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Cancer Immunology, Immunotherapy : CII Sep 2023Radiotherapy (XRT), a well-known activator of the inflammasome and immune priming, is in part capable of reversing resistance to anti-PD1 treatment. The NLRP3...
Radiotherapy (XRT), a well-known activator of the inflammasome and immune priming, is in part capable of reversing resistance to anti-PD1 treatment. The NLRP3 inflammasome is a pattern recognition receptor which is activated by both exogenous and endogenous stimuli, leading to a downstream inflammatory response. Although NLRP3 is typically recognized for its role in exacerbating XRT-induced tissue damage, the NLRP3 inflammasome can also yield an effective antitumor response when used in proper dosing and sequencing with XRT. However, whether NLRP3 agonist boosts radiation-induced immune priming and promote abscopal responses in anti-PD1 resistant model is still unknown. Therefore, in this study, we paired intratumoral injection of an NLRP3 agonist with XRT to stimulate the immune system in both wild type (344SQ-P) and anti-PD1 resistant (344SQ-R) murine-implanted lung adenocarcinoma models. We found that the combination of XRT + NLPR3 agonist enhanced the control of implanted lung adenocarcinoma primary as well as secondary tumors in a radiological dose-dependent manner, in which 12Gyx3 fractions of stereotactic XRT was better than 5Gyx3, while 1Gyx2 did not improve the NLRP3 effect. Survival and tumor growth data also showed significant abscopal response with the triple therapy (12Gyx3 + NLRP3 agonist + α-PD1) in both 344SQ-P and 344SQ-R aggressively growing models. Multiple pro-inflammatory cytokines (IL-1b, IL-4, IL-12, IL-17, IFN-γ and GM-CSF) were elevated in the serum of mice treated with XRT + NLRP3 or triple therapy. The Nanostring results showed that NLRP3 agonist is capable of increasing antigen presentation, innate function, and T-cell priming. This study can be of particular importance to treat patients with immunologically-cold solid tumors whom are also refractory to prior checkpoint treatments.
Topics: Mice; Animals; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; Antigen Presentation; Cytokines; Adenocarcinoma of Lung
PubMed: 37289257
DOI: 10.1007/s00262-023-03471-x -
Cancer Medicine Feb 2023Non-Small Cell Lung Carcinoma (NSCLC) remains a leading cause of cancer death. Resistance to therapy is a significant problem, highlighting the need to find new ways of...
Non-Small Cell Lung Carcinoma (NSCLC) remains a leading cause of cancer death. Resistance to therapy is a significant problem, highlighting the need to find new ways of sensitising tumour cells to therapeutic agents. βIII-tubulin is associated with aggressive tumours and chemotherapy resistance in a range of cancers including NSCLC. βIII-tubulin expression has been shown to impact kinase signalling in NSCLC cells. Here, we sought to exploit this interaction by identifying co-activity between βIII-tubulin suppression and small-molecule kinase inhibitors. To achieve this, a forced-genetics approach combined with a high-throughput drug screen was used. We show that activity of the multi-kinase inhibitor Amuvatinib (MP-470) is enhanced by βIII-tubulin suppression in independent NSCLC cell lines. We also show that this compound significantly inhibits cell proliferation among βIII-tubulin knockdown cells expressing the receptor tyrosine kinase c-Met. Together, our results highlight that βIII-tubulin suppression combined with targeting specific receptor tyrosine kinases may represent a novel therapeutic approach for otherwise difficult-to-treat lung carcinomas.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Tubulin; Cell Proliferation; Drug Resistance, Neoplasm; Cell Line, Tumor
PubMed: 35946957
DOI: 10.1002/cam4.5128 -
Frontiers in Immunology 2022Radiation therapy (XRT) has a well-established role in cancer treatment. Given the encouraging results on immunostimulatory effects, radiation has been increasingly used...
