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Annals of Oncology : Official Journal... Feb 2024Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC.
PATIENTS AND METHODS
Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety.
RESULTS
A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group.
CONCLUSION
In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975.
Topics: Humans; Antibodies, Monoclonal, Humanized; Axitinib; Carcinoma, Renal Cell; Kidney Neoplasms; Sunitinib; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37872020
DOI: 10.1016/j.annonc.2023.09.3108 -
Theranostics 2023Glioblastoma (GBM) is an aggressive malignant primary brain cancer with poor survival. Hypoxia is a hallmark of GBM, which promotes tumor cells spreading (invasion)...
Glioblastoma (GBM) is an aggressive malignant primary brain cancer with poor survival. Hypoxia is a hallmark of GBM, which promotes tumor cells spreading (invasion) into the healthy brain tissue. To better elucidate the influence of hypoxia on GBM invasion, we proposed a data-driven modeling framework for predicting cellular hypoxia (CHPF) by integrating single cell transcriptome profiling and hypoxia gene signatures. We characterized the hypoxia status landscape of GBM cells and observed that hypoxic cells were only present in the tumor core. Then, by investigating the cell-cell communication between immune cells and tumor cells, we discovered significant interaction between macrophages and tumor cells in hypoxic microenvironment. Notably, we dissected the functional heterogeneity of tumor cells and identified a hypoxic subpopulation that had highly invasive potential. By constructing cell status specific gene regulatory networks, we further identified 14 critical regulators of tumor invasion induced by hypoxic microenvironment. Finally, we confirmed that knocking down two critical regulators and could reduce the invasive ability of GBM under hypoxic conditions. Additionally, we revealed the therapeutic effect of Axitinib and Entinostat through the mice model. Our work revealed the critical regulators in hypoxic subpopulation with high invasive potential in GBM, which may have practical implications for clinical targeted-hypoxia cancer drug therapy.
Topics: Mice; Animals; Glioblastoma; Transcription Factors; Brain Neoplasms; Cell Line, Tumor; Hypoxia; Cell Hypoxia; Sequence Analysis, RNA; Tumor Microenvironment
PubMed: 37441593
DOI: 10.7150/thno.81407 -
Cardio-oncology (London, England) Dec 2023Immune checkpoint inhibitors (ICI) and Tyrosine kinase inhibitors (TKI) are effective for several types of cancers, but they can have several cardiotoxicity sides... (Review)
Review
BACKGROUND
Immune checkpoint inhibitors (ICI) and Tyrosine kinase inhibitors (TKI) are effective for several types of cancers, but they can have several cardiotoxicity sides effects. We present a case of TKI-ICI toxicity resulting in multiorgan inflammatory syndrome with myocarditis and thrombotic STEMI that were successfully treated with high-dose steroids and PCI.
CASE PRESENTATION
Seventy-two year-old man patient treated with on pembrolizumab 200 mg IV every 3 weeks and Axitinib 5 mg PO q12h for the past 5 months complained of acute shortness of breath, altered mental status, and chronic diarrhea. Coronary angiography demonstrated a thrombotic lesion in the right coronary artery (RCA) that was treated successfully with percutaneous coronary intervention (PCI). Despite PCI he continued to complain of shortness of breath further workup with Cardiac MRI (CMR) was obtained showed an ejection fraction of 38%, small pericardial effusion, and delayed gadolinium enhancement (DGE) in the inferior wall suggestive of myocarditis. An empirical trial of high-dose steroids improved all patient symptoms and ejection fraction; therefore, the chemotherapy regimen was changed.
CONCLUSION
This case report highlights the potential vasculogenic effects of Axitinib and immune-related myocarditis of pembrolizumab. Cardiologists and oncologists should be vigilant for the cardiotoxic effects of Axitinib and pembrolizumab.
