PKPD modeling of acquired resistance to anti-cancer drug treatment
AbstractNon-small cell lung cancer (NSCLC) patients greatly benefit from the treatment with tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR). However, emergence of acquired resistance inevitable occurs after long-term treatment in most patients and limits clinical improvement. In the present study, resistance to drug treatment in patient-derived NSCLC xenograft mice was assessed and modeling and simulation was applied to understand the dynamics of drug resistance as a basis to explore more beneficial drug regimen. Two semi-mechanistic models were fitted to tumor growth inhibition profiles during and after treatment with erlotinib or gefitinib. The base model proposes that as a result of drug treatment, tumor cells stop proliferating and undergo several stages of damage before they eventually die. The acquired resistance model adds a resistance term to the base model which assumes that resistant cells are emerging from the pool of damaged tumor cells. As a result, tumor cells sensitive to drug treatment will either die or be converted to a drug resistant cell population which is proliferating at a slower growth rate as compared to the sensitive cells. The observed tumor growth profiles were better described by the resistance model and emergence of resistance was concluded. In simulation studies, the selection of resistant cells was explored as well as the time-variant fraction of resistant over sensitive cells. The proposed model provides...
SummaryAnaplastic lymphoma kinase (ALK), which belongs to the insulin receptor tyrosine kinase superfamily, plays an important role in nervous system development. Due to chromosomal translocations, point mutations, and gene amplification, constitutively activated ALK has been implicated in a variety of human cancers, including anaplastic large-cell lymphoma (ALCL), non-small cell lung cancer, and neuroblastoma. We evaluated the anti-cancer activity of the ALK inhibitor KRCA-0008 using ALCL cell lines that express NPM (nucleophosmin)-ALK. KRCA-0008 strongly suppressed the proliferation and survival of NPM-ALK-positive ALCL ...
Conclusion: Atezolizumab is more efficient and more costly than docetaxel in the 2nd line treatment of NSCLC of stage IIIB or IV, in France, with results consistent to previous French authorities' evaluation of immunotherapies in similar indication. Lastly, atezolizumab is a cost saving alternative to nivolumab, based on list price. PMID: 31951770 [PubMed - as supplied by publisher]
In this study, compound Liuju formula was taken as an example to isolate compounds with synergistic biological activity through systems pharmacology strategy. Through pharmacokinetic evaluation, 37 potentially active compounds were screened out. Meanwhile, 116 targets of these compounds were obtained by combing with the target prediction model. Through network analysis, we found that multicomponent drugs can present a synergistic effect through regulating inflammatory signaling pathway, invasion pathway, proliferation, and apoptosis pathway. Finally, it was confirmed that the bioactive compounds of compound Liuju formula h...
ConclusionFollowing 1L EGFR-TKI treatment, 19% of patients were tested for EGFR T790M, and most (69%) had no record of receiving any subsequent therapy.
Bristol-Myers Squibb Company (NYSE: BMY) announced the U.S. Food and Drug Administration (FDA) has accepted its supplemental Biologics License Application (sBLA) for Opdivo (nivolumab) in combination with Yervoy (ipilimumab) for the first-line treatment of patients with metastatic or recurrent non-small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumor aberrations.
Conclusion T4 stage patients had worse survival in N2 group. To get a more precisely stratification, skip metastasis and number of involved lymph node stations should be considered in future N stage classification. DOI: 10.3779/j.issn.1009-3419.2020.01.03
Conclusion The expression of TRIM59 is closely related to the prognosis of NSCLC patients, and it is an independent risk factor for NSCLC patients. DOI: 10.3779/j.issn.1009-3419.2020.01.04
Immune checkpoint inhibitor (ICI) has been proven to be a major breakthrough in patients with advanced non-small cell lung cancer. Up to now, neoadjuvant therapy using ICI are rare. However, in the context of cancer immunotherapy, neoadjuvant treatment may offer an extra advantage. In this review, we will disscuss the existing preclinical data and emerging clinical findings in the neoadjuvant setting and its potential mechanism of action. We will also highlight the potential damage and the questions that are required to be answered. DOI: 10.3779/j.issn.1009-3419.2020.01.09