The Wnt signaling pathway controls several cell processes, such as motility and proliferation during embryonic development. Wnt signaling is also involved in the maintenance of potency and the ...induction of differentiation in stem cells. Aberrant Wnt signaling is implicated in several cancer types. Particularly in colorectal cancer (CRC), the Wnt-β-catenin signaling cascade is at the center of the carcinogenesis, and mutations in this pathway can be found in almost all CRC patients. We discuss the potential of targeting Wnt-β-catenin signaling with a brief overview of the pathway and the most promising pathway inhibitors.
The Salvador-Warts-Hippo pathway controls cell fate and tissue growth. The main function of the Hippo pathway is to prevent YAP and TAZ translocation to the nucleus where they induce the ...transcription of genes involved in cell proliferation, survival, and stem cell maintenance. Hippo signaling is, thus, a complex tumor suppressor, and its deregulation is a key feature in many cancers. Recent mounting evidence suggests that the overexpression of Hippo components can be useful prognostic biomarkers. Moreover, Hippo signaling appears to be intimately linked to some of the most important signaling pathways involved in cancer development and progression. A better understanding of the Hippo pathway is thus essential to untangle tumor biology and to develop novel anticancer therapies. Here, we comment on the progress made in understanding Hippo signaling and its connections, and also on how new drugs modulating this pathway, such as Verteporfin and C19, are highly promising cancer therapeutics.
Highlights • TAS-102 is an oral fluorothymidine agent for the treatment of cancer. • TAS-102 is a combination of the thymidine analog trifluridine (FTD) and tipiracil. • Tipiracil, a thymidine ...phosphorylase inhibitor, improves FTD bioavailability. • Compared with 5-fluorouracil (5-FU), TAS-102 has a distinct mechanism of action and metabolism. • TAS-102 has demonstrated efficacy in 5-FU-refractory cancers.
Tertiary lymphoid structures (TLSs) provide an immunological antineoplastic effect. Recent evidences link a unique 12‐chemokine (CCL2, ‐3, ‐4, ‐5, ‐8, ‐18, ‐19, ‐21, CXCL9, ‐10, ‐11, ‐13) signature ...status from tumor tissue and the TLS expression. However, the potential significance of 12‐chemokine signature status for clinical use is unknown. We aimed to evaluate the association of 12‐chemokine signature status with patient outcomes in colorectal cancer (CRC). We used integrated data of resected 975 CRC cases within three independent cohorts from France, Japan and the United States (GSE39582, KUMAMOTO from Kumamoto university hospital and TCGA). The association of 12‐chemokine signature status with clinicopathological features, patient outcome, TLS expression status and key tumor molecular features was analyzed. Patients with low 12‐chemokine signature status had a significant shorter relapse‐free survival in discovery cohort (HR: 1.61, 95% CI: 1.11–2.39, p = 0.0123), which was confirmed in validation cohort (HR: 3.31, 95% CI: 1.33–10.08, p = 0.0087). High 12‐chemokine signature status had significant associations with right‐sided tumor, high tumor‐localized TLS expression, BRAF mutant, CIMP‐high status and MSI‐high status. Furthermore, RNA‐seq based analysis showed that high 12‐chemokine signature status was strongly associated with inflammation‐related, immune cells‐related and apoptosis pathways (using gene set enrichment analysis), and more tumor‐infiltrating immune cells, such as cytotoxic T lymphocytes and myeloid dendritic cells (using MCP‐counter analysis). We investigated a promising effect of 12‐chemokine signature status in CRC patients who underwent resection. Our data may be helpful in developing novel immunological treatment strategies for CRC.
What's new?
Chronic inflammation at tumor sites is linked to the emergence of ectopic formations known as tertiary lymphoid structures (TLSs), which combat tumor progression. Here, analyses of human colorectal cancer (CRC) tissue show that high expression of a previously identified 12‐chemokine signature predicts high TLS expression at tumor sites and is associated with increased presence of tumor infiltrating immune cells and reduced CRC recurrence rate. High 12‐chemokine signature status was further linked to key clinicopathological and molecular features of CRC. The findings indicate that the 12‐chemokine signature is informative for host immune status and may have a prognostic role in CRC.
The phase III CRYSTAL study demonstrated that addition of cetuximab to fluorouracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival, progression-free survival, and ...objective response in the first-line treatment of patients with KRAS codon 12/13 (exon 2) wild-type metastatic colorectal cancer (mCRC). Outcome was reassessed in subgroups defined by extended RAS mutation testing.
Existing DNA samples from KRAS exon 2 wild-type tumors from CRYSTAL study patients were reanalyzed for other RAS mutations in four additional KRAS codons (exons 3 and 4) and six NRAS codons (exons 2, 3, and 4) using beads, emulsion, amplification, and magnetics technology. No tissue microdissection was performed. A ≥ 5% mutant allele cutoff was used to call mutations.
