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Immune checkpoint blockade in cancer treatment: a double-edged sword cross-targeting the host as an "innocent bystander".

Targeted immune checkpoint blockade augments anti-tumor immunity and induces durable responses in patients with melanoma and other solid tumors. It also induces specific "immune-related adverse events" (irAEs). IrAEs mainly include gastrointestinal, dermatological, hepatic and endocrinological toxicities. Off-target effects that arise appear to account for much of the toxicity of the immune checkpoint blockade. These unique "innocent bystander" effects are likely a direct result of breaking immune tolerance upon immune check point blockade and require specific treatment guidelines that include

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… Everolimus | III | Efficacy | NCT01968109 | Solid Tumors | Anti-LAG-3 +/− Anti-PD-1 | I | Safety | NCT01592370 | Hematologic Malignancy | Nivolumab | I | Safety | NCT01721772 | Melanoma | Nivolumab vs . …

Reconciling uncertainty of costs and outcomes with the need for access to orphan medicinal products: a comparative study of managed entry agreements across seven European countries.

BackgroundNational payers across Europe have been increasingly looking into innovative reimbursement approaches - called managed entry agreements (MEAs) - to balance the need to provide rapid access to potentially beneficial orphan medicinal products (OMPs) with the requirements to circumscribe uncertainty, obtain best value for money or to ensure affordability. This study aimed to identify, describe and classify MEAs applied to OMPs by national payers and to analyse their practice in Europe.MethodsTo identify and describe MEAs, national health technology assessments and reimbursement decision

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… Only one is on-going (i.e. everolimus). …

The PI3K inhibitor buparlisib suppresses osteoclast formation and tumour cell growth in bone metastasis of lung cancer, as evidenced by multimodality molecular imaging.

Non‑small cell lung cancer (NSCLC) metastasis commonly occurs in bone, which often results in pathological fractures. Sustained phosphoinositide‑3‑kinase (PI3K) signalling promotes the growth of PI3K‑dependent NSCLC and elevates osteoclastogenic potential. The present study investigated the effects of a PI3K inhibitor on NSCLC growth in bone and osteoclast formation, and aimed to determine whether it could control symptoms associated with bone metastasis. A bone metastasis xenograft model was established by implanting NCI‑H460‑luc2 lung cancer cells, which contain a phosphatidylinositol‑​4,5‑b

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… Targeted therapy for non-small cell lung cancer: Current standards and the promise of the future Transl Lung Cancer Res 4 36 54 2015 25806345 10.3978/j.issn.2218-6751.2014.05.01 PMC4367711 18 La Monica S Galetti M Alfieri RR Cavazzoni A Ardizzoni A Tiseo M Capelletti M Goldoni M Tagliaferri S Mutti A Everolimus …

Muscle cramps and neuropathies in patients with allogeneic hematopoietic stem cell transplantation and graft-versus-host disease.

OBJECTIVE: Graft-versus-host disease (GVHD) is an immune-mediated multisystemic disorder and the leading cause of morbidity after allogeneic hematopoietic stem cell transplantation. Peripheral nervous system manifestations of GVHD are rare but often disabling. Whereas immune-mediated neuropathies are an established feature of GVHD, muscle cramps are not well characterized. METHODS: In a single-centre retrospective cohort we studied 27 patients (age 23 to 69 years) with GVHD (acute n = 6, chronic n = 21) who complained of symptoms suggestive of peripheral nervous system complications. Clinical

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… GVHD was treated with systemic or topic steroids (n = 23), mycophenolat mofetil (n = 13), tacrolimus (n = 8), cyclosporin (n = 3), everolimus (n = 3), or other immunosuppressants (n = 5). …

Mechanisms of resistance to antibody-drug conjugates in cancer therapy: molecular basis and therapeutic strategies.

Antibody-drug conjugates (ADCs) have emerged as a transformative class in oncology, integrating the target specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule payloads. By harnessing tumor-specific antigen recognition, ADCs enable the selective delivery of chemotherapeutic agents, thereby enhancing therapeutic efficacy while reducing systemic toxicity. Their clinical success across both hematologic malignancies and solid tumors underscores their potential to redefine targeted cancer therapy. However, the clinical durability of ADCs is increasingly undermined by

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… Encouragingly, mechanistic target of rapamycin (mTOR) inhibitors may help overcome ADC resistance by promoting lysosomal processing - a phenomenon observed with combinations of everolimus and T-DM1 [ 51 ] . …

Mass spectrometry-based metabolomics in health and medical science: a systematic review.

