ABSTRACT
Background: Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine is synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Methods: In this single arm multicohort phase I trial, we evaluated the safety and efficacy of Ribociclib plus Gemcitabine in patients with advanced solid tumors. Patients received Gemcitabine intravenously on days 1 and 8 followed by Ribociclib days 8-14, with treatment repeated every 3 weeks. Results: The study enrolled 43 patients between October 2017 and September 2019. The escalation phase (19 patients) determined the MTD and recommended phase II dose (RP2D) to be ribociclib 800mg daily and gemcitabine 1000mg/m2 for the expansion phase (24 patients). One patient experienced Grade 4 thrombocytopenia. Eleven patients experienced Grade 3 adverse events (AE), the most common being neutropenia, thrombocytopenia, and anemia. No partial or complete responses were observed. 15/22 (68%) of efficacy evaluable patients who received the MTD achieved best response of stable disease. Conclusions: The addition of Ribociclib to Gemcitabine was tolerated well and yielded stability of tumors in both cohorts. Ribociclib and gemcitabine could have synergistic activity in certain tumor types, and our data provides support for the combination. Clinical Trial Registration: NCT03237390.
ABSTRACT
Colorectal cancer (CRC) is a complex disease with diverse etiologies and clinical outcomes. Despite considerable progress in development of CRC therapeutics, challenges remain regarding the diagnosis and management of advanced stage metastatic CRC (mCRC). In particular, the five-year survival rate is very low since mCRC is currently rarely curable. Over the past decade, cancer treatment has significantly improved with the introduction of cancer immunotherapies, specifically immune checkpoint inhibitors. Therapies aimed at blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 target inhibitory pathways of the immune system, and thereby enhance anti-tumor immunity. These therapies thus have shown promising results in many clinical trials alone or in combination. The efficacy and safety of immunotherapy, either alone or in combination with CRC, have been investigated in several clinical trials. Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. Unfortunately, these drugs benefit only a small percentage of patients, with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients. To this end, primary and secondary resistance to immunotherapy remains a significant issue, and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.
Subject(s)
Clinical Trials as Topic , Colorectal Neoplasms , Immune Checkpoint Inhibitors , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/immunology , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/adverse effects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Immunotherapy/methods , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , Treatment Outcome , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunologyABSTRACT
BACKGROUND: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. RESULTS: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56-62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997M mutation. CONCLUSIONS: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.
ABSTRACT
Mivavotinib (TAK-659/CB-659), a dual SYK/FLT3 inhibitor, reduced immunosuppressive immune cell populations and suppressed tumor growth in combination with anti-PD-1 therapy in cancer models. This dose-escalation/expansion study investigated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mivavotinib plus nivolumab in patients with advanced solid tumors. Patients received oral mivavotinib 60-100 mg once-daily plus intravenous nivolumab 3 mg/kg on days 1 and 15 in 28-day cycles until disease progression or unacceptable toxicity. The dose-escalation phase evaluated the recommended phase II dose (RP2D; primary endpoint). The expansion phase evaluated overall response rate (primary end point) at the RP2D in patients with triple-negative breast cancer (TNBC). During dose-escalation (n = 24), two dose-limiting toxicities (grade 4 lipase increased and grade 3 pyrexia) occurred in patients who received mivavotinib 80 mg and 100 mg, respectively. The determined RP2D was once-daily mivavotinib 80 mg plus nivolumab 3 mg/kg. The expansion phase was terminated at ~50% enrollment (n = 17) after failing to meet an ad hoc efficacy futility threshold. Among all 41 patients, common treatment-emergent adverse events (TEAEs) included dyspnea (48.8%), aspartate aminotransferase increased, and pyrexia (46.3% each). Common grade ≥3 TEAEs were hypophosphatemia and anemia (26.8% each). Mivavotinib plasma exposure was generally dose-proportional (60-100 mg). One patient had a partial response. Mivavotinib 80 mg plus nivolumab 3 mg/kg was well tolerated with no new safety signals beyond those of single-agent mivavotinib or nivolumab. Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. TRIAL REGISTRATION ID: NCT02834247.