Mutation status was evaluable in 430 (64.6%) of 666 patients with KRAS exon 2 wild-type tumors. Other RAS mutations were detected in 63 (14.7%) of 430 patients. In those with RAS wild-type tumors, a significant benefit across all efficacy end points was associated with the addition of cetuximab to FOLFIRI. In patients with other RAS tumor mutations, no difference in efficacy outcomes between treatment groups was seen. The safety profile in RAS subgroups was similar and in line with expectations.
In the first-line treatment of mCRC, patients with RAS wild-type tumors derived a significant benefit from the addition of cetuximab to FOLFIRI; patients with RAS tumor mutations did not. Molecular testing of tumors for all activating RAS mutations is essential before considering anti-epidermal growth factor receptor therapy, thereby allowing the further tailoring of cetuximab administration to maximize patient benefit.
Dysregulation of human epidermal growth factor receptor (ErbB/HER) pathways by over-expression or constitutive activation can promote tumor processes including angiogenesis and metastasis and is ...associated with poor prognosis in many human malignancies. In addition to cancer, ErbB signaling has also been implicated in cardiovascular and neurodegenerative diseases. Conversely, inhibition of ErbB pathways with targeted agents, such as monoclonal antibodies (MoAbs) or tyrosine kinase inhibitors (TKIs), blocks cell cycle progression, inhibits the production of pro-angiogenic factors and induces apoptosis in numerous in vitro and xenograft models. Accordingly, the ErbB receptor family with their most prominent members EGFR and HER-2 represents validated targets for anti-cancer therapy, and anti-ErbB MoAbs (cetuximab, panitumumab, and trastuzumab) and TKIs (gefitinib, erlotinib, and lapatinib) have now been approved for the treatment of advanced colorectal cancer, squamous cell carcinoma of the head and neck, advanced non-small-cell lung cancer, as well as pancreatic and breast cancer. Although results have been encouraging, more work remains to be done.
Background
Early detection and management of treatment‐related adverse events (TRAEs) in patients receiving immune checkpoint inhibitors may improve outcomes. In CheckMate 142, nivolumab (3 mg/kg) ...plus low‐dose ipilimumab (1 mg/kg) provided durable clinical benefit (objective response rate ORR 55%, median duration of response not reached, 12‐month overall survival OS rate 85%) and manageable safety for previously treated microsatellite instability‐high and/or mismatch repair‐deficient (MSI‐H/dMMR) metastatic colorectal cancer (mCRC). In‐depth safety and additional efficacy outcomes from CheckMate 142 are presented.
Materials and Methods
Safety assessments included frequency of TRAEs, select TRAEs (sTRAEs), and immune‐mediated adverse event incidences; time to onset (TTO); time to resolution (TTR); immune‐modulating medication (IMM) use; dose delay; and sTRAE occurrence after resuming therapy. Efficacy assessments included ORR and survival analyses in patients with sTRAEs with or without concomitant IMM treatment and patients without sTRAEs.
Results
Among 119 patients, 25%, 23%, 19%, 5%, 5%, and 29% experienced an endocrine, gastrointestinal, hepatic, pulmonary, renal, or skin sTRAE, respectively; the majority (57%) were grade 1/2. sTRAEs occurred early (median TTO, 5.2–12.6 weeks). Nonendocrine sTRAEs resolved in most (>71%) patients (median TTR, 1.5–9.0 weeks). IMMs were used to manage sTRAEs in 22%–56% of patients (most resolved). Of patients with dose delay because of sTRAEs, 25 of 29 resumed treatment. Patients with or without sTRAEs had comparable ORR (57% vs. 52%) and 12‐month OS rates (93% vs. 75%). Similar results were observed in patients with or without sTRAEs regardless of IMM use (ORR 52% vs. 57%; OS rates 87% vs. 82%).
Conclusion
The benefit‐risk profile of nivolumab plus low‐dose ipilimumab provides a promising treatment option for patients with previously treated MSI‐H/dMMR mCRC.
Implications for Practice
Nivolumab (NIVO) plus low‐dose (1 mg/kg) ipilimumab (IPI) received U.S. Food and Drug Administration approval for patients with microsatellite instability‐high and/or mismatch repair‐deficient (MSI‐H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on results from CheckMate 142. In this safety analysis, the majority of select treatment‐related adverse events (sTRAEs) occurred early, were managed using evidence‐based treatment algorithms, and resolved. Efficacy outcomes were comparable between patients with or without sTRAEs regardless of the use of concomitant immune‐modulating medications. The benefit‐risk profile of NIVO + low‐dose IPI provides a promising treatment option for MSI‐H/dMMR mCRC.
