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Expert Opinion on Drug Discovery Sep 2019: The treatment of lung disease faces significant challenges due to intrinsic antibiotic resistance. New drugs are needed to cure this incurable disease. The key... (Review)
Review
: The treatment of lung disease faces significant challenges due to intrinsic antibiotic resistance. New drugs are needed to cure this incurable disease. The key anti-tubercular rifamycin, rifampicin, suffers from low potency against and is not used clinically. Recently, another member of the rifamycin class, rifabutin, was shown to be active against the opportunistic pathogen. : In this review, the authors discuss the rifamycins as a reemerging drug class for treating infections. The authors focus on the differential potency of rifampicin and rifabutin against in the context of intrinsic antibiotic resistance and bacterial uptake and metabolism. Reports of rifamycin-based drug synergies and rifamycin potentiation by host-directed therapy are evaluated. : While repurposing rifabutin for lung disease may provide some immediate relief, the repositioning (chemical optimization) of rifamycins offers long-term potential for improving clinical outcomes. Repositioning will require a multifaceted approach involving renewed screening of rifamycin libraries, medicinal chemistry to improve 'bacterial cell pharmacokinetics', better models of bacterial pathophysiology and infection, and harnessing of drug synergies and host-directed therapy towards the development of a better drug regimen.
Topics: Animals; Anti-Bacterial Agents; Drug Repositioning; Humans; Lung Diseases; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Rifabutin; Rifampin; Rifamycins
PubMed: 31195849
DOI: 10.1080/17460441.2019.1629414 -
Lung Cancer (Amsterdam, Netherlands) May 2024Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic... (Review)
Review
Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). In clinical trials, lorlatinib has shown durable efficacy and a manageable safety profile in treatment-naive patients and in those who have experienced progression while receiving first- and/or second-generation ALK TKIs. Lorlatinib has a distinct safety profile from other ALK TKIs, including hyperlipidemia and central nervous system effects. Clinical trial data showed that most adverse events (AEs) can be managed effectively or reversed with dose modifications (such as dose interruptions or reductions) or with concomitant medications without compromising clinical efficacy or quality of life for patients. A pragmatic approach to managing AEs related to lorlatinib is required. We present patient-focused recommendations for the evaluation and management of select AEs associated with lorlatinib developed by clinicians and nurses with extensive lorlatinib expertise in routine clinical practice. The recommendations follow the general framework of "prepare, monitor, manage, reassess" to streamline AE management and assist in practical, actionable, and personalized patient care.
Topics: Humans; Lactams; Aminopyridines; Carcinoma, Non-Small-Cell Lung; Pyrazoles; Lung Neoplasms; Protein Kinase Inhibitors; Lactams, Macrocyclic; Anaplastic Lymphoma Kinase; Drug-Related Side Effects and Adverse Reactions; Antineoplastic Agents; Disease Management
PubMed: 38554546
DOI: 10.1016/j.lungcan.2024.107535 -
Journal of Thoracic Oncology : Official... Nov 2023Circulating tumor DNA (ctDNA) has been used as a biomarker for prognostication and response to treatment. Here, we evaluate ctDNA as a potential biomarker for response...
INTRODUCTION
Circulating tumor DNA (ctDNA) has been used as a biomarker for prognostication and response to treatment. Here, we evaluate ctDNA as a potential biomarker for response to lorlatinib, a third-generation ALK tyrosine kinase inhibitor in patients with treatment-naive, advanced, ALK-positive NSCLC in the ongoing phase 3 CROWN study (NCT03052608).
METHODS
Molecular responses were calculated using mean variant allele frequency (VAF), longitudinal mean change in VAF (dVAF), and ratio to baseline. Efficacy assessments (progression-free survival [PFS] and objective response rate) were paired with individual patient ctDNA and analyzed for association.
