conventional chemotherapy
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2022 ◽  
Vol 14 (1) ◽  
Author(s):  
Garyfallia Pantelaiou-Prokaki ◽  
Iga Mieczkowska ◽  
Geske E. Schmidt ◽  
Sonja Fritzsche ◽  
Evangelos Prokakis ◽  
...  

Abstract Background Basal-like breast cancer (BLBC) is one of the most aggressive malignant diseases in women with an increased metastatic behavior and poor prognosis compared to other molecular subtypes of breast cancer. Resistance to chemotherapy is the main cause of treatment failure in BLBC. Therefore, novel therapeutic strategies counteracting the gain of aggressiveness underlying therapy resistance are urgently needed. The epithelial-to-mesenchymal transition (EMT) has been established as one central process stimulating cancer cell migratory capacity but also acquisition of chemotherapy-resistant properties. In this study, we aimed to uncover epigenetic factors involved in the EMT-transcriptional program occurring in BLBC cells surviving conventional chemotherapy. Results Using whole transcriptome data from a murine mammary carcinoma cell line (pG-2), we identified upregulation of Hdac4, 7 and 8 in tumor cells surviving conventional chemotherapy. Subsequent analyses of human BLBC patient datasets and cell lines established HDAC8 as the most promising factor sustaining tumor cell viability. ChIP-sequencing data analysis identified a pronounced loss of H3K27ac at regulatory regions of master transcription factors (TFs) of epithelial phenotype like Gata3, Elf5, Rora and Grhl2 upon chemotherapy. Interestingly, impairment of HDAC8 activity reverted epithelial-TFs levels. Furthermore, loss of HDAC8 activity sensitized tumor cells to chemotherapeutic treatments, even at low doses. Conclusion The current study reveals a previously unknown transcriptional repressive function of HDAC8 exerted on a panel of transcription factors involved in the maintenance of epithelial cell phenotype, thereby supporting BLBC cell survival to conventional chemotherapy. Our data establish HDAC8 as an attractive therapeutically targetable epigenetic factor to increase the efficiency of chemotherapeutics. Graphical abstract


2022 ◽  
Author(s):  
M.S Sudheesh ◽  
Sabitha M ◽  
K Pavithran

The field of cancer nanomedicine has been fueled by the expectation of mitigating the inefficiencies and life-threatening side effects of conventional chemotherapy. Nanomedicine proposes to utilize the unique nanoscale properties...


INDIAN DRUGS ◽  
2021 ◽  
Vol 58 (11) ◽  
pp. 7-17
Author(s):  
Goutam K. Jena ◽  
Chinam N. Patra ◽  

Skin carcinoma is a frequently occurring cancer caused due to ultra violet rays of the Sun. It starts from normal skin cells but later on transforms into cells which undergo uncontrolled mitosis. Skin cancer is not as deadly as other cancers and has no metastasis and is not life threatening. Conventional chemotherapy has in general failed to treat skin cancer due to non specific targeting, which is accompanied by several side effects. Novel therapeutic approach based on nanotechnology have emerged as the best alternative for skin cancer treatment. We presented current scenario of nano based particulate drug carrier approaches for effective therapy for skin carcinoma by reducing side effects. This approach also reduces frequency of administration and improves patient compliance. Nanotechnology has emerged as the best alternative for conventional therapy for the effective treatment of skin cancer. Nanoparticles can specifically target skin carcinoma and are able to sustain drug release and reduce side effects to a greater extent.


Haematologica ◽  
2021 ◽  
Author(s):  
Karen L. Bride ◽  
Hai Hu ◽  
Anastasia Tikhonova ◽  
Tori J. Fuller ◽  
Tiffaney L. Vincent ◽  
...  