Radiation therapy (XRT) has a well-established role in cancer treatment. Given the encouraging results on immunostimulatory effects, radiation has been increasingly used with immune-check-point inhibitors in metastatic disease, especially when immunotherapy fails due to tumor immune evasion. We hypothesized that using high-dose stereotactic radiation in cycles (pulses) would increase T-cell priming and repertoire with each pulse and build immune memory in an incremental manner. To prove this hypothesis, we studied the combination of anti-CTLA-4 and Pulsed radiation therapy in our 344SQ non-small cell lung adenocarcinoma murine model. Primary and secondary tumors were bilaterally implanted in 129Sv/Ev mice. In the Pulsed XRT group, both primary and secondary tumors received 12Gyx2 radiation one week apart, and blood was collected seven days afterwards for TCR repertoire analysis. As for the delayed-Pulse group, primary tumors received 12Gyx2, and after a window of two weeks, the secondary tumors received 12Gyx2. Blood was collected seven days after the second cycle of radiation. The immunotherapy backbone for both groups was anti-CTLA-4 antibody to help with priming. Treatment with Pulsed XRT + anti-CTLA-4 led to significantly improved survival and resulted in a delayed tumor growth, where we observed enhanced antitumor efficacy at primary tumor sites beyond XRT + anti-CTLA-4 treatment group. More importantly, Pulsed XRT treatment led to increased CD4 effector memory compared to single-cycle XRT. Pulsed XRT demonstrated superior efficacy to XRT in driving antitumor effects that were largely dependent on CD4 T cells and partially dependent on CD8 T cells. These results suggest that combinatorial strategies targeting multiple points of tumor immune evasion may lead to a robust and sustained antitumor response.
Topics: Mice; Animals; Tumor Burden; CD8-Positive T-Lymphocytes; Immunologic Memory; Immunotherapy; Adenocarcinoma; Receptors, Antigen, T-Cell
PubMed: 36275767
DOI: 10.3389/fimmu.2022.984318 -
Oncotarget Feb 2015c-Kit/α-PDGFR targeted therapies are effective for gastrointestinal stromal tumors (GIST), but, >50% develop drug resistance.
BACKGROUND
c-Kit/α-PDGFR targeted therapies are effective for gastrointestinal stromal tumors (GIST), but, >50% develop drug resistance.
METHODS
RTK expression (c-Kit, c-Met, AXL, HER-1, HER-2, IGF-1R) in pre-/post-imatinib (IM) GIST patient samples (n=16) and 4 GIST cell lines were examined for RTK inhibitor activity. GIST-882 cells were cultured in IM every other day, cells collected (1 week to 6 months) and analyzed by qRT-PCR and Western blotting.
RESULTS
Immunohistochemistry pre-/post-IM demonstrated continued expression of c-Kit and HER1, while a subset expressed IGF-1R, c-Met and AXL. In GIST cells (GIST-882, GIST430/654, GIST48) c-Kit, HER1 and c-Met are co-expressed. Acute IM over-express c-Kit while chronic IM, lose c-Kit and HER-1 in GIST882 cells. GIST882 and GIST430/654 cells have an IC50 0.077 and 0.59 µM to IM respectively. GIST48 have an IC50 0.66 µM to IM, 0.91 µM to amuvatinib [AMU] and 0.67 µM to erlotinib (Erl). Synergistic combinations: GIST882, AMU + Erl (CI 0.20); IM + AMU (CI 0.50), GIST430/654, IM + afatinib (CI 0.39); IM + AMU (CI 0.42), GIST48, IM + afatinib (CI 0.03); IM + AMU (CI 0.04); AMU + afatinib (CI 0.36); IM + Erl (CI 0.63).
CONCLUSION
Targeting c-Kit plus HER1 or AXL/c-Met abrogates IM resistance in GIST.
Topics: Afatinib; Aged; Aged, 80 and over; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; Erlotinib Hydrochloride; Female; Gastrointestinal Stromal Tumors; Gene Expression Regulation, Neoplastic; Humans; Imatinib Mesylate; Immunoblotting; Immunohistochemistry; Male; Middle Aged; Molecular Targeted Therapy; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-kit; Proto-Oncogene Proteins c-met; Pyrimidines; Quinazolines; Receptor Protein-Tyrosine Kinases; Reverse Transcriptase Polymerase Chain Reaction; Thiourea; Axl Receptor Tyrosine Kinase
PubMed: 25557174
DOI: 10.18632/oncotarget.3021 -
Oncotarget Oct 2017Amuvatinib (MP-470) is a multi-targeted kinase inhibitor with potent activity against c-Kit, synergistic with DNA-damaging agents. We evaluated amuvatinib in combination...
BACKGROUND
Amuvatinib (MP-470) is a multi-targeted kinase inhibitor with potent activity against c-Kit, synergistic with DNA-damaging agents. We evaluated amuvatinib in combination with platinum-etoposide (EP) chemotherapy by objective response rate, survival, and tolerability in platinum-refractory small cell lung cancer (SCLC) patients.