RESULTS
Compared with baseline, mean VAF at week 4 was decreased in both treatment arms. Considering all detected somatic variants, a reduction in dVAF (≤0) was associated with a longer PFS in the lorlatinib arm. The hazard ratio (HR) for a dVAF less than or equal to 0 versus more than 0 was 0.50 (95% confidence interval [CI]: 0.23-1.12) in the lorlatinib arm. A similar association was not observed for crizotinib (HR = 1.00, 95% CI: 0.49-2.03). Comparing molecular responders with nonresponders, patients treated with lorlatinib who had a molecular response had longer PFS (HR = 0.37, 95% CI: 0.16-0.85); patients treated with crizotinib who had a molecular response had similar PFS as those without a molecular response (HR = 1.48, 95% CI: 0.67-3.30).
CONCLUSIONS
In patients with treatment-naive, advanced, ALK-positive NSCLC, early ctDNA dynamics predicted better outcome with lorlatinib but not with crizotinib. These results suggest that ctDNA may be used to monitor and potentially predict efficacy of lorlatinib treatment.
Topics: Humans; Crizotinib; Lung Neoplasms; Circulating Tumor DNA; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Lactams, Macrocyclic; Protein Kinase Inhibitors; Biomarkers
PubMed: 37295609
DOI: 10.1016/j.jtho.2023.05.021 -
Nature Immunology Aug 2021T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8 T cells acquire a distinct epigenetic state,...
T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8 T cells acquire a distinct epigenetic state, but it is not known whether that chromatin landscape is fixed or plastic following the resolution of a chronic infection. Here we show that the epigenetic state of exhaustion is largely irreversible, even after curative therapy. Analysis of chromatin accessibility in HCV- and HIV-specific responses identifies a core epigenetic program of exhaustion in CD8 T cells, which undergoes only limited remodeling before and after resolution of infection. Moreover, canonical features of exhaustion, including super-enhancers near the genes TOX and HIF1A, remain 'epigenetically scarred.' T cell exhaustion is therefore a conserved epigenetic state that becomes fixed and persists independent of chronic antigen stimulation and inflammation. Therapeutic efforts to reverse T cell exhaustion may require new approaches that increase the epigenetic plasticity of exhausted T cells.
Topics: 2-Naphthylamine; Anilides; Antigens, Viral; Antiviral Agents; CD8-Positive T-Lymphocytes; Chromatin; Cyclopropanes; Epigenesis, Genetic; Hepacivirus; Hepatitis C, Chronic; High Mobility Group Proteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunologic Memory; Lactams, Macrocyclic; Proline; Ribavirin; Ritonavir; Sulfonamides; Uracil; Valine
PubMed: 34312547
DOI: 10.1038/s41590-021-00979-1 -
PloS One 2022Mycobacterium tuberculosis strains with phenotypically susceptible rpoB mutations (rifampicin discordant) have emerged following implementation of rapid molecular drug...
INTRODUCTION
Mycobacterium tuberculosis strains with phenotypically susceptible rpoB mutations (rifampicin discordant) have emerged following implementation of rapid molecular drug resistance testing for tuberculosis. Whilst rifampicin resistance is known to be associated with resistance to other rifamycins (rifapentine and rifabutin) as well as isoniazid and pyrazinamide, rifampicin discordant strains have shown high rates of susceptibility to isoniazid and rifabutin. However, pyrazinamide susceptibly testing results have not been reported.
MATERIALS AND METHODS
We evaluated pyrazinamide resistance in 80 rifampicin discordant and 25 rifampicin and isoniazid susceptible isolates from KwaZulu-Natal in South Africa using Mycobacteria Growth Indicator Tube method and sequencing of the pncA. We also compared susceptibility of pyrazinamide with that of isoniazid.
RESULTS
Pyrazinamide resistance was found in 6/80 (7.5%) rifampicin discordant isolates. All pyrazinamide resistant isolates were also resistant to isoniazid and pyrazinamide resistance was found to be associated with isoniazid resistance. No pyrazinamide resistance was found among the isoniazid susceptible isolates.