Despite improvements in outcomes for children with B and T-cell acute lymphoblastic leukemia (B-ALL and T-ALL), patients with resistant or relapsed disease fare poorly. Previous studies have demonstrated the essential role of cyclin D3 in T-ALL disease initiation and progression and that targeting of the CDK4/6-cyclin D complex can suppress T-ALL proliferation, leading to efficient cell death in animal models. Studies in leukemia and other malignancies, suggest that schedule is important when combining CDK4/6 inhibitors (CDKis) with cytotoxic agents. Based on these observations, we broadened evaluation of two CDKis, palbociclib (PD-0332991, Pfizer) and ribociclib (LEE011, Novartis) in B and T-ALL as single agent and in combination with conventional cytotoxic chemotherapy, using different schedules in preclinical models. As monotherapy, CDKis caused cell cycle arrest with a significant decrease in S phase entry and were active in vivo across a broad number of patient-derived xenograft samples. Prolonged monotherapy induces resistance, for which we identified a potential novel mechanism using transcriptome profiling. Importantly, simultaneous but not sequential treatment of CDKis with conventional chemotherapy (dexamethasone, L-asparaginase and vincristine) led to improved efficacy compared to monotherapy in vivo. We provide novel evidence that combining CDKis and conventional chemotherapy can be safe and effective. These results led to the rational design of a clinical trial.


2021 ◽  
Vol 11 ◽  
Author(s):  
Elodie Jouberton ◽  
Sébastien Schmitt ◽  
Aurélie Maisonial-Besset ◽  
Emmanuel Chautard ◽  
Frédérique Penault-Llorca ◽  
...  

One of the current challenges in oncology is to develop imaging tools to early detect the response to conventional chemotherapy and adjust treatment strategies when necessary. Several studies evaluating PET imaging with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) as a predictive tool of therapeutic response highlighted its insufficient specificity and sensitivity. The [18F]FDG uptake reflects only tumor metabolic activity and not treatment-induced cell death, which seems to be relevant for therapeutic evaluation. Therefore, to evaluate this parameter in vivo, several cell death radiotracers have been developed in the last years. However, few of them have reached the clinical trials. This systematic review focuses on the use of [18F]ML-10 (2-(5-[18F]fluoropentyl)-2-methylmalonic acid) as radiotracer of apoptosis and especially as a measure of tumor response to treatment. A comprehensive literature review concerning the preclinical and clinical investigations conducted with [18F]ML-10 was performed. The abilities and applications of this radiotracer as well as its clinical relevance and limitations were discussed. Most studies highlighted a good ability of the radiotracer to target apoptotic cells. However, the increase in apoptosis during treatment did not correlate with the radiotracer tumoral uptake, even using more advanced image analysis (voxel-based analysis). [18F]ML-10 PET imaging does not meet current clinical expectations for early detection of the therapeutic response to conventional chemotherapy. This review has pointed out the challenges of applying various apoptosis imaging strategies in clinical trials, the current methodologies available for image analysis and the future of molecular imaging to assess this therapeutic response.


Author(s):  
Utku Donem Gundogdu ◽  
Funda Karabag Çoban

Objectives: Despite newly developed treatment modalities, colorectal cancer is still the leading cause of cancer deaths. In recent years, studies have been carried out to suggest that lipid metabolism may play a role in cancer development and metastasis. Methods: Lipid metabolism both in conventional chemotherapy. It has also been found that it plays a central role in resistance to targeted therapies. In our study, we planned to compare the atherogenic plasma index levels of patients diagnosed with colon cancer before chemotherapy and in the month of chemotherapy. Results and Conclusions: Evaluating the effect on the atherogenic plasma index after chemotherapy, we thought that lipid-regulating treatments would contribute to both cancer development and disease control.


Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 7-14
Author(s):  
Marlise R. Luskin

Abstract Unlike younger adults with acute lymphoblastic leukemia (ALL), older adults are rarely cured due to a combination of intrinsic disease resistance and treatment-related toxicities. Novel therapeutics such as inotuzumab ozogamicin, blinatumomab, venetoclax, and ABL kinase inhibitors have high activity in ALL and are well tolerated by older adults. Frontline treatment regimens for older adults using novel therapeutics with reduction or omission of conventional chemotherapy are being developed with early results demonstrating high remission rates and lower toxicity, but long-term efficacy and toxicity data are lacking. Collaboration between academic and pharmaceutical stakeholders is needed to develop clinical trials to define the optimal treatment regimens for older adults with ALL.