Metabolomics is the study of the investigation of small molecules derived from cellular and organism metabolism, which reflects the outcomes of the complex network of biochemical reactions in living systems. As the most recent member of the omics family, there has been notable progress in metabolomics in the last decade, mainly driven by the improvement in mass spectrometry (MS). MS-based metabolomic strategies in modern health and medical science studies provide innovative tools for novel diagnostic and prognostic approaches, as well as an augmented role in drug development, nutrition science

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… Rigo-Bonnin R. et al. , Therapeutic Drug Monitoring of Everolimus: Comparability of Concentrations Determined by 2 Immunoassays and a Liquid Chromatography Tandem Mass Spectrometry Method Ther. Drug Monit. 2017 39 2 102 108 10.1097/FTD.0000000000000376 28125504 Fan Y. Li Y. …

Randomized phase II study of valproic acid in combination with bevacizumab and oxaliplatin/fluoropyrimidine regimens in patients with RAS-mutated metastatic colorectal cancer: the REVOLUTION study protocol.

BackgroundDespite effective treatments, metastatic colorectal cancer (mCRC) prognosis is still poor, mostly in RAS-mutated tumors, thus suggesting the need for novel combinatorial therapies. Epigenetic alterations play an important role in initiation and progression of cancers, including CRC. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with chemotherapy in the treatment of solid tumors. Owing to its HDACi activity and its safe use for epileptic disorders, valproic acid (VPA) is a good candidate for anticancer therapy that we have largely explored preclinically tra

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… Neuro Oncol 2015 ; 17 : 862 – 867 . 25572329 10.1093/neuonc/nou350 PMC4483124 41 Strickler JH Starodub AN Jia J , et al Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors . …

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13.

Objective To determine the availability of data on overall survival and quality of life benefits of cancer drugs approved in Europe.Design Retrospective cohort study.Setting Publicly accessible regulatory and scientific reports on cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013.Main outcome measures Pivotal and postmarketing trials of cancer drugs according to their design features (randomisation, crossover, blinding), comparators, and endpoints. Availability and magnitude of benefit on overall survival or quality of life determined at time of approval and after marke

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… Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol 2014;25:2357-62. 10.1093/annonc/mdu456. pmid:25231953 . 8. Prasad V, Kim C, Burotto M, Vandross A. …

Panobinostat reduces hypoxia-induced cisplatin resistance of non-small cell lung carcinoma cells via HIF-1α destabilization.

BackgroundLung cancer is one of the most frequent cancer types and the leading cause of cancer death worldwide. Cisplatin is a widely used chemotherapeutic for non-small cell lung carcinoma (NSCLC), however, its positive effects are diminished under hypoxia. We wanted to determine if co-treatment with cisplatin and histone deacetalyse (HDAC) inhibitor panobinostat can reduce hypoxia-induced cisplatin resistance in NSCLC cells, and to elucidate mechanism involved.MethodsExpression status of different HDACS was determined in two cell lines and in tumor tissue from 20 patients. Cells were treated

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… The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin lymphoma cell lines. Blood. 2012;119:4017–4025. doi: 10.1182/blood-2011-01-331421. 24. Wang H, Cao Q, Dudek AZ. …

Targeting the AMP-Activated Protein Kinase for Cancer Prevention and Therapy.

Despite the advances in biomedical research and clinical applications, cancer remains a leading cause of death worldwide. Given the limitations of conventional chemotherapeutics, including serious toxicities and reduced quality of life for patients, the development of safe and efficacious alternatives with known mechanism of action is much needed. Prevention of cancer through dietary intervention may hold promise and has been investigated extensively in the recent years. AMP-activated protein kinase (AMPK) is an energy sensor that plays a key role in the regulation of protein and lipid metabol

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… Oncogene ( 2013 ) 32 : 2682 – 9 10.1038/onc.2012.279 22751115 PMC3465498 44 Liu H Scholz C Zang C Schefe JH Habbel P Regierer AC Metformin and the mTOR inhibitor everolimus (RAD001) sensitize breast cancer cells to the cytotoxic effect of chemotherapeutic drugs in vitro . …

Potential role of immunotherapy and targeted therapy in the treatment of cancer: A contemporary nursing practice.