CONCLUSION
Given the low prevalence of pyrazinamide resistance in rifampicin discordant TB, this anti-TB drug still has a significant role in the treatment of these patients. Performing pyrazinamide susceptibility testing remains a challenge, our findings show that isoniazid susceptible isolates are unlikely to be resistant to pyrazinamide among the discordant TB isolates.
Topics: Antitubercular Agents; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Pyrazinamide; Rifabutin; Rifampin; South Africa; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 36129921
DOI: 10.1371/journal.pone.0274688 -
World Journal of Gastroenterology Jan 2023Due to increasing resistance rates of () to different antibiotics, failures in eradication therapies are becoming more frequent. Even though eradication criteria and...
BACKGROUND
Due to increasing resistance rates of () to different antibiotics, failures in eradication therapies are becoming more frequent. Even though eradication criteria and treatment algorithms for first-line and second-line therapy against infection are well-established, there is no clear recommendation for third-line and rescue therapy in refractory infection.
AIM
To perform a systematic review evaluating the efficacy and safety of rescue therapies against refractory infection.
METHODS
A systematic search of available rescue treatments for refractory infection was conducted on the National Library of Medicine's PubMed search platform based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized or non-randomized clinical trials and observational studies evaluating the effectiveness of infection rescue therapies were included.
RESULTS
Twenty-eight studies were included in the analysis of mean eradication rates as rescue therapy, and 21 of these were selected for analysis of mean eradication rate as third-line treatment. For rifabutin-, sitafloxacin-, levofloxacin-, or metronidazole-based triple-therapy as third-line treatment, mean eradication rates of 81.6% and 84.4%, 79.4% and 81.5%, 55.7% and 60.6%, and 62.0% and 63.0% were found in intention-to-treat (ITT) and per-protocol (PP) analysis, respectively. For third-line quadruple therapy, mean eradication rates of 69.2% and 72.1% were found for bismuth quadruple therapy (BQT), 88.9% and 90.9% for bismuth quadruple therapy, three-in-one, Pylera (BQT-Pylera), and 61.3% and 64.2% for non-BQT) in ITT and PP analysis, respectively. For rifabutin-, sitafloxacin-, levofloxacin-, or metronidazole-based triple therapy as rescue therapy, mean eradication rates of 75.4% and 78.8%, 79.4 and 81.5%, 55.7% and 60.6%, and 62.0% and 63.0% were found in ITT and PP analysis, respectively. For quadruple therapy as rescue treatment, mean eradication rates of 76.7% and 79.2% for BQT, 84.9% and 87.8% for BQT-Pylera, and 61.3% and 64.2% for non-BQT were found in ITT and PP analysis, respectively. For susceptibility-guided therapy, mean eradication rates as third-line and rescue treatment were 75.0% in ITT and 79.2% in PP analysis.
CONCLUSION
We recommend sitafloxacin-based triple therapy containing vonoprazan in regions with low macrolide resistance profile. In regions with known resistance to macrolides or unavailability of bismuth, rifabutin-based triple therapy is recommended.
Topics: Humans; Helicobacter Infections; Anti-Bacterial Agents; Metronidazole; Helicobacter pylori; Bismuth; Levofloxacin; Proton Pump Inhibitors; Drug Therapy, Combination; Macrolides; Drug Resistance, Bacterial; Tetracycline; Rifabutin
PubMed: 36687120
DOI: 10.3748/wjg.v29.i2.390 -
BMC Microbiology Jul 2022Recently, Mycobacterium avium complex (MAC) infections have been increasing, especially in immunocompromised and older adults. The rapid increase has triggered a global...
BACKGROUND
Recently, Mycobacterium avium complex (MAC) infections have been increasing, especially in immunocompromised and older adults. The rapid increase has triggered a global health concern due to limited therapeutic strategies and adverse effects caused by long-term medication. To provide more evidence for the treatment of MAC, we studied the in vitro inhibitory activities of 17 antimicrobial agents against clinical MAC isolates.