PubMed: 38057847
DOI: 10.1186/s40959-022-00152-z -
Frontiers in Pharmacology 2023Vascular endothelial growth factor (VEGF) contributes to angiogenesis and vasculogenesis. The occurrence and progression of tumors are accompanied by angiogenesis.... (Review)
Review
Vascular endothelial growth factor (VEGF) contributes to angiogenesis and vasculogenesis. The occurrence and progression of tumors are accompanied by angiogenesis. Vascular endothelial growth factor inhibitors (VEGFI) have been used in anti-tumor treatment. However, aortic dissection (AD) is one of the VEGFI-associated adverse reactions with cute onset, rapid progression, and high case fatality rate. We collected case reports of VEGFI related to aortic dissection in PubMed and CNKI (China National Knowledge Infrastructure) from inception to 28 April 2022. Seventeen case reports were selected. The medication included sunitinib, sorafenib, pazopanib, axitinib, apatinib, anlotinib, bevacizumab, and ramucirumab. This review discusses the pathology, risk factors, diagnosis, and treatment of AD. Vascular endothelial growth factor inhibitors are related to aortic dissection. Although current literature lacks clear statistical evidence on the population, we offer points to encourage further confirmation of the best methods of care for these patients.
PubMed: 37426822
DOI: 10.3389/fphar.2023.1189910 -
Cancers Dec 2023Solitary fibrous tumors (SFT) are rare mesenchymal neoplasms that account for less than 2% of all soft tissue masses. In the latest WHO 2020 Classification of Soft... (Review)
Review
Solitary fibrous tumors (SFT) are rare mesenchymal neoplasms that account for less than 2% of all soft tissue masses. In the latest WHO 2020 Classification of Soft Tissue Tumors, extrameningeal SFT was listed as intermediate (rarely metastasizing) or malignant neoplasms. Due to the lack of characteristic clinical features, their diagnosis and treatment remain challenging. The pathogenesis of SFT is often associated with the presence of fusions of the NAB2-STAT6 gene on the 12q13 chromosome. Cytoplasmic CD34 positive staining is considerably characteristic for most SFTs; less frequently, factor XII, vimentin, bcl-2, and CD99 are present. A key factor in the diagnosis is the prevalent nuclear location of STAT6 expression. Radical resection is the mainstay of localized SFTs. In the case of unresectable disease, only radiotherapy or radio-chemotherapy may significantly ensure long-term local control of primary and metastatic lesions. To date, no practical guidelines have been published for the treatment of advanced or metastatic disease. Classical anthracycline-based chemotherapy is applicable. The latest studies suggest that antiangiogenic therapies should be considered after first-line treatment. Other drugs, such as imatinib, figitumumab, axitinib, and eribulin, are also being tested. Definitive radiotherapy appears to be a promising therapeutic modality. Since standards for the treatment of advanced and metastatic diseases are not available, further investigation of novel agents is necessary.
PubMed: 38136399
DOI: 10.3390/cancers15245854 -
The Journal of Experimental Medicine Nov 2023Clonal hematopoiesis (CH) is defined as clonal expansion of mutant hematopoietic stem cells absent diagnosis of a hematologic malignancy. Presence of CH in solid tumor...
Clonal hematopoiesis (CH) is defined as clonal expansion of mutant hematopoietic stem cells absent diagnosis of a hematologic malignancy. Presence of CH in solid tumor patients, including colon cancer, correlates with shorter survival. We hypothesized that bone marrow-derived cells with heterozygous loss-of-function mutations of DNMT3A, the most common genetic alteration in CH, contribute to the pathogenesis of colon cancer. In a mouse model that combines colitis-associated colon cancer (CAC) with experimental CH driven by Dnmt3a+/Δ, we found higher tumor penetrance and increased tumor burden compared with controls. Histopathological analysis revealed accentuated colonic epithelium injury, dysplasia, and adenocarcinoma formation. Transcriptome profiling of colon tumors identified enrichment of gene signatures associated with carcinogenesis, including angiogenesis. Treatment with the angiogenesis inhibitor axitinib eliminated the colon tumor-promoting effect of experimental CH driven by Dnmt3a haploinsufficiency and rebalanced hematopoiesis. This study provides conceptually novel insights into non-tumor-cell-autonomous effects of hematopoietic alterations on colon carcinogenesis and identifies potential therapeutic strategies.
