7 research outputs found
RE-EDS Using GAFF Topologies: Application to Relative Hydration Free-Energy Calculations for Large Sets of Molecules
Free-energy differences between pairs of end-states can be estimated based on
molecular dynamics (MD) simulations using standard pathway-dependent methods
such as thermodynamic integration (TI), free-energy perturbation, or Bennett's
acceptance ratio. Replica-exchange enveloping distribution sampling (RE-EDS),
on the other hand, allows for the sampling of multiple end-states in a single
simulation without the specification of any pathways. In this work, we use the
RE-EDS method as implemented in GROMOS together with generalized AMBER force
field (GAFF) topologies, converted to a GROMOS-compatible format with a newly
developed GROMOS++ program amber2gromos, to compute relative hydration free
energies for a series of benzene derivatives. The results obtained with RE-EDS
are compared to the experimental data as well as calculated values from the
literature. In addition, the estimated free-energy differences in water and in
vacuum are compared to values from TI calculations carried out with GROMACS.
The hydration free energies obtained using RE-EDS for multiple molecules are
found to be in good agreement with both the experimental data and the results
calculated using other free-energy methods. While all considered free-energy
methods delivered accurate results, the RE-EDS calculations required the least
amount of total simulation time. This work serves as a validation for the use
of GAFF topologies with the GROMOS simulation package and the RE-EDS approach.
Furthermore, the performance of RE-EDS for a large set of 28 end-states is
assessed with promising results
Molekulargenetik und Molekularpathologie beim Prostatakarzinom
Beim hÀufigsten bösartigen Tumor des Mannes, dem Prostatakarzinom, konnten in den letzten Jahren grosse Fortschritte im Bereich der molekularpathologischen Charakterisierung erzielt werden. Diese Erkenntnisse haben entscheidend zur Entwicklung zielgerichteter Therapien in fortgeschrittenen Stadien des Prostatakarzinoms beigetragen. Die molekularpathologischen Ergebnisse geben zudem wichtige Hinweise auf eine mögliche genetische PrÀdisposition
A multicenter phase II trial of anti-EGFR-immunoliposomes loaded with doxorubicin in patients with advanced triple negative breast cancer
Advanced triple negative breast cancer (TNBC) is an aggressive, but initially chemo-sensitive disease. The prognosis is poor and more than three quarters of patients experience progression 12Â months after the initiation of conventional first-line chemotherapy. Approximately two thirds of TNBC express epidermal growth factor receptor 1 (EGFR). We have developed an anti-EGFR targeted nanocontainer drug by inserting anti-EGFR antibody fragments into the membrane of pegylated liposomes (anti-EGFR-ILs-dox). The payload consists of doxorubicin, a standard drug for TNBC. In a first-in-human phase I trial in 26 patients with various advanced solid malignancies, anti-EGFR-ILs-dox has shown little toxicity and encouraging efficacy. In this single-arm phase II trial, we assessed the efficacy of anti-EGFR-ILs-dox as first-line therapy in patients with advanced, EGFRâ+âTNBC. The primary endpoint was progression-free survival at 12Â months (PFS12m). Secondary endpoints included overall response rate (ORR), duration of response (DOR), time to progression (TTP), overall survival (OS) and adverse events (AEs). 48 patients received anti-EGFR-ILs-dox 50Â mg/m iv, on day one of a 28Â days-cycle until progression. The Kaplan-Meier estimate for PFS12m was 13% (one-sided 90% CI 7%, 95% CI [5%, 25%]), median PFS was 3.5Â months (95% CI 1.9, 5.4). The trial has not reached its primary endpoint. There were no new toxicity signals. Based on these results, anti-EGFR-ILs-dox should not be further developed for TNBC. It remains an open question whether anti-EGFR-ILs-dox would offer more opportunities in other EGFR-expressing malignancies, where targeting this receptor has already shown anticancer effects.Trial registration: This trial was registered at clinicaltrials.gov: NCT02833766. Registered 14/07/2016
Update Swiss guideline for counselling and testing for predisposition to breast, ovarian, pancreatic and prostate cancer
This paper presents the Swiss guideline for genetic counselling and testing of individuals with an increased probability for carrying mutations in high risk cancer predisposition genes, particularly BRCA1 and BRCA2. It aims to help providers of genetic counselling to identify valuable candidates for testing and serves as a basis for reimbursement claims to Swiss insurance companies
Phase I trial of the androgen receptor modulator CR1447 in breast cancer patients
CR1447 (4-hydroxytestosterone, 4-OHT) binds to the androgen receptor and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells in preclinical studies. The objective of this first-in man trial was to evaluate the safety and to determine the dose of CR1447, administered as an ointment, for Phase II. Escalating doses (100, 200, 400 mg) of CR1447 were administered topically on a daily basis to patients with ER-positive/AR-positive/HER2-negative advanced breast cancer pretreated with several lines of therapy. 14 patients have been treated for a total of 42 cycles. Two patients, one at dose level 100 mg and one at dose level 200 mg, showed early tumour progression and were replaced. Related adverse events were all †grade 2 and included fatigue, bone and joint pain, stiffness, dry skin and mouth, nausea, sweating, urinary tract infection, rash, headache and distress. No drug-related dose-limiting toxicities (DLTs) were seen. Two patients (17%) achieved stable disease at 3 months. Pharmacokinetic analysis confirmed dose-dependent transdermal uptake of CR1447. 4-OH-androstenedione (4-OHA), a key metabolite of 4-OHT, was undetectable in most of the plasma samples. Urine metabolites of 4-OHT and 4-OHA indicate high exposure of 4-OHT after topical administration. Oestradiol serum concentrations did not increase, confirming preclinical data that CR1447 is not converted to estrogens in vivo. In conclusion, CR1447 administered transdermally as an ointment is well tolerated and appears to have single-agent activity in heavily pretreated ER-positive/HER2-negative breast cancer patients. The recommended phase II dose is 400 mg/day
Phase I trial of the androgen receptor modulator CR1447 in breast cancer patients.