RESULTS
A total of 111 clinical MAC isolates were enrolled in the study and they were identified as M. intracellulare, M. avium, M. marseillense, M. colombiense, M. yongonense, and two isolates could not be identified at the species level. MAC strains had relatively low (0-21.6%) resistance to clarithromycin, amikacin, bedaquiline, rifabutin, streptomycin, and clofazimine, and the resistant rates to isoniazid, rifampin, linezolid, doxycycline, and ethionamide were very high (72.1-100%). In addition, M. avium had a significantly higher resistance rate than that of M. intracellulare for ethambutol (92.3% vs 40.7%, P < 0.001), amikacin (15.4% vs 1.2%, P = 0.049), and cycloserine (69.2% vs 25.9%, P = 0.004).
CONCLUSIONS
Our results supported the current usage of macrolides, rifabutin, and aminoglycosides in the regimens for MAC infection, and also demonstrated the low resistance rate against new drugs, such as clofazimine, tedizolid, and bedaquiline, suggesting the possible implementation of these drugs in MAC treatment.
Topics: Aged; Amikacin; Anti-Bacterial Agents; Anti-Infective Agents; Clarithromycin; Clofazimine; Humans; Microbial Sensitivity Tests; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Rifabutin
PubMed: 35804298
DOI: 10.1186/s12866-022-02582-2 -
Cancer Research Communications Dec 2023Survival rates among patients with high-risk neuroblastoma remain low and novel therapies for recurrent neuroblastomas are required. ALK is commonly mutated in primary...
UNLABELLED
Survival rates among patients with high-risk neuroblastoma remain low and novel therapies for recurrent neuroblastomas are required. ALK is commonly mutated in primary and relapsed neuroblastoma tumors and ALK tyrosine kinase inhibitors (TKI) are promising treatments for ALK-driven neuroblastoma; however, innate or adaptive resistance to single-agent ALK-TKIs remain a clinical challenge. Recently, SHP2 inhibitors have been shown to overcome ALK-TKI resistance in lung tumors harboring ALK rearrangements. Here, we have assessed the efficacy of the SHP2 inhibitor TNO155 alone and in combination with the ALK-TKIs crizotinib, ceritinib, or lorlatinib for the treatment of ALK-driven neuroblastoma using in vitro and in vivo models. In comparison to wild-type, ALK-mutant neuroblastoma cell lines were more sensitive to SHP2 inhibition with TNO155. Moreover, treatment with TNO155 and ALK-TKIs synergistically reduced cell growth and promoted inactivation of ALK and MAPK signaling in ALK-mutant neuroblastoma cells. ALK-mutant cells engrafted into larval zebrafish and treated with single agents or dual SHP2/ALK inhibitors showed reduced growth and invasion. In murine ALK-mutant xenografts, tumor growth was likewise reduced or delayed, and survival was prolonged upon combinatorial treatment of TNO155 and lorlatinib. Finally, we show that lorlatinib-resistant ALK-F1174L neuroblastoma cells harbor additional RAS-MAPK pathway alterations and can be resensitized to lorlatinib when combined with TNO155 in vitro and in vivo. Our results report the first evaluation of TNO155 in neuroblastoma and suggest that combinatorial inhibition of ALK and SHP2 could be a novel approach to treating ALK-driven neuroblastoma, potentially including the increasingly common tumors that have developed resistance to ALK-TKIs.
SIGNIFICANCE
These findings highlight the translatability between zebrafish and murine models, provide evidence of aberrant RAS-MAPK signaling as an adaptive mechanism of resistance to lorlatinib, and demonstrate the clinical potential for SHP2/ALK inhibitor combinations for the treatment of ALK-mutant neuroblastoma, including those with acquired tolerance or potentially resistance to ALK-TKIs.
Topics: Humans; Mice; Animals; Zebrafish; Anaplastic Lymphoma Kinase; Drug Resistance, Neoplasm; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Lactams, Macrocyclic; Neuroblastoma
PubMed: 38032104
DOI: 10.1158/2767-9764.CRC-23-0234 -
Cancer Chemotherapy and Pharmacology Apr 2022Platinum-containing therapy is standard treatment for relapsed Diffuse Large B-Cell Lymphoma (DLBCL). However, the efficacy of treatment is limited by drug resistance...