Subject(s)
Nivolumab , Triple Negative Breast Neoplasms , Humans , Clinical Trials, Phase II as Topic , Fever , Nivolumab/adverse effects , Protein Kinase Inhibitors , Triple Negative Breast Neoplasms/drug therapy , FemaleABSTRACT
Tissue-resident macrophages (TRMs) are abundant immune cells within pre-metastatic sites, yet their functional contributions to metastasis remain incompletely understood. Here, we show that alveolar macrophages (AMs), the main TRMs of the lung, are susceptible to downregulation of the immune stimulatory transcription factor IRF8, impairing anti-metastatic activity in models of metastatic breast cancer. G-CSF is a key tumor-associated factor (TAF) that acts upon AMs to reduce IRF8 levels and facilitate metastasis. Translational relevance of IRF8 downregulation was observed among macrophage precursors in breast cancer and a CD68hiIRF8loG-CSFhi gene signature suggests poorer prognosis in triple-negative breast cancer (TNBC), a G-CSF-expressing subtype. Our data highlight the underappreciated, pro-metastatic roles of AMs in response to G-CSF and identify the contribution of IRF8-deficient AMs to metastatic burden. AMs are an attractive target of local neoadjuvant G-CSF blockade to recover anti-metastatic activity.
ABSTRACT
PIEZO1 plays a crucial role in the human body as a mechanosensory ion channel. It has been demonstrated that PIEZO1 is important in tissue development and regulating many essential physiological processes. Studies have suggested that the PIEZO1 ion channel plays a role in invasion and progression in cancer; elevated levels of PIEZO1 have been correlated with increased migration in breast cancer cells, chemo-resistance and invasion in gastric cancer cells, and increased invasion of osteosarcoma cells. In addition, high PIEZO1 expression levels were correlated with a worse prognosis in glioma patients. On the other hand, studies in lung cancer have attributed high PIEZO1 levels to better patient outcomes. However, the clinical impact of PIEZO1 in breast cancer is not well characterized. Therefore, our goal was to determine the clinical relevance of PIEZO1 in breast cancer. An analysis of breast cancer data from The Cancer Genome Atlas (TCGA) was conducted to investigate PIEZO1 expression levels and correlation to survival, followed by validation in an independent dataset, GSE3494. We also performed gene set enrichment analysis (GSEA) and pathway enrichment analysis. We also analyzed the immune cell composition in breast tumors from TCGA through a CIBERSORT algorithm. Our results demonstrated that the PIEZO1 expression levels are higher in hormone-receptor (HR)-negative than in HR-positive cohorts. High PIEZO1 expression is correlated with a significant decrease in survival in HR-negative cohorts, especially in triple-negative breast cancer (TNBC), suggesting that PIEZO1 could be utilized as a prognostic biomarker in HR-negative breast cancer. GSEA showed that various signaling pathways associated with more invasive phenotypes and resistance to treatments, including epithelial-mesenchymal transition (EMT), hypoxia, and multiple signaling pathways, are enriched in high-PIEZO1 HR-negative tumors. Our results also demonstrated a decrease in CD8+ and CD4+ T cell infiltration in high-PIEZO1 HR-negative tumors. Further investigations are necessary to elucidate the mechanistic roles of PIEZO1 in HR-negative breast cancer.
ABSTRACT
Targeted agents and immunotherapies have revolutionized cancer treatment, offering promising options for various cancer types. Unlike traditional therapies the principle of "more is better" is not always applicable to these new therapies due to their unique biomedical mechanisms. As a result, various phase I-II clinical trial designs have been proposed to identify the optimal biological dose that maximizes the therapeutic effect of targeted therapies and immunotherapies by jointly monitoring both efficacy and toxicity outcomes. This review article examines several innovative phase I-II clinical trial designs that utilize accumulated efficacy and toxicity outcomes to adaptively determine doses for subsequent patients and identify the optimal biological dose, maximizing the overall therapeutic effect. Specifically, we highlight three categories of phase I-II designs: efficacy-driven, utility-based, and designs incorporating multiple efficacy endpoints. For each design, we review the dose-outcome model, the definition of the optimal biological dose, the dose-finding algorithm, and the software for trial implementation. To illustrate the concepts, we also present two real phase I-II trial examples utilizing the EffTox and ISO designs. Finally, we provide a classification tree to summarize the designs discussed in this article.