Topics: Animals; Mice; Carcinogenesis; Colitis-Associated Neoplasms; Colonic Neoplasms; Loss of Heterozygosity; Mutation
PubMed: 37615936
DOI: 10.1084/jem.20230011 -
Journal of Pharmaceutical Sciences Nov 2023Disadvantages of systemically administered immunomodulatory anti-tumor therapies include poor efficacy and high toxicity. Direct intratumoral injection of a drug is...
Disadvantages of systemically administered immunomodulatory anti-tumor therapies include poor efficacy and high toxicity. Direct intratumoral injection of a drug is often associated with rapid efflux from the site of administration, thus reducing local exposure and therapeutic efficacy, while potentially increasing systemic adverse events. To address this, a sustained release prodrug technology was developed using a transient conjugation (TransCon) technology to provide long-term high local drug exposure after injection in the tumor while minimizing systemic exposure. TransCon technology for systemic delivery is clinically validated, with multiple compounds in late-stage clinical development and approval of a once-weekly growth hormone for pediatric growth hormone deficiency. As a further application of this technology, this report describes the design, preparation, and functional characterization of hydrogel microspheres as insoluble, yet degradable carrier system. Microspheres were obtained after reaction of PEG-based polyamine dendrimers and bifunctional crosslinkers. Resiquimod, a TLR7/8 agonist, and axitinib, a vascular endothelial growth factor tyrosine kinase inhibitor, were chosen as anti-cancer drugs. The drugs were covalently attached to the carrier by linkers, which released the drugs under physiological conditions. Essentially all resiquimod or axitinib was released over weeks before physical degradation of the hydrogel microsphere was observed. In summary, TransCon Hydrogel technology allows localized sustained-release drug delivery for cancer therapy enabling high local drug concentrations while at the same time ensuring low systemic drug exposure over weeks with a single injection, which may improve the therapeutic index and improve efficacy, while minimizing systemic adverse events. A hydrogel prodrug of resiquimod, TransCon TLR7/8 agonist, is currently being investigated in clinical trials of patients with solid tumors (NCT04799054).
Topics: Humans; Child; Hydrogels; Prodrugs; Vascular Endothelial Growth Factor A; Axitinib; Toll-Like Receptor 7; Angiogenesis Inhibitors; Growth Hormone; Drug Delivery Systems
PubMed: 37279836
DOI: 10.1016/j.xphs.2023.05.018 -
Clinical Cancer Research : An Official... Dec 2023Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a...
PURPOSE
Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI).
EXPERIMENTAL DESIGN
HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then cotreated with both HC-5404 and VEGFR-TKI in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC.
RESULTS
VEGFR-TKI including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKI across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ∼20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, nine out of 18 models responded with ≥50% tumor regression from baseline in the combination group.
CONCLUSIONS
By disrupting an adaptive stress response evoked by VEGFR-TKI, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard-of-care therapies in RCC.
Topics: Animals; Humans; Carcinoma, Renal Cell; Axitinib; Tyrosine Kinase Inhibitors; Kidney Neoplasms; Protein Kinase Inhibitors
PubMed: 37733811
DOI: 10.1158/1078-0432.CCR-23-1182 -
Computers in Biology and Medicine Oct 2023Osteosarcoma (OS) is a highly invasive malignant neoplasm with poor prognosis. The tumor microenvironment (TME) plays an essential role in the occurrence and development...