摘要
背景。在接受免疫检查点抑制剂治疗的患者中，早期发现和管理治疗相关不良事件 (TRAE) 可改善预后。在 CheckMate 142 研究中，纳武单抗 (3 mg/kg) 联合低剂量易普利姆玛单抗 (1 mg/kg) 可提供持久的临床疗效 客观反应率 (ORR)为 55%，未达到中位反应持续时间，12 个月的总生存(OS)率为 85%，且对于既往已接受微卫星不稳定性高/错配修复缺陷(MSI‐H/dMMR)转移性结直肠癌 (mCRC) 治疗的患者具有可控的安全特性。此外，还介绍了 CheckMate 142 的深度安全性及其他疗效。
材料和方法。安全性评估包括TRAE发生频率、选择性TRAE (sTRAE) 及免疫介导型不良事件的发生率；发生时间 (TTO)；消退时间 (TTR)；免疫调节药物 (IMM) 的使用；剂量延迟；恢复治疗后出现sTRAE。疗效评估包括对sTRAE伴有或不伴IMM的患者及不伴sTRAE的患者的ORR和生存率进行分析。
结果。在 119 名患者中，25%、23%、19%、5%、5% 及 29% 的患者分别出现了内分泌系统、胃肠、肝脏、肺、肾脏或皮肤方面的sTRAE；多数 (57%) 属于 1/2 级。sTRAE发生于早期(中位TTO，5.2–12.6 周)。多数(超过 71%)患者的非内分泌系统sTRAE消退(中位TTR，1.5–9.0 周)。22%–56% 的患者使用IMM治疗sTRAE(多数均消退)。在由于sTRAE而导致剂量延迟的患者中，29 例中有 25 例恢复了治疗。对于伴有或不伴sTRAE的患者，在ORR(57% vs. 52%)和 12 个月的OS率(93% vs. 75%)方面相差无几。经观察发现，无论IMM使用与否，伴有或不伴sTRAE的患者均取得了类似的疗效(ORR 52% vs. 57%；OS率 87% vs. 82%)。
结论。根据对纳武单抗联合低剂量易普利姆玛单抗的疗效‐风险分析，此种疗法将有望成为既往已接受MSI‐H/dMMR mCRC治疗者的首选治疗方案。
实践意义:纳武单抗 (NIVO) 联合低剂量 (1 mg/kg) 易普利姆玛单抗 (IPI) 疗法获得了美国食品和药品管理局的批准，可用于患微卫星不稳定高/错配修复缺陷 (MSI‐H/dMMR) 转移性结直肠癌 (mCRC) 且在接受氟尿嘧啶、奥沙利铂及伊立替康的治疗后病情恶化(基于 CheckMate 142 研究的结果)的患者。在此项安全性分析中，大多数选择性治疗相关不良事件 (sTRAE) 均发生于早期，在采用循证治疗方法进行治疗后消退。无论是否同时使用免疫调节药物，伴有或不伴sTRAE的患者均取得了类似的疗效。根据对NIVO联合低剂量IPI的疗效‐风险分析，此种疗法将有望成为MSI‐H/dMMR mCRC的首选治疗方案
Because of unique mechanisms of action, immune checkpoint inhibitor use is associated with adverse events that differ from chemotherapy‐related adverse events. This article analyzes the safety profile of nivolumab plus low‐dose ipilimumab in previously treated patients with microsatellite instability‐high and/or mismatch repair‐deficient metastatic colorectal cancer.
Bevacizumab is the first antiangiogenic therapy proven to slow metastatic disease progression in patients with cancer. Although it has changed clinical practice, some patients do not respond or ...gradually develop resistance, resulting in rather modest gains in terms of overall survival. A major challenge is to develop robust biomarkers that can guide selection of patients for whom bevacizumab therapy is most beneficial. Here, we discuss recent progress in finding such markers, including the first results from randomized phase III clinical trials evaluating the efficacy of bevacizumab in combination with comprehensive biomarker analyses. In particular, these studies suggest that circulating levels of short vascular endothelial growth factor A (VEGF-A) isoforms, expression of neuropilin-1 and VEGF receptor 1 in tumors or plasma, and genetic variants in VEGFA or its receptors are strong biomarker candidates. The current challenge is to expand this first set of markers and to validate it and implement it into clinical practice. A first prospective biomarker study known as MERiDiAN, which will treat patients stratified for circulating levels of short VEGF-A isoforms with bevacizumab and paclitaxel, is planned and will hopefully provide us with new directions on how to treat patients more efficiently.
The world of molecular profiling has undergone revolutionary changes over the last few years as knowledge, technology, and even standard clinical practice have evolved. Broad molecular profiling is ...now nearly essential for all patients with metastatic solid tumors. New agents have been approved based on molecular testing instead of tumor site of origin. Molecular profiling methodologies have likewise changed such that tests that were performed on patients a few years ago are no longer complete and possibly inaccurate today. As with all rapid change, medical providers can quickly fall behind or struggle to find up‐to‐date sources to ensure he or she provides optimum care. In this review, the authors provide the current state of the art for molecular profiling/precision medicine, practice standards, and a view into the future ahead.
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