METHODS
This study used a Simon 2-stage design requiring ≥3 centrally confirmed responses in the first 21 subjects. Subjects received EP with 300 mg amuvatinib orally three times daily in cycles of 21 days. A three-day amuvatinib run-in period before EP occurred in Cycle 1. Subjects received the same EP chemotherapy regimen given prior to progression/relapse.
RESULTS
Among 23 subjects treated, we observed four PRs (17.4%) per RECIST 1.1, only two of which were centrally confirmed (8.7%, response duration 119, 151 days). Three subjects (13%) had confirmed stable disease. c-Kit H-score was ≥100 in two subjects whose respective durations of disease control were 151 and 256 days.
CONCLUSIONS
The addition of amuvatinib to EP chemotherapy in unselected, platinum-refractory SCLC did not meet the primary endpoint of ≥3 confirmed responses in stage 1. However, high c-Kit expression in two subjects with durable disease control suggests the potential for further study of amuvatinib in SCLC patients with high c-Kit expression.
PubMed: 29113403
DOI: 10.18632/oncotarget.19888 -
Nature Communications Sep 2020Immunotherapies revolutionized cancer treatment by harnessing the immune system to target cancer cells. However, most patients are resistant to immunotherapies and the...
Immunotherapies revolutionized cancer treatment by harnessing the immune system to target cancer cells. However, most patients are resistant to immunotherapies and the mechanisms underlying this resistant is still poorly understood. Here, we report that overexpression of BMP7, a member of the TGFB superfamily, represents a mechanism for resistance to anti-PD1 therapy in preclinical models and in patients with disease progression while on immunotherapies. BMP7 secreted by tumor cells acts on macrophages and CD4 T cells in the tumor microenvironment, inhibiting MAPK14 expression and impairing pro-inflammatory responses. Knockdown of BMP7 or its neutralization via follistatin in combination with anti-PD1 re-sensitizes resistant tumors to immunotherapies. Thus, we identify the BMP7 signaling pathway as a potential immunotherapeutic target in cancer.
Topics: Animals; Antibodies, Monoclonal, Humanized; Bone Morphogenetic Protein 7; CD4-Positive T-Lymphocytes; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Follistatin; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Immunotherapy; Mice; Mitogen-Activated Protein Kinase 14; Neoplasms; Programmed Cell Death 1 Receptor; RAW 264.7 Cells; Smad1 Protein; Transcriptome; Tumor Microenvironment
PubMed: 32973129
DOI: 10.1038/s41467-020-18617-z -
Oncogene Mar 2014Despite significant progress in the treatment of breast cancer, particularly through the use of targeted therapy, relapse and chemoresistance remain a major hindrance to...
Despite significant progress in the treatment of breast cancer, particularly through the use of targeted therapy, relapse and chemoresistance remain a major hindrance to the fight to minimize the burden of the disease. It is becoming increasingly clear that a rare subpopulation of cells known as cancer stem cells (CSC), able to be generated through epithelial-to-mesenchymal transition (EMT) and capable of tumor initiation and self-renewal, contributes to treatment resistance and metastases. This means that a more effective therapy should target both the chemoresistant CSCs and the proliferating epithelial cells that give rise to them to reverse EMT and to attenuate their conversion to CSCs. Here, we demonstrate a novel function of AXL in acting upstream to induce EMT in normal and immortalized human mammary epithelial cells in an apparent positive feedback loop mechanism and regulate breast CSC (BCSC) self-renewal and chemoresistance. Downregulation of AXL using MP470 (Amuvatinib) reversed EMT in mesenchymal normal human mammary epithelial cells and murine BCSCs attenuating self-renewal and restored chemosensitivity of the BCSCs. AXL expression was also found to be associated with the expression of stem cell genes, regulation of metastases genes, increased tumorigenicity and was important for BCSC invasion and migration. Inactivation of AXL also led to the downregulation of nuclear factor-κB pathway and reduced tumor formation in vivo. Taken together, our data suggest that targeted therapy against AXL, in combination with systemic therapies, has the potential to improve response to anticancer therapies and to reduce breast cancer recurrence and metastases.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Female; Humans; Mice; Mice, Transgenic; Molecular Targeted Therapy; NF-kappa B; Neoplasm Transplantation; Neoplastic Stem Cells; Piperazines; Proto-Oncogene Proteins; Pyrimidines; Receptor Protein-Tyrosine Kinases; Signal Transduction; Thiourea; Tumor Burden; Up-Regulation; Axl Receptor Tyrosine Kinase
PubMed: 23474758
DOI: 10.1038/onc.2013.57 -
Frontiers in Immunology 2022The efficacy of immunoradiotherapy consisting of radiation therapy and immune checkpoint blockade relies on effectively promoting the systemic antitumor immune...