2021 ◽  
Vol 11 ◽  
Author(s):  
Shervin Taslimi ◽  
Karanbir Brar ◽  
Yosef Ellenbogen ◽  
Jiawen Deng ◽  
Winston Hou ◽  
...  

BackgroundBrain metastases (BM) from non-small-cell lung cancer (NSCLC) are frequent and carry significant morbidity, and current management options include varying local and systemic therapies. Here, we performed a systematic review and network meta-analysis to determine the ideal treatment regimen for NSCLC BMs with targetable EGFR-mutations/ALK-rearrangements.MethodsWe searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CENTRAL and references of key studies for randomized controlled trials (RCTs) published from inception until June 2020. Comparative RCTs including ≥10 patients were selected. We used a frequentist random-effects model for network meta-analysis (NMA) and assessed the certainty of evidence using the GRADE approach. Our primary outcome of interest was intracranial progression-free survival (iPFS).ResultsWe included 24 studies representing 19 trials with 1623 total patients. Targeted tyrosine kinase inhibitors (TKIs) significantly improved iPFS, with second-and third- generation TKIs showing the greatest benefit (HR=0.25, 95%CI 0.15-0.40). Overall PFS was also improved compared to conventional chemotherapy (HR=0.47, 95%CI 0.36-0.61). In EGFR-mutant patients, osimertinib showed the greatest benefit in iPFS (HR=0.32, 95%CI 0.15-0.69) compared to conventional chemotherapy, while gefitinib + chemotherapy showed the greatest overall PFS benefit (HR=0.26, 95%CI 0.10-0.70). All ALKi improved overall PFS compared to conventional chemotherapy, with alectinib having the greatest benefit (HR=0.13, 95%CI 0.07-0.24).ConclusionsIn patients with NSCLC BMs and EGFR/ALK mutations, targeted TKIs improve intracranial and overall PFS compared to conventional modalities such as chemotherapy, with greater efficacy seen using newer generations of TKIs. This data is important for treatment selection and patient counseling, and highlights areas for future RCT research.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=179060.


2021 ◽  
Vol 08 ◽  
Author(s):  
Klara Mladenić ◽  
Mirela Sedić

Background: Colorectal cancer (CRC) is a widespread tumour type amongst men and women. Despite the available screening tests, advanced stage CRC is the most frequent diagnosis. It is treated with cytotoxic chemotherapeutics 5-fluorouracil (5-FU), oxaliplatin (Ox) and irinotecan (CPT-11) that eventually lose their effectiveness as chemoresistance develops. Methods: In this review, the compilation and analysis of PUBMED-retrieved literature data was comprehensively presented and some novel and/or previously poorly described molecular features of CRC unresponsiveness to conventional chemotherapy drugs identified using bioinformatics approach. Complex interactions between previously reported biomarkers of resistance to 5-FU, Ox and CPT-11 were analysed by STRING and cytoHubba accompanied by KEGG pathway enrichment analysis using DAVID functional annotation tool. Results: The bioinformatics analysis has revealed that 5-FU affects ribosome biogenesis and functioning (translational activity) leading to colon cancer cells resistance to 5-FU. Unresponsiveness of CRC to Ox was associated with Rap1 signalling pathway, which opens the possibility of using RAP1A inhibitors as an adjuvant to oxaliplatin in CRC. Furthermore, stem cell markers c-Myc and CD44 as well as Akt kinase emerged as novel resistance biomarkers whose pharmacological targeting could elevate the therapeutic efficacy of irinotecan. Lastly, several pathways common to the resistance to all three drugs were revealed including miRNAs in cancer, proteoglycans in cancer, cellular senescence and the sphingolipid signalling pathway. Conclusion: This paper gives a comprehensive overview of resistance mechanisms to 5-FU, Ox and irinotecan in colon cancer and reveals several novel molecular players and associated mechanisms that could account for development of chemoresistance and whose targeting might enable design of novel combination strategies to overcome resistance to conventional treatment in CRC.


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