Immunotherapy and targeted therapy have emerged as promising therapeutic options for cancer patients. Immunotherapies induce a host immune response that mediates long-lived tumor destruction, while targeted therapies suppress molecular mechanisms that are important for tumor maintenance and growth. In addition, cytotoxic agents and targeted therapies regulate immune responses, which increases the chances that these therapeutic approaches may be efficiently combined with immunotherapy to ameliorate clinical outcomes. Various studies have suggested that combinations of therapies that target diff

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… Isocitrate dehydrogenase-2 (IDH2) inhibitor Enasidenib | Relapsed or refractory AML with an IDH2 mutation | Diarrhea, decreased appetite, vomiting, nausea | [ 87 , 88 ] Mammalian target of rapamycin (mTOR) inhibitor Temsirolimus | aRCC | Anorexia, edema, nausea, mucositis, asthenia, rash | [ 89 , 90 ] Everolimus … Combined everolimus and endocrine therapy in advanced HR-positive, HER2-negative Chinese breast cancer patients: a retrospective study. Ann. Transl. Med. 2021;9 doi: 10.21037/ATM-21-3840. 1334–1334. 92. Antolin A.A., Ameratunga M., Banerji U., Clarke P.A., Workman P., Al-Lazikani B. …

DLBCL 1L-What to Expect beyond R-CHOP?

The R-CHOP immunochemotherapy protocol has been the first-line (1L) standard of care (SOC) for diffuse large B-cell lymphoma (DLBCL) patients for decades and is curative in approximately two-thirds of patients. Numerous randomized phase III trials, most of them in an "R-CHOP ± X" design, failed to further improve outcomes. This was mainly due to increased toxicity, the large proportion of patients not in need of more than R-CHOP, and the extensive molecular heterogeneity of the disease, raising the bar for "one-size-fits-all" concepts. Recently, an R-CHP regimen extended by the anti-CD79b anti

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… Equally discouraging results were obtained regarding small compounds such as Lenalidomide in the “REMARC” trial or the mTOR inhibitor Everolimus, where no differences in OS were seen [ 87 , 120 , 121 , 122 ]. …

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma.

Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multistep nature of the process offers multiple regulation points prone to be deregulated and cause different human diseases but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within the tumo

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… When looking at mTOR inhibitors as autophagy inducers in CCA, preclinical evaluation of everolimus (RAD001) showed a reduction in cell proliferation with increased apoptosis and decreased invasion [ 132 ], although no reference to autophagy is clearly shown in spite of the association of PI3K/AKT/mTOR … Among mTOR inhibitors, Everolimus is administered as monotherapy ( NCT01525719 —unknown and NCT00973713 —unknown), in combination with gemcitabine and oxaliplatin ( NCT02836847 —recruiting) and with FOLFIRINOX ( NCT03768375 —recruiting), and sorafenib is administered alone ( NCT00238212 —completed), …

Epimutational profile of hematologic malignancies as attractive target for new epigenetic therapies.

In recent years, recurrent somatic mutations in epigenetic regulators have been identified in patients with hematological malignancies. Furthermore, chromosomal translocations in which the fusion protein partners are themselves epigenetic regulators or where epigenetic regulators are recruited/targeted by oncogenic fusion proteins have also been described. Evidence has accumulated showing that "epigenetic drugs" are likely to provide clinical benefits in several hematological malignancies, granting their approval for the treatment of myelodysplastic syndromes and cutaneous T-cell lymphomas. A

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… Completed II | | HL | NCT00866333 | Ongoing Givinostat | I/II | | HL | NCT00496431 | Terminated II | | CLL | NCT00792831 | Terminated ITF2357 | II | | MM | NCT00792506 | Terminated Mocetinostat | I/II | | DLBCL, FL | NCT02282358 | Recruiting II | | HL | NCT00358982 | Terminated Panobinostat | I | Everolimus … | HL, MM, NHL | NCT00962507 | Completed I | | CTCL | NCT00412997 | Completed I | | HL, NHL | NCT01032148 | Recruiting I | | AML | NCT01242774 | Completed I | | HL | NCT00742027 | Completed I | | MM | NCT00532389 | Completed I/II | Everolimus | HL, MM, NHL | NCT00918333 | Ongoing I/II | | AHM | …

Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation.

Pancreatic neuroendocrine tumors (PNETs) are characterized by dysregulated signaling pathways that are crucial for tumor formation and progression. The efficacy of traditional therapies is limited, particularly in the treatment of PNETs at an advanced stage. Epigenetic alterations profoundly impact the activity of signaling pathways in cancer development, offering potential opportunities for drug development. There is currently a lack of extensive research on epigenetic regulation in PNETs. To fill this gap, we first summarize major signaling events that are involved in PNET development. Then,

Therapeutic Advances in Oncology.

Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant therapeutic modalities in oncology. Antibody-drug conjugates, bispecific antibodies, peptides, cell, and gene-therapies are emerging to address the unmet patient need. Advancement in the discovery and development platforms, identification of novel targets, and emergence of new technologies have greatly expanded the treatment options for patients. Here, we provide an overview of various therapeutic modalities and the current treatment

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… The mTOR inhibitor Afinitor (everolimus) was approved in 2012 for metastatic HR-positive/HER-negative breast cancer in combination with an AI exemestane in patients whose cancer had progressed despite treatment with letrozole or anastrozole [ 44 ]. …

Metabolic Cooperation and Competition in the Tumor Microenvironment: Implications for Therapy.

The tumor microenvironment (TME) is an ensemble of non-tumor cells comprising fibroblasts, cells of the immune system, and endothelial cells, besides various soluble secretory factors from all cellular components (including tumor cells). The TME forms a pro-tumorigenic cocoon around the tumor cells where reprogramming of the metabolism occurs in tumor and non-tumor cells that underlies the nature of interactions as well as competitions ensuring steady supply of nutrients and anapleoretic molecules for the tumor cells that fuels its growth even under hypoxic conditions. This metabolic reprogram

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… Further, several rapalogs such as temsirolimus and everolimus have been shown to exert anticancer effects (Table 1 ) although upregulation of PI3K/Akt pathway following treatment with rapalogs remains a matter of concern necessitating the deployment of combination strategies to inhibit this response …

Transcriptome Meta-Analysis of Triple-Negative Breast Cancer Response to Neoadjuvant Chemotherapy.

Triple-negative breast cancer (TNBC) is a heterogeneous disease with varying responses to neoadjuvant chemotherapy (NAC). The identification of biomarkers to predict NAC response and inform personalized treatment strategies is essential. In this study, we conducted large-scale gene expression meta-analyses to identify genes associated with NAC response and survival outcomes. The results showed that immune, cell cycle/mitotic, and RNA splicing-related pathways were significantly associated with favorable clinical outcomes. Furthermore, we integrated and divided the gene association results from

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… A Randomized Phase II Neoadjuvant Study of Cisplatin, Paclitaxel With or Without Everolimus in Patients with Stage II/III Triple-Negative Breast Cancer (TNBC): Responses and Long-term Outcome Correlated with Increased Frequency of DNA Damage Response Gene Mutations, TNBC Subtype, AR Status, and Ki67 …

Could Local Application of Hypoxia Inducible Factor 1-α Enhancer Deferoxamine Be Promising for Preventing of Medication-Related Osteonecrosis of the Jaw?

This experimental study investigates the prophylactic effect of deferoxamine (DFO) on medication-related osteonecrosis of the jaw (MRONJ). Thirty-six female Sprague Dawley rats received zoledronic acid (ZA) for eight weeks to create an osteonecrosis model. DFO was locally applied into the extraction sockets with gelatin sponge (GS) carriers to prevent MRONJ. The specimens were histopathologically and histomorphometrically evaluated. Hypoxia-inducible factor 1-alpha (HIF-1α) protein levels in the extraction sockets were quantified. New bone formation rate differed significantly between groups (

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… AAOMS recently recognized other medications causing MRONJ, including fusion proteins (aflibercept), mammalian target of rapamycin (mTOR) inhibitors (everolimus), selective estrogen receptor modulators (raloxifene), immunosuppressants (methotrexate and corticosteroids), and antiresorptives prescribed …

Treatment of acute kidney injury in cancer patients.

Acute kidney injury (AKI), either of pre-renal, renal or post-renal origin, is an important complication in cancer patients, resulting in worse prognosis, withdrawal from effective oncological treatments, longer hospitalizations and increased costs. The aim of this article is to provide a literature review of general and cause-specific treatment strategies for AKI, providing a helpful guide for clinical practice. We propose to classify AKI as patient-related, cancer-related and treatment-related in order to optimize therapeutic interventions. In the setting of patient-related causes, proper as

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… carfilzomib) | Underlying cause is not known; may respond to complement inhibition or plasmapheresis Pentostatine | Dose-dependent toxicity EGFR inhibitor (e.g. cetuximab, gefitinib, erlotinib) | Renal TMA Calcineurin inhibitor (e.g. ciclosporin, tacrolimus) | Renal TMA mTOR inibitors (e.g. sirolimus, everolimus …