermore, IRAK1/4 Inhibitor I enhanced the inhibition of ERK phosphorylation by lenvatinib in 8305C, HTC/C3, and 8505C cells. In an HTC/C3 xenograft mouse model, tumor volume was lower in the combined IRAK1/4 Inhibitor I and lenvatinib group compared with that in the vehicle control, IRAK1/4 Inhibitor I, and lenvatinib groups. IRAK1/4 Inhibitor I was identified as a promising compound that enhances the antiproliferative and antitumor effects of lenvatinib in ATC.

LPIN1 downregulation enhances anticancer activity of the novel HDAC/PI3K dual inhibitor FK-A11.

Phosphatidylinositol-3 kinase (PI3K) inhibitor and histone deacetylase (HDAC) inhibitor have been developed as potential anticancer drugs. However, the cytotoxicity of PI3K inhibitor or HDAC inhibitor alone is relatively weak. We recently developed a novel HDAC/PI3K dual inhibitor FK-A11 and confirmed its enhanced cytotoxicity when compared to that of PI3K inhibitor or HDAC inhibitor alone on several cancer cell lines. However, the in vivo antitumor activity of FK-A11 was insufficient. We conducted high-throughput RNA interfering screening and identified gene LPIN1 which enhances the cytotoxicity of FK-A11. Downregulation of LPIN1 enhanced simultaneous inhibition of HDAC and PI3K by FK-A11 and enhanced the cytotoxicity of FK-A11. Propranolol, a beta-adrenoreceptor which is also a LPIN1 inhibitor, enhanced the in vitro and in vivo cytotoxicity and antitumor effect of FK-A11. These findings should help in the development of FK-A11 as a novel HDAC/PI3K dual inhibitor.

Tumor suppressor miR-193a-3p enhances efficacy of BRAF/MEK inhibitors in BRAF-mutated colorectal cancer.

Patients with BRAF-mutated colorectal cancer (CRC) have a poor prognosis despite recent therapeutic advances such as combination therapy with BRAF, MEK, and epidermal growth factor receptor (EGFR) inhibitors. To identify microRNAs (miRNAs) that can improve the efficacy of BRAF inhibitor dabrafenib (DAB) and MEK inhibitor trametinib (TRA), we screened 240 miRNAs in BRAF-mutated CRC cells and identified five candidate miRNAs. Overexpression of miR-193a-3p, one of the five screened miRNAs, in CRC cells inhibited cell proliferation by inducing apoptosis. Reverse-phase protein array analysis revealed that proteins with altered phosphorylation induced by miR-193a-3p were involved in several oncogenic pathways including MAPK-related pathways. Furthermore, overexpression of miR-193a-3p in BRAF-mutated cells enhanced the efficacy of DAB and TRA through inhibiting reactivation of MAPK signaling and inducing inhibition of Mcl1. Inhibition of Mcl1 by siRNA or by Mcl1 inhibitor increased the antiproliferative effect of combination therapy with DAB, TRA, and anti-EGFR antibody cetuximab. Collectively, our study demonstrated the possibility that miR-193a-3p acts as a tumor suppressor through regulating multiple proteins involved in oncogenesis and affects cellular sensitivity to MAPK-related pathway inhibitors such as BRAF inhibitors, MEK inhibitors, and/or anti-EGFR antibodies. Addition of miR-193a-3p and/or modulation of proteins involved in the miR-193a-3p-mediated pathway, such as Mcl1, to EGFR/BRAF/MEK inhibition may be a potential therapeutic strategy against BRAF-mutated CRC.

Advanced colorectal cancer subtypes (aCRCS) help select oxaliplatin-based or irinotecan-based therapy for colorectal cancer.

Oxaliplatin (OX) and irinotecan (IRI) are used as key drugs for the first-line treatment of metastatic colorectal cancer (mCRC). However, no biomarkers have been identified to decide which of the drugs is initially used. In this translational research (TR) of the TRICOLORE trial, the advanced colorectal cancer subtype (aCRCS) was analyzed as a potential biomarker for the selection of OX or IRI. We collected 335 (68.8%) formalin-fixed, paraffin-embedded (FFPE) primary tumor specimens from 487 patients registered in the TRICOLORE trial and performed direct sequencing and immunohistochemical staining of CRC-related genes, comprehensive gene-expression analysis, and genome-wide methylation analysis. The progression-free survival (PFS) of the IRI group was significantly better compared with the OX group in BRAF wild-type (WT), PTEN-positive, and aCRCS A1 patients. Among the molecular factors, aCRCS were only associated with the PFS of OX and IRI groups. The PFS of the IRI group was significantly better compared with the OX group in aCRCS A1 + B1 (hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.41-0.82; P = .0023). In contrast, the OX group had better PFS compared with the IRI group in aCRCS B2, although this was not statistically significant (HR = 1.66; 95% CI = 0.94-2.96; P = .083). Nearly half of patients with mCRC (46.8%, aCRCS A1 + B1) respond well to IRI, while only about 18.5% (aCRCS B2) of patients with mCRC responded well to OX. In conclusion, the aCRCS might be a predictive factor for the clinical outcomes of OX-based and IRI-based therapies.