Subject(s)
Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Immunotherapy , Neoplasms , Research Design , Humans , Neoplasms/drug therapy , Neoplasms/therapy , Immunotherapy/methods , Clinical Trials, Phase I as Topic/methods , Clinical Trials, Phase II as Topic/methods , Dose-Response Relationship, Drug , Molecular Targeted Therapy/methods , Algorithms , Adaptive Clinical Trials as Topic/methodsABSTRACT
BACKGROUND: Presence of cytotoxic T lymphocytes (CTL) in the tumor microenvironment (TME) predicts the effectiveness of cancer immunotherapies. The ability of toll-like receptor 3 (TLR3) ligands, interferons (IFNs) and COX2 inhibitors to synergistically induce CTL-attracting chemokines (but not regulatory T cell (Treg)-attractants) in the TME, but not in healthy tissues, observed in our preclinical studies, suggested that their systemic application can reprogram local TMEs. METHODS: Six evaluable patients (33-69 years) with metastatic triple-negative breast cancer received six doses of systemic chemokine-modulating (CKM) regimen composed of TLR3 ligand (rintatolimod; 200 mg; intravenous), IFN-α2b (20 MU/m2; intravenous) and COX2 inhibitor (celecoxib; 2×200 mg; oral) over 2 weeks. The predetermined primary endpoint was the intratumoral change in the expression of CTL marker, CD8α, in the post-CKM versus pre-CKM tumor biopsies. Patients received follow-up pembrolizumab (200 mg, intravenously, every 3 weeks), starting 3-8 days after completion of CKM. RESULTS: Post-CKM biopsies showed selectively increased CTL markers CD8α (average 10.2-fold, median 5.5-fold, p=0.034) and granzyme B (GZMB; 6.1-fold, median 5.8-fold, p=0.02), but not FOXP3 (Treg marker) relative to HPRT1 expression, resulting in the increases in average CD8α/FOXP3 ratio and GZMB/FOXP3 ratio. CKM increased intratumoral CTL-attractants CCL5 and CXCL10, but not Treg-attractants CCL22 or CXCL12. In contrast, CD8+ T cells and their CXCR3+ subset showed transient decreases in blood. One clinical response (breast tumor autoamputation) and three stable diseases were observed. The patient with clinical response remains disease free, with a follow-up of 46 months as of data cut-off. CONCLUSIONS: Short-term systemic CKM selectively increases CTL numbers and CTL/Treg ratios in the TME, while transiently decreasing CTL numbers in the blood. Transient effects of CKM suggest that its simultaneous application with checkpoint blockade and other forms of immunotherapy may be needed for optimal outcomes.
Subject(s)
Breast Neoplasms , T-Lymphocytes, Cytotoxic , Humans , Female , T-Lymphocytes, Cytotoxic/metabolism , CD8-Positive T-Lymphocytes/metabolism , Breast Neoplasms/pathology , Toll-Like Receptor 3/metabolism , Tumor Microenvironment , Ligands , Interferon-alpha/metabolism , Forkhead Transcription Factors/metabolismABSTRACT
Pancreatic ductal adenocarcinoma (PDA) is a clinically challenging disease with limited treatment options. Despite a small percentage of cases with defective mismatch DNA repair (dMMR), PDA is included in the most immune-resistant cancer types that are poorly responsive to immune checkpoint blockade (ICB) therapy. To facilitate drug discovery combating this immunosuppressive tumor type, a high-throughput drug screen platform is established with the newly developed T cell-incorporated pancreatic tumor organoid model. Tumor-specific T cells are included in the pancreatic tumor organoids by two-step cell packaging, fully recapitulating immune infiltration in the immunosuppressive tumor microenvironment (TME). The organoids are generated with key components in the original tumor, including epithelial, vascular endothelial, fibroblast and macrophage cells, and then packaged with T cells into their outside layer mimicking a physical barrier and enabling T cell infiltration and cytotoxicity studies. In the PDA organoid-based screen, epigenetic inhibitors ITF2357 and I-BET151 are identified, which in combination with anti-PD-1 based therapy show considerably greater anti-tumor effect. The combinatorial treatment turns the TME from immunosuppressive to immunoactive, up-regulates the MHC-I antigen processing and presentation, and enhances the effector T cell activity. The standardized PDA organoid model has shown great promise to accelerate drug discovery for the immunosuppressive cancer.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , T-Lymphocytes , Pancreatic Neoplasms/drug therapy , Carcinoma, Pancreatic Ductal/drug therapy , Immunotherapy , Organoids/pathology , Tumor Microenvironment , Pancreatic NeoplasmsABSTRACT