PURPOSE
Platinum-containing therapy is standard treatment for relapsed Diffuse Large B-Cell Lymphoma (DLBCL). However, the efficacy of treatment is limited by drug resistance leading to relapse. Cisplatin resistance has been linked to impairments of the DNA damage response, and several DNA repair proteins have been identified as clients of the molecular chaperone Hsp90. Here, we investigated the combinatory treatment of cisplatin and the Hsp90 inhibitor, 17AAG, in DLBCL cells to evaluate if inhibition of Hsp90 could sensitize DLBCL cells to cisplatin treatment.
METHODS
Cell viability was assessed for cisplatin and 17AAG as monotherapies and for 25 different combinations in 7 DLBCL cell lines, where the Bliss Independence Model and the Combination Index were applied to assess their interaction. Induction of apoptosis and DNA damage response were evaluated by measuring Annexin V and γH2AX levels after 48 h of exposure.
RESULTS
17AAG synergized with cisplatin in DLBCL cells as detected in both interaction assessment models, resulting in a lower viability after 48 h for the combination-treated cells compared to both vehicle and single drug-treated cells. The combination also induced a stronger apoptotic response and an increase in DNA damage in 17AAG, cisplatin- and combination-treated cells compared to vehicle-treated cells, with the effect of the combination generally being higher than compared to both single drugs.
CONCLUSION
This study demonstrates that 17AAG sensitizes DLBCL cells to cisplatin treatment. This effect is correlated with increased apoptotic and DNA damage response, potentially mediated by downregulation of Hsp90 clients in DNA repair pathways. Thus, cisplatin resistance could plausibly be overcome by combining the treatment with an Hsp90 inhibiting drug.
Topics: Antineoplastic Agents; Apoptosis; Benzoquinones; Cell Line, Tumor; Cisplatin; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Lymphoma, Large B-Cell, Diffuse; Neoplasm Recurrence, Local
PubMed: 35190872
DOI: 10.1007/s00280-022-04407-5 -
Biomolecules Feb 2023Autoimmune disorders and some types of blood cancer originate when B lymphocytes malfunction. In particular, when B cells produce antibodies recognizing the body's...
Autoimmune disorders and some types of blood cancer originate when B lymphocytes malfunction. In particular, when B cells produce antibodies recognizing the body's proteins, it leads to various autoimmune disorders. Additionally, when B cells of various developmental stages transform into cancer cells, it results in blood cancers, including multiple myeloma, lymphoma, and leukemia. Thus, new methods of targeting B cells are required for various patient groups. Here, we used protein kinase inhibitors alectinib, brigatinib, ceritinib, crizotinib, entrectinib, and lorlatinib previously approved as drugs treating anaplastic lymphoma kinase (ALK)-positive lung cancer cells. We hypothesized that the same inhibitors will efficiently target leukocyte tyrosine kinase (LTK)-positive, actively protein-secreting mature B lymphocytes, including plasma cells. We isolated CD19-positive human B cells from the blood of healthy donors and used two alternative methods to stimulate cell maturation toward plasma cells. Using cell proliferation and flow cytometry assays, we found that ceritinib and entrectinib eliminate plasma cells from B cell populations. Alectinib, brigatinib, and crizotinib also inhibited B cell proliferation, while lorlatinib had no or limited effect on B cells. More generally, we concluded that several drugs previously developed to treat ALK-positive malignant cells can be also used to treat LTK-positive B cells.
Topics: Humans; Crizotinib; Carcinoma, Non-Small-Cell Lung; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Anaplastic Lymphoma Kinase; Lung Neoplasms; Receptor Protein-Tyrosine Kinases; Protein Kinase Inhibitors; Lactams, Macrocyclic; B-Lymphocytes
PubMed: 36979373
DOI: 10.3390/biom13030438