CR1447 (4-hydroxytestosterone, 4-OHT) binds to the androgen receptor and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells in preclinical studies. The objective of this first-in man trial was to evaluate the safety and to determine the dose of CR1447, administered as an ointment, for Phase II. Escalating doses (100, 200, 400âmg) of CR1447 were administered topically on a daily basis to patients with ER-positive/AR-positive/HER2-negative advanced breast cancer pretreated with several lines of therapy. 14 patients have been treated for a total of 42 cycles. Two patients, one at dose level 100âmg and one at dose level 200âmg, showed early tumour progression and were replaced. Related adverse events were all †grade 2 and included fatigue, bone and joint pain, stiffness, dry skin and mouth, nausea, sweating, urinary tract infection, rash, headache and distress. No drug-related dose-limiting toxicities (DLTs) were seen. Two patients (17%) achieved stable disease at 3 months. Pharmacokinetic analysis confirmed dose-dependent transdermal uptake of CR1447. 4-OH-androstenedione (4-OHA), a key metabolite of 4-OHT, was undetectable in most of the plasma samples. Urine metabolites of 4-OHT and 4-OHA indicate high exposure of 4-OHT after topical administration. Oestradiol serum concentrations did not increase, confirming preclinical data that CR1447 is not converted to estrogens in vivo In conclusion, CR1447 administered transdermally as an ointment is well tolerated and appears to have single-agent activity in heavily pretreated ER-positive/HER2-negative breast cancer patients. The recommended phase II dose is 400âmg/day
A multicenter phase II trial of anti-EGFR-immunoliposomes loaded with doxorubicin in patients with advanced triple negative breast cancer.
Advanced triple negative breast cancer (TNBC) is an aggressive, but initially chemo-sensitive disease. The prognosis is poor and more than three quarters of patients experience progression 12Â months after the initiation of conventional first-line chemotherapy. Approximately two thirds of TNBC express epidermal growth factor receptor 1 (EGFR). We have developed an anti-EGFR targeted nanocontainer drug by inserting anti-EGFR antibody fragments into the membrane of pegylated liposomes (anti-EGFR-ILs-dox). The payload consists of doxorubicin, a standard drug for TNBC. In a first-in-human phase I trial in 26 patients with various advanced solid malignancies, anti-EGFR-ILs-dox has shown little toxicity and encouraging efficacy. In this single-arm phase II trial, we assessed the efficacy of anti-EGFR-ILs-dox as first-line therapy in patients with advanced, EGFRâ+âTNBC. The primary endpoint was progression-free survival at 12Â months (PFS12m). Secondary endpoints included overall response rate (ORR), duration of response (DOR), time to progression (TTP), overall survival (OS) and adverse events (AEs). 48 patients received anti-EGFR-ILs-dox 50Â mg/m2 iv, on day one of a 28Â days-cycle until progression. The Kaplan-Meier estimate for PFS12m was 13% (one-sided 90% CI 7%, 95% CI [5%, 25%]), median PFS was 3.5Â months (95% CI 1.9, 5.4). The trial has not reached its primary endpoint. There were no new toxicity signals. Based on these results, anti-EGFR-ILs-dox should not be further developed for TNBC. It remains an open question whether anti-EGFR-ILs-dox would offer more opportunities in other EGFR-expressing malignancies, where targeting this receptor has already shown anticancer effects.Trial registration: This trial was registered at clinicaltrials.gov: NCT02833766. Registered 14/07/2016