PURPOSE: About 50% of breast cancers are defined as HER2-low and may benefit from HER2-directed antibody-drug conjugates. While tissue sequencing has evaluated potential differences in genomic profiles for patients with HER2-low breast cancer, genetic alterations in circulating tumor DNA (ctDNA) have not been well described. EXPERIMENTAL DESIGN: We retrospectively analyzed 749 patients with metastatic breast cancer (MBC) and ctDNA evaluation by Guardant360 from three academic medical centers. Tumors were classified as HER2-low, HER2-0 (IHC 0) or HER2-positive. Single-nucleotide variants, copy-number variants, and oncogenic pathways were compared across the spectrum of HER2 expression. Overall survival (OS) was evaluated by HER2 status and according to oncogenic pathways. RESULTS: Patients with HER2-low had higher rates of PIK3CA mutations [relative risk ratio (RRR), 1.57; P = 0.024] compared with HER2-0 MBC. There were no differences in ERBB2 alterations or oncogenic pathways between HER2-low and HER2-0 MBC. Patients with HER2-positive MBC had more ERBB2 alterations (RRR, 12.43; P = 0.002 for amplification; RRR, 3.22; P = 0.047 for mutations, in the hormone receptor-positive cohort), fewer ERS1 mutations (RRR, 0.458; P = 0.029), and fewer ER pathway alterations (RRR, 0.321; P < 0.001). There was no difference in OS for HER2-low and HER2-0 MBC [HR, 1.01; 95% confidence interval (CI), 0.79-1.29], while OS was improved in HER2-positive MBC (HR, 0.32; 95% CI, 0.21-0.49; P < 0.001). CONCLUSIONS: We observed a higher rate of PIK3CA mutations, but no significant difference in ERBB2 alterations, oncogenic pathways, or prognosis, between patients with HER2-low and HER2-0 MBC. If validated, our findings support the conclusion that HER2-low MBC does not represent a unique biological subtype.
Subject(s)
Breast Neoplasms , Circulating Tumor DNA , Female , Humans , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Breast Neoplasms/pathology , Circulating Tumor DNA/genetics , Class I Phosphatidylinositol 3-Kinases/genetics , Mutation , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Retrospective StudiesABSTRACT
PURPOSE OF REVIEW: It is well described that tumor-directed aberrant myelopoiesis contributes to the generation of various myeloid populations with tumor-promoting properties. A growing number of recent studies have revealed the importance of the previously unappreciated roles of erythroid progenitor cells (EPCs) in the context of cancer, bringing the updated concept that altered erythropoiesis also facilitates tumor growth and progression. Better characterization of EPCs may provide attractive therapeutic opportunities. RECENT FINDINGS: EPCs represent a heterogeneous population. They exhibit crucial pro-tumor activities by secreting growth factors and modulating the immune response. Cancers induce potent EPC expansion and suppress their differentiation. Recent single-cell transcriptome and lineage tracking analyses have provided novel insight that tumor-induced EPCs are able to be transdifferentiated into immunosuppressive myeloid cells to limit T-cell function and immunotherapy. Therapeutic strategies targeting key factors of EPC-driven immunosuppression, reducing the amount of EPCs, and promoting EPC differentiation and maturation have been extensively investigated. SUMMARY: This review summarizes the current state of knowledge as to the fascinating biology of EPCs, highlights mechanisms by which they exert the tumor promoting activities, as well as the perspectives on future directions and strategies to target these cells for potential therapeutic benefit.
