Publications by authors named "M M Cameron"

1,095 Publications

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Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway.

J Transl Med 2022 05 14;20(1):225. Epub 2022 May 14.

Section for Cancergenomics, Department of Pathology, Stavanger University Hospital, Stavanger, Norway.

Background: Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients.

Methods: In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient's tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like 'admissible' monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system.

Discussion: Precision oncology means to stratify treatment based on specific patient characteristics and the molecular profile of the tumor. Use of targeted drugs is currently restricted to specific biomarker-defined subgroups of patients according to their market authorization. However, other cancer patients might also benefit of treatment with these drugs if the same biomarker is present. The emerging technologies in molecular diagnostics are now being implemented in Norway and it is publicly reimbursed, thus more cancer patients will have a more comprehensive genomic profiling of their tumour. Patients with actionable genomic alterations in their tumour may have the possibility to try precision cancer drugs through IMPRESS-Norway, if standard treatment is no longer an option, and the drugs are available in the study. This might benefit some patients. In addition, it is a good example of a public-private collaboration to establish a national infrastructure for precision oncology. Trial registrations EudraCT: 2020-004414-35, registered 02/19/2021; ClinicalTrial.gov: NCT04817956, registered 03/26/2021.
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http://dx.doi.org/10.1186/s12967-022-03432-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9107632PMC
May 2022

A pilot study to troubleshoot quality control metrics when assessing circulating miRNA expression data reproducibility across study sites.

Cancer Biomark 2022 ;33(4):467-478

Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Background: Given the growing interest in using microRNAs (miRNAs) as biomarkers of early disease, establishment of robust protocols and platforms for miRNA quantification in biological fluids is critical.

Objective: The goal of this multi-center pilot study was to evaluate the reproducibility of NanoString nCounter™ technology when analyzing the abundance of miRNAs in plasma and cystic fluid from patients with pancreatic lesions.

Methods: Using sample triplicates analyzed across three study sites, we assessed potential sources of variability (RNA isolation, sample processing/ligation, hybridization, and lot-to-lot variability) that may contribute to suboptimal reproducibility of miRNA abundance when using nCounter™, and evaluated expression of positive and negative controls, housekeeping genes, spike-in genes, and miRNAs.

Results: Positive controls showed a high correlation across samples from each site (median correlation coefficient, r> 0.9). Most negative control probes had expression levels below background. Housekeeping and spike-in genes each showed a similar distribution of expression and comparable pairwise correlation coefficients of replicate samples across sites. A total of 804 miRNAs showed a similar distribution of pairwise correlation coefficients between replicate samples (p= 0.93). After normalization and selecting miRNAs with expression levels above zero in 80% of samples, 55 miRNAs were identified; heatmap and principal component analysis revealed similar expression patterns and clustering in replicate samples.

Conclusions: Findings from this pilot investigation suggest the nCounter platform can yield reproducible results across study sites. This study underscores the importance of implementing quality control procedures when designing multi-center evaluations of miRNA abundance.
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http://dx.doi.org/10.3233/CBM-210255DOI Listing
May 2022

Morphing Natural Product Platensimycin via Heck, Sonogashira, and One-Pot Sonogashira/Cycloaddition Reactions to Produce Antibiotics with In Vivo Activity.

Antibiotics (Basel) 2022 Mar 23;11(4). Epub 2022 Mar 23.

Xiangya International Academy of Translational Medicine, Central South University, Changsha 410013, China.

Type II fatty acid synthases are promising drug targets against major bacterial pathogens. Platensimycin (PTM) is a potent inhibitor against -ketoacyl-[acyl carrier protein] synthase II (FabF) and -ketoacyl-[acyl carrier protein] synthase I (FabB), while the poor pharmacokinetics has prevented its further development. In this work, thirty-two PTM derivatives were rapidly prepared via Heck, Sonogashira, and one-pot Sonogashira/cycloaddition cascade reactions based on the Gram-scale synthesis of 6-iodo PTM (). About half of the synthesized compounds were approximately equipotent to PTM against the tested strains. Among them, the representative compounds , , and exhibited different plasma protein binding affinity or stability in the human hepatic microsome assay and showed improved in vivo efficacy over PTM in a mouse peritonitis model. In addition, was also effective in an -infected skin mouse model. Our study not only significantly expands the known PTM derivatives with improved antibacterial activities in vivo, but showcased that C-C cross-coupling reactions are useful tools to functionalize natural product drug leads.
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http://dx.doi.org/10.3390/antibiotics11040425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9027111PMC
March 2022

Phase 3 Efficacy and Safety of Abrocitinib in Adults with Moderate-to-Severe Atopic Dermatitis After Switching from Dupilumab (JADE EXTEND).

J Am Acad Dermatol 2022 Apr 16. Epub 2022 Apr 16.

Pfizer Inc., New York, NY, USA.

Background: Abrocitinib efficacy by prior dupilumab response status in patients with moderate-to-severe atopic dermatitis (AD) has not previously been assessed in phase 3 studies.

Objective: Examine efficacy and safety of abrocitinib among patients who received prior dupilumab.

Methods: Patients with moderate-to-severe AD received abrocitinib 200 mg or 100 mg once-daily in JADE EXTEND (phase 3 extension) after dupilumab in double-blind, placebo-controlled phase 3 JADE COMPARE.

Results: Among prior dupilumab responders, ≥75% improvement in Eczema Area and Severity Index (EASI-75) was achieved in 93.5% and 90.2% of patients who received 12 weeks of abrocitinib 200 mg and 100 mg, respectively; ≥4-point improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) was achieved in 89.7% and 81.6%, respectively. Among prior dupilumab nonresponders, EASI-75 was achieved with abrocitinib 200 mg and 100 mg in 80.0% and 67.7% and PP-NRS4 in 77.3% and 37.8%, respectively. Most common adverse events among abrocitinib-treated patients were nasopharyngitis, nausea, acne, and headache. Conjunctivitis occurred less frequently with abrocitinib in comparison to prior dupilumab.

Limitations: Short-term, 12-week analysis; no placebo arm.

Conclusion: Efficacy and safety profile of abrocitinib in JADE EXTEND supports the role of abrocitinib as a treatment for patients with moderate-to-severe AD, regardless of prior dupilumab response status.
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http://dx.doi.org/10.1016/j.jaad.2022.04.009DOI Listing
April 2022

An allosteric inhibitor against the therapy-resistant mutant forms of EGFR in non-small cell lung cancer.

Nat Cancer 2022 Apr 14;3(4):402-417. Epub 2022 Apr 14.

Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Epidermal growth factor receptor (EGFR) therapy using small-molecule tyrosine kinase inhibitors (TKIs) is initially efficacious in patients with EGFR-mutant lung cancer, although drug resistance eventually develops. Allosteric EGFR inhibitors, which bind to a different EGFR site than existing ATP-competitive EGFR TKIs, have been developed as a strategy to overcome therapy-resistant EGFR mutations. Here we identify and characterize JBJ-09-063, a mutant-selective allosteric EGFR inhibitor that is effective across EGFR TKI-sensitive and resistant models, including those with EGFR T790M and C797S mutations. We further uncover that EGFR homo- or heterodimerization with other ERBB family members, as well as the EGFR L747S mutation, confers resistance to JBJ-09-063, but not to ATP-competitive EGFR TKIs. Overall, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs to define more effective strategies to treat EGFR-mutant lung cancer.
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http://dx.doi.org/10.1038/s43018-022-00351-8DOI Listing
April 2022
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