Osteosarcoma (OS) is a highly invasive malignant neoplasm with poor prognosis. The tumor microenvironment (TME) plays an essential role in the occurrence and development of OS. Regulatory T cells (Tregs) are known to facilitate immunosuppression, tumor progression, invasion, and metastasis. However, the effect of Tregs in the TME of OS remains unclear. In this study, single-cell RNA sequencing (scRNA-seq) data was used to identify Tregs and various other cell clusters in the TME of OS. Gene set variation analysis (GSVA) was used to investigate the signaling pathways in Tregs from OS and adjacent tissues. The CellChat and iTALK packages were used to analyze cellular communication. In addition, a prognostic model was established based on the Tregs-specific genes using bulk RNA-seq from the TARGET database, and it was verified using a Gene Expression Omnibus dataset. The pRRophetic package was used to predict drug sensitivity. Immunohistochemistry was used to verify the expression of candidate genes in OS. Based on the above methods, we showed that the OS samples were highly infiltrated with Tregs. GSVA revealed that oxidative phosphorylation, angiogenesis and mammalian target of rapamycin complex 1 (mTORC1) were highly activated in Tregs from OS compared with those from adjacent tissues. Using cellular communication analysis, we found that Tregs interacted with osteoblastic, endothelial, and myeloid cells via C-X-C motif chemokine ligand (CXCL) signaling; particularly, they strongly affected the expression of C-X-C motif chemokine receptor 4 (CXCR4) and interacted with other cell clusters through CXCL12/transforming growth factor β1 (TGFB1) to collectively enable tumor growth and progression. Subsequently, two Tregs-specific genes-CD320 and MAF-were screened through univariate, least absolute shrinkage and selection operator regression (LASSO) and multivariate analysis to construct a prognostic model, which showed excellent prognostic accuracy in two independent cohorts. In addition, drug sensitivity analysis demonstrated that OS patients at high Tregs risk were sensitive to sunitinib, sorafenib, and axitinib. We also used immunohistochemistry to validate that CD320 and MAF were significantly upregulated in OS tissues compared with adjacent tissues. Overall, this study reveals the heterogeneity of Tregs in the OS TME, providing new insights into the invasion and treatment of this cancer.
PubMed: 37669584
DOI: 10.1016/j.compbiomed.2023.107417 -
Aging Nov 2023Recent years have seen a sharp rise in the amount of research on the connection between oxidative stress, autophagy, and cancer cells. However, the significant functions...
Recent years have seen a sharp rise in the amount of research on the connection between oxidative stress, autophagy, and cancer cells. However, the significant functions of oxidative stress and autophagy-related genes (OARGs) in gastric cancer (GC) are yet to be investigated integrally. Therefore, it will be a new and promising concept to search for novel OARG-related biomarkers to predict the prognosis and treatment response of GC. First, we assessed changes in prognosis and tumor microenvironment (TME) characteristics across the various oxidative stress and autophagy-related modification patterns based on a detailed analysis of 17 OARGs with prognostic significance of 808 GC samples. We identified three distinct OARG alteration patterns which displayed unique biological characteristics and immune cell infiltration features. Using principal component analysis methods, the OARGscore was developed to evaluate the OARG modification patterns of certain tumors. The negative connection between OARGscore and immune cells was statistically significant. Increased survival, a higher incidence of mutations, and a better response to immunotherapy were all predicted to be related to patients' high-OARGscore. In addition, the candidate chemotherapeutic drugs were predicted using the oncoPredict program. The low-OARGscore group was predicted to benefit more from Ribociclib, Alisertib, Niraparib, Epirubicin, Olaparib, and Axitinib, while patients in the high-OARGscore group were predicted to benefit more from Afatinib, Oxaliplatin, Paclitaxel, 5-Fluorouracil, Dabrafenib and Lapatinib. Our findings offer a specific method for predicting a patient's prognosis and susceptibility to immunotherapy, as well as a promising insight of oxidative stress and autophagy in GC.
Topics: Humans; Stomach Neoplasms; Tumor Microenvironment; Autophagy; Fluorouracil; Afatinib; Prognosis
PubMed: 37950729
DOI: 10.18632/aging.205194