Subject(s)
Erythroid Precursor Cells , Neoplasms , Humans , Cell Differentiation , Neoplasms/therapyABSTRACT
Patients with ER+/HER2+ breast cancer (BC) are less likely to achieve pathological complete response (pCR) after chemotherapy with dual HER2 blockade than ER-/HER2+ BC. Endocrine therapy plus trastuzumab is effective in advanced ER+/HER2+ BC. Inhibition of CDK4/6 and HER2 results in synergistic cell proliferation reduction. We combined palbociclib, letrozole, and trastuzumab (PLT) as a chemotherapy-sparing regimen. We evaluated neoadjuvant PLT in early ER+/HER2+ BC. Primary endpoint was pCR after 16 weeks. Research biopsies were performed for whole exome and RNA sequencing, PAM50 subtyping, and Ki67 assessment for complete cell cycle arrest (CCCA: Ki67 ≤ 2.7%). After 26 patients, accrual stopped due to futility. pCR (residual cancer burden-RCB 0) was 7.7%, RCB 0/I was 38.5%. Grade (G) 3/4 treatment-emergent adverse events occurred in 19. Among these, G3/4 neutropenia was 50%, hypertension 26.9%, and leucopenia 7.7%. Analysis indicated CCCA in 85% at C1 day 15 (C1D15), compared to 27% at surgery after palbociclib was discontinued. Baseline PAM50 subtyping identified 31.2% HER2-E, 43.8% Luminal B, and 25% Luminal A. 161 genes were differentially expressed comparing C1D15 to baseline. MKI67, TK1, CCNB1, AURKB, and PLK1 were among the genes downregulated, consistent with CCCA at C1D15. Molecular Signatures Database gene-sets analyses demonstrated downregulated processes involved in proliferation, ER and mTORC1 signaling, and DNA damage repair at C1D15, consistent with the study drug's mechanisms of action. Neoadjuvant PLT showed a pCR of 7.7% and an RCB 0/I rate of 38.5%. RNA sequencing and Ki67 data indicated potent anti-proliferative effects of study treatments. ClinicalTrials.gov- NCT02907918.
ABSTRACT
While immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape in oncology, they are effective in select subsets of patients. Efficacy may be limited by tumor-driven immune suppression, of which 1 key mechanism is the development of myeloid-derived suppressor cells (MDSCs). A fundamental gap in MDSC therapeutics is the lack of approaches that target MDSC biogenesis. We hypothesized that targeting MDSC biogenesis would mitigate MDSC burden and bolster tumor responses to ICIs. We tested a class of agents, dihydroorotate dehydrogenase (DHODH) inhibitors, that have been previously shown to restore the terminal differentiation of leukemic myeloid progenitors. DHODH inhibitors have demonstrated preclinical safety and are under clinical study for hematologic malignancies. Using mouse models of mammary cancer that elicit robust MDSC responses, we demonstrated that the DHODH inhibitor brequinar (a) suppressed MDSC production from early-stage myeloid progenitors, which was accompanied by enhanced myeloid maturation; (b) augmented the antitumor and antimetastatic activities of programmed cell death 1-based (PD-1-based) ICI therapy in ICI-resistant mammary cancer models; and (c) acted in concert with PD-1 blockade through modulation of MDSC and CD8+ T cell responses. Moreover, brequinar facilitated myeloid maturation and inhibited immune-suppressive features in human bone marrow culture systems. These findings advance the concept of MDSC differentiation therapy in immuno-oncology.
Subject(s)
Breast Neoplasms , Mammary Neoplasms, Animal , Myeloid-Derived Suppressor Cells , Animals , Mice , Humans , Female , Programmed Cell Death 1 Receptor , Immunotherapy , Immunologic FactorsABSTRACT
BACKGROUND: Limited data exist to characterise molecular differences in circulating tumour DNA (ctDNA) for patients with invasive lobular carcinoma (ILC). We analysed metastatic breast cancer patients with ctDNA testing to assess genomic differences among patients with ILC, invasive ductal carcinoma (IDC), and mixed histology. METHODS: We retrospectively analysed 980 clinically annotated patients (121 ILC, 792 IDC, and 67 mixed histology) from three academic centers with ctDNA evaluation by Guardant360™. Single nucleotide variations (SNVs), copy number variations (CNVs), and oncogenic pathways were compared across histologies. FINDINGS: ILC was significantly associated with HR+ HER2 negative and HER2 low. SNVs were higher in patients with ILC compared to IDC or mixed histology (Mann Whitney U test, P < 0.05). In multivariable analysis, HR+ HER2 negative ILC was significantly associated with mutations in CDH1 (odds ratio (OR) 9.4, [95% CI 3.3-27.2]), ERBB2 (OR 3.6, [95% confidence interval (CI) 1.6-8.2]), and PTEN (OR 2.5, [95% CI 1.05-5.8]) genes. CDH1 mutations were not present in the mixed histology cohort. Mutations in the PI3K pathway genes (OR 1.76 95% CI [1.18-2.64]) were more common in patients with ILC. In an independent cohort of nearly 7000 metastatic breast cancer patients, CDH1 was significantly co-mutated with targetable alterations (PIK3CA, ERBB2) and mutations associated with endocrine resistance (ARID1A, NF1, RB1, ESR1, FGFR2) (Benjamini-Hochberg Procedure, all q < 0.05). INTERPRETATION: Evaluation of ctDNA revealed differences in pathogenic alterations and oncogenic pathways across breast cancer histologies with implications for histologic classification and precision medicine treatment. FUNDING: Lynn Sage Cancer Research Foundation, OncoSET Precision Medicine Program, and UL1TR001422.
