Pharmacometric approaches for linking pharmacokinetic and pharmacodynamic models of sunitinib and pazopanib with clinical outcome

Aim of this thesis was to build a modeling framework for patients with metastatic renal cell carcinoma (mRCC) treated with two common first-line therapies, sunitinib and pazopanib. Therefore, as part of the European-wide EuroTARGET project, which aimed at identifying predictive biomarkers in mRCC patients, a pharmacokinetic (PK) phase IV study was conducted in Germany and the Netherlands. Based on a center-specific schedule up to 12 blood samples per patient were collected in conjunction with blood pressure measurements. Plasma concentrations of the respective study drug and the soluble VEGF receptors 2 and 3 were quantified for each time-point using previously established analytical methods. Published pharmacokinetic and pharmacodynamics (PK/PD) models were used as basis for this work. For both sunitinib and pazopanib, reliable individual PK parameters could be obtained and successfully linked to PD models for the potential biomarkers. Covariate analysis of the PK/PD models revealed two single nucleotide polymorphisms with influence on the intrinsic activity of sunitinib on sVEGFR-2 plasma concentrations (VEGFR-3 rs6877011 and ABCB1 rs2032582). The final PK/PD models were then used to establish a link to clinical outcome parameters including progression-free survival and the two most commonly observed adverse events in the mRCC population. In a model-based time-to-event analysis, a high sVEGFR-2 baseline plasma concentration was associated with a worse prognosis for sunitinib patients. In a combined analysis of sunitinib and pazopanib the absolute sVEGFR-2 plasma concentration over time was a potentially predictive factor. Hence, this model allows the prediction of PFS based on the measured sVEGFR-2 plasma concentration. Myelosuppression and fatigue as treatment-associated adverse events were analyzed separately using first-order continuous Markov models. Here, active sunitinib plasma concentration proved to be influential as a higher exposition did result in prolonged time frames of myelosuppression. However, a similar effect was not observed for fatigue. The modeling framework presented in this thesis provides a better understanding of the relationship between the exposure, pharmacological response, and clinical outcome of antiangiogenic drugs and is therefore an important step towards finding optimal dosing schedules and identifying potential predictive biomarkers for both drugs

ROS1 genomic rearrangements are rare actionable drivers in microsatellite stable colorectal cancer

c-Ros oncogene 1, receptor tyrosine kinase (ROS1) genomic rearrangements have been reported previously in rare cases of colorectal cancer (CRC), yet little is known about the frequency, molecular characteristics, and therapeutic vulnerabilities of ROS1-driven CRC. We analyzed a clinical dataset of 40 589 patients with CRC for ROS1 genomic rearrangements and their associated genomic characteristics (Foundation Medicine, Inc [FMI]). We moreover report the disease course and treatment response of an index patient with ROS1-rearranged metastatic CRC. ROS1 genomic rearrangements were identified in 34 (0.08%) CRC samples. GOPC-ROS1 was the most common ROS1 fusion identified (11 samples), followed by TTC28-ROS1 (3 samples). Four novel 5' gene partners of ROS1 were identified (MCM9, SRPK1, EPHA6, P4HA1). Contrary to previous reports on fusion-positive CRC, ROS1-rearrangements were found exclusively in microsatellite stable (MSS) CRCs. KRAS mutations were significantly less abundant in ROS1-rearranged vs ROS1 wild type cases. The index patient presented with chemotherapy-refractory metastatic right-sided colon cancer harboring GOPC-ROS1. Molecularly targeted treatment with crizotinib induced a rapid and sustained partial response. After 15 months on crizotinib disseminated tumor progression occurred and KRAS Q61H emerged in tissue and liquid biopsies. ROS1 rearrangements define a small, yet therapeutically actionable molecular subgroup of MSS CRC. In summary, the high prevalence of GOPC-ROS1 and noncanonical ROS1 fusions pose diagnostic challenges. We advocate NGS-based comprehensive molecular profiling of MSS CRCs that are wild type for RAS and BRAF and patient enrollment in precision trials. Keywords: ROS1 rearrangement; acquired resistance; colorectal cancer; crizotinib; molecular subgroups; precision treatmen