The efficacy of immunoradiotherapy consisting of radiation therapy and immune checkpoint blockade relies on effectively promoting the systemic antitumor immune response's activation while simultaneously reducing local factors favoring immune suppression. We previously demonstrated that NBTXR3, a nanoparticle radioenhancer, significantly improved immune responses in a murine anti-PD1-resistant metastatic lung cancer model. We hypothesize that radioactivated-NBTXR3 addition to anti-PD1 and a second-generation anti-CTLA4 could improve treatment effectiveness. To test this hypothesis, we inoculated mice with 344SQR cells in the right and left legs to establish primary and secondary tumors. The primary tumors were intratumorally injected with NBTXR3 nanoparticles on day 7, followed by three fractions of 12 Gy radiation on days 8, 9, and 10. The secondary tumors received two fractions of 1Gy radiation on days 13 and 14. Multiple rounds of anti-PD1, anti-CTLA4 or nonfucosylated anti-CTLA4 were given to the mice. Immune profiling of the tumors revealed that the combination of NBTXR3 with immunoradiotherapy significantly upregulated the activities of a wide range of antitumor immune pathways and reduced the abundance of regulatory suppressor T cells. This combination effectively eradicated the primary and secondary tumors and increased animal survival to 75%. Remarkably, previously treated with NBTXR3-containing treatment, the survivor mice exhibited a long-lasting antitumor memory immune response. This data provides compelling evidence of the efficacy of NBTXR3 to synergize with the immunoradiotherapy approach when combined with an anti-PD1 and multiple checkpoints such as a second generation anti-CTLA4 and show the potential for clinical uses of antitumor immunomodulatory effects of NBTXR3.
Topics: Animals; Mice; Radioimmunotherapy; Programmed Cell Death 1 Receptor; Lung Neoplasms; Immunotherapy; Antineoplastic Agents
PubMed: 36405757
DOI: 10.3389/fimmu.2022.1022011 -
Journal of Hematology & Oncology Oct 2016
PubMed: 27737688
DOI: 10.1186/s13045-016-0335-5 -
Vaccines Aug 2022The pandemic of SARS-CoV-2 infections is a severe threat to human life and the world economic condition. Although vaccination has reduced the outspread, but still the...
The pandemic of SARS-CoV-2 infections is a severe threat to human life and the world economic condition. Although vaccination has reduced the outspread, but still the situation is not under control because of the instability of RNA sequence patterns of SARS-CoV-2, which requires effective drugs. Several studies have suggested that the SARS-CoV-2 infection causing hub differentially expressed genes (Hub-DEGs). However, we observed that there was not any common hub gene (Hub-DEGs) in our analyses. Therefore, it may be difficult to take a common treatment plan against SARS-CoV-2 infections globally. The goal of this study was to examine if more representative Hub-DEGs from published studies by means of hub of Hub-DEGs (hHub-DEGs) and associated potential candidate drugs. In this study, we reviewed 41 articles on transcriptomic data analysis of SARS-CoV-2 and found 370 unique hub genes or studied genes in total. Then, we selected 14 more representative Hub-DEGs (, , , , , , , , , , , , , ) as hHub-DEGs by their protein-protein interaction analysis. Their associated biological functional processes, transcriptional, and post-transcriptional regulatory factors. Then we detected hHub-DEGs guided top-ranked nine candidate drug agents (Digoxin, Avermectin, Simeprevir, Nelfinavir Mesylate, Proscillaridin, Linifanib, Withaferin, Amuvatinib, Atazanavir) by molecular docking and cross-validation for treatment of SARS-CoV-2 infections. Therefore, the findings of this study could be useful in formulating a common treatment plan against SARS-CoV-2 infections globally.
PubMed: 36016137
DOI: 10.3390/vaccines10081248