Subject(s)
Breast Neoplasms , Carcinoma, Ductal, Breast , Carcinoma, Lobular , Circulating Tumor DNA , Humans , Female , Breast Neoplasms/pathology , Carcinoma, Lobular/genetics , Carcinoma, Lobular/metabolism , Carcinoma, Lobular/pathology , Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Ductal, Breast/pathology , Circulating Tumor DNA/genetics , Retrospective Studies , DNA Copy Number Variations , Phosphatidylinositol 3-Kinases/geneticsABSTRACT
With the advent of immune checkpoint blockade (ICB) therapy, treatment strategies for late-stage cancers have seen a radical advancement. In this issue of the JCI, Wang et al. characterize the functional role of miR-155 in breast cancer and its potential in harnessing the efficacy of immunotherapy. The study reports that high expression levels of miR-155 in breast cancer cells downregulated suppressor of cytokine signaling 1 (SOCS1), increased the phosphorylated STAT1 (pSTAT1)/pSTAT3 ratio, and thereby stimulated chemoattractants for tumor infiltration of effector T cells. Moreover, miR-155 overexpression set the stage for ICB therapy via increased programmed death ligand 1 (PD-L1) expression on cancer cells and enhanced immunological memory response via the release of miR-155-containing extracellular vesicles. Collectively, these data suggest that miR-155 is a strong candidate as a prognostic biomarker for ICB therapy.
Subject(s)
Breast Neoplasms , MicroRNAs , B7-H1 Antigen/metabolism , Biomarkers , Breast Neoplasms/drug therapy , Breast Neoplasms/therapy , Chemotactic Factors/therapeutic use , Cytokines , Female , Humans , Immune Checkpoint Inhibitors , Immunotherapy , MicroRNAs/genetics , MicroRNAs/metabolismABSTRACT
BACKGROUND: Mechanically gated PIEZO channels lead to an influx of cations, activation of additional Ca2+ channels, and cell depolarization. This study aimed to investigate PIEZO2's role in breast cancer. METHODS: The clinical relevance of PIEZO2 expression in breast cancer patient was analyzed in a publicly available dataset. Utilizing PIEZO2 overexpressed breast cancer cells, and in vitro and in vivo experiments were conducted. RESULTS: High expression of PIEZO2 was correlated with a worse survival in triple-negative breast cancer (TNBC) but not in other subtypes. Increased PEIZO2 channel function was confirmed in PIEZO2 overexpressed cells after mechanical stimulation. PIEZO2 overexpressed cells showed increased motility and invasive phenotypes as well as higher expression of SNAIL and Vimentin and lower expression of E-cadherin in TNBC cells. Correspondingly, high expression of PIEZO2 was correlated with the increased expression of epithelial-mesenchymal transition (EMT)-related genes in a TNBC patient. Activated Akt signaling was observed in PIEZO2 overexpressed TNBC cells. PIEZO2 overexpressed MDA-MB-231 cells formed a significantly higher number of lung metastases after orthotopic implantation. CONCLUSION: PIEZO2 activation led to enhanced SNAIL stabilization through Akt activation. It enhanced Vimentin and repressed E-cadherin transcription, resulting in increased metastatic potential and poor clinical outcomes in TNBC patients.