ROS1 genomic rearrangements are rare actionable drivers in microsatellite stable colorectal cancer.

c-Ros oncogene 1, receptor tyrosine kinase (ROS1) genomic rearrangements have been reported previously in rare cases of colorectal cancer (CRC), yet little is known about the frequency, molecular characteristics, and therapeutic vulnerabilities of ROS1-driven CRC. We analyzed a clinical dataset of 40 589 patients with CRC for ROS1 genomic rearrangements and their associated genomic characteristics (Foundation Medicine, Inc [FMI]). We moreover report the disease course and treatment response of an index patient with ROS1-rearranged metastatic CRC. ROS1 genomic rearrangements were identified in 34 (0.08%) CRC samples. GOPC-ROS1 was the most common ROS1 fusion identified (11 samples), followed by TTC28-ROS1 (3 samples). Four novel 5' gene partners of ROS1 were identified (MCM9, SRPK1, EPHA6, P4HA1). Contrary to previous reports on fusion-positive CRC, ROS1-rearrangements were found exclusively in microsatellite stable (MSS) CRCs. KRAS mutations were significantly less abundant in ROS1-rearranged vs ROS1 wild type cases. The index patient presented with chemotherapy-refractory metastatic right-sided colon cancer harboring GOPC-ROS1. Molecularly targeted treatment with crizotinib induced a rapid and sustained partial response. After 15 months on crizotinib disseminated tumor progression occurred and KRAS Q61H emerged in tissue and liquid biopsies. ROS1 rearrangements define a small, yet therapeutically actionable molecular subgroup of MSS CRC. In summary, the high prevalence of GOPC-ROS1 and noncanonical ROS1 fusions pose diagnostic challenges. We advocate NGS-based comprehensive molecular profiling of MSS CRCs that are wild type for RAS and BRAF and patient enrollment in precision trials

Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis

Metastasis is the major cause of death in cancer patients. Circulating tumor cells need to migrate through the endothelial layer of blood vessels to escape the hostile circulation and establish metastases at distant organ sites. Here, we identified the membrane-bound metalloprotease ADAM17 on endothelial cells as a key driver of metastasis. We show that TNFR1-dependent tumor cell–induced endothelial cell death, tumor cell extravasation, and subsequent metastatic seeding is dependent on the activity of endothelial ADAM17. Moreover, we reveal that ADAM17-mediated TNFR1 ectodomain shedding and subsequent processing by the γ-secretase complex is required for the induction of TNF-induced necroptosis. Consequently, genetic ablation of ADAM17 in endothelial cells as well as short-term pharmacological inhibition of ADAM17 prevents long-term metastases formation in the lung. Thus, our data identified ADAM17 as a novel essential regulator of necroptosis and as a new promising target for antimetastatic and advanced-stage cancer therapie

Hypercapnic Failure in Acute Exacerbated COPD Patients: Severe Airflow Limitation as an Early Warning Signal

Background: Hypercapnic failure is a severe complication of COPD disease progression, which is associated with a high morbidity and mortality. The aim of this study was to examine the association of comorbidity and clinical risk factors with the development of hypercapnia in acute exacerbated COPD patients. Methods: In this retrospective monocentric cohort study, we examined the influence of the clinical parameters and the comorbidity of hospitalized patients with the acute exacerbation of COPD on the development of hypercapnia by performing multivariate logistic regression and a receiver operating characteristic analysis. Results: In total, 275 patient cases with COPD exacerbation were enrolled during the period from January 2011 until March 2015, where 104 patients (37.8%) with hypercapnia were identified. The logistic regression analysis revealed severe airflow limitation (decreased FEV1) as the main factor associated with the development of hypercapnia. In the ROC analysis, we determined an FEV1 of 42.12%, which was predicted with a sensitivity of 82.6% and specificity of 55%, and an absolute value of FEV1 of 0.8 L, with a sensitivity of 0.62 and specificity of 0.79 as the cut off points, respectively. We could not verify an association with the patient’s condition or the laboratory surrogate parameters of organ failure. Conclusion: Severe airflow limitation is an important risk factor that is associated with hypercapnic failure in acute exacerbated COPD patients. Validation in prospective cohorts is warranted and should focus on more intensive monitoring of these at-risk patients