Subject(s)
Triple Negative Breast Neoplasms , Cadherins/genetics , Cadherins/metabolism , Cell Line, Tumor , Cell Movement/genetics , Epithelial-Mesenchymal Transition/genetics , Humans , Ion Channels/genetics , Phenotype , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Triple Negative Breast Neoplasms/pathology , Vimentin/genetics , Vimentin/metabolismABSTRACT
Background: CIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy which has shown survival benefit as a switch maintenance treatment after platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). The primary objective of this trial is to establish the safety and recommended phase II dose (RP2D) of CIMAvax-EGF in combination with nivolumab as second-line therapy for NSCLC. Methods: Patients with immune checkpoint inhibitor-naive metastatic NSCLC were enrolled using a "3+3" dose-escalation design. Toxicities were graded according to CTCAE V4.03. Thirteen patients (one unevaluable), the majority with PD-L1 0%, were enrolled into two dose levels of CIMAvax-EGF. Findings: The combination was determined to be safe and tolerable. The recommended phase 2 dose of CIMAvax-EGF was 2.4 mg. Humoral response to CIMAvax-EGF was achieved earlier and in a greater number of patients with the combination compared to historical control. Four out of 12 evaluable patients had an objective response.
ABSTRACT
Proviral integration of Moloney virus 2 (PIM2) is a prosurvival factor of cancer cells and a possible therapeutic target in hematological malignancies. However, the attempts at inhibiting PIM2 have yielded underwhelming results in early clinical trials on hematological malignancies. Recently, a novel panPIM inhibitor, JP11646, was developed. The present study examined the utility of targeting PIM2 in multiple solid cancers and investigated the antitumor efficacy and the mechanisms of action of JP11646. When PIM2 expression was compared between normal and cancer tissues in publicly available datasets, PIM2 was found to be overexpressed in several types of solid cancers. PIM2 ectopic overexpression promoted tumor growth in in vivo xenograft breast cancer mouse models. The panPIM inhibitor, JP11646, suppressed in vitro cancer cell proliferation in a concentrationdependent manner in multiple types of cancers; a similar result was observed with siRNAmediated PIM2 knockdown, as well as an increased in cell apoptosis. By contrast, another panPIM inhibitor, AZD1208, suppressed the expression of downstream PIM2 targets, but not PIM2 protein expression, corresponding to no apoptosis induction. As a mechanism of PIM2 protein degradation, it was found that the proteasome inhibitor, bortezomib, reversed the apoptosis induced by JP11646, suggesting that PIM2 degradation by JP11646 is proteasomedependent. JP11646 exhibited significant anticancer efficacy with minimal toxicities at the examined doses and schedules in multiple in vivo mice xenograft solid cancer models. On the whole, the present study demonstrates that PIM2 promotes cancer progression in solid tumors. JP11646 induces apoptosis at least partly by PIM2 protein degradation and suppresses cancer cell proliferation in vitro and in vivo. JP11646 may thus be a possible treatment strategy for multiple types of solid cancers.
Subject(s)
Breast Neoplasms , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Cell Line, Tumor , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Female , Humans , Mice , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitorsABSTRACT
PURPOSE: Irinotecan is a commonly used chemotherapeutic in solid tumor malignancies. Oratecan is an investigational product comprised of encequidar methanesulfonate, a novel minimally absorbed P-glycoprotein pump inhibitor, and irinotecan. This study sought to determine the maximum tolerated dose (MTD) of oratecan in patients with advanced malignancies. METHODS: Using a "3 + 3â³ dose-escalation design, patients were treated with oratecan on day 1 every 21 days. The irinotecan dose was escalated from 20 to 320 mg/m2. The encequidar methanesulfonate dose was fixed at 15 mg (12.9 mg free base). PK sampling for irinotecan, encequidar and its major metabolites was performed following a single dose of oratecan during cycle 1. Patients were treated until disease progression or unacceptable toxicity. RESULTS: Thirty-five patients were treated. The MTD was determined to be 280 mg/m2 every 21 days. Irinotecan and SN-38 plasma concentration-time profile showed that irinotecan exposure increased with dose and followed biexponential decay. Nine of 17 patients at oratecan dose levels 200 mg/m2 and above had SN-38 exposures comparable to those with intravenous irinotecan at standard dosing. None of the 35 patients achieved a radiologic response, ten patients had SD for > 8 weeks; the median progression-free survival for all treated patients was 9 weeks (95% CI 8.6-13.9). CONCLUSIONS: The MTD of oratecan was encequidar methanesulfonate 15 mg plus irinotecan 280 mg/m2. Exposure for irinotecan and SN-38 increased with increased dose. Potential antitumor activity was observed at the 280 and 320 mg/m2 dose levels. The safety profile of oratecan was comparable to that of intravenous irinotecan.