Redemptive History and Preaching

This article was originally presented at Dordt College\u27s 1990 Spring Ministers Conference

TARGETING EPHB6 SYNTHETIC LETHALITY IN BREAST CANCER

Traditionally, cancer treatments focus on proteins impacted by either an increase in expression or a gain-of-function mutation. Loss-of-function mutations or especially down-regulation usually cannot be targeted directly through stabilization or activation, so alternative approaches are needed to target these changes in cancer cells. One approach is based on the synthetic lethality concept, where lethality occurs only when inhibition of a gene partner to the loss-of-function alteration is inhibited. EphB6, a kinase-dead member of the Eph receptor tyrosine kinase family, has anti-malignant properties and is often down-regulated in breast cancer, making it a strong candidate for the synthetic lethality approach. To support the development of EphB6-based therapies, our lab previously completed a genome-wide shRNA screen in an effort to find novel EphB6 interactions, searching specifically for molecules synthetically lethal with EphB6 that also had FDA-approved inhibitors. One of the identified hits, the Src kinase, was successfully validated with and FDA-approved Src inhibitor, KX2-391, in triple-negative breast cancer models representing the most aggressive breast cancer subtype. Met was another promising target identified, but it was not properly validated. This thesis describes the further assessment of the EphB6-Src and EphB6-Met synthetic lethal interactions in various breast cancer subtypes. Also reported here is the screening of the library of over 1800 FDA-approved compounds that allowed us to identify a new drug (the INHIBITOR) synthetic lethal with EphB6 that selectively eliminates EphB6-deficient TNBC cells. The results laid out in this thesis strongly suggest that synthetic lethal interactions of EphB6 discovered in TNBC appear to be restricted to this breast subtype, and also indicate that using small-molecule Met inhibitors, especially ARQ-197, or the newly identified INHIBITOR could represent valuable options for treating TNBC patients with low EphB6 expression in tumor cells

Biodegradable hollow fibres for the controlled release of hormones

Poly(l-lactide), (PLLA), hollow fibres were prepared using a dry-wet phase inversion spinning process. The effect of several spinning parameters (i.e. bore medium flow rate, spinning dope extrusion rate, fibre take-up rate, and spinning height) on the hollow fibre dimensions is reported. The use of several spinning systems (i.e. different solvent/non-solvent pairs with or without additive) resulted in PLLA hollow fibres with varying asymmetric membrane structures, i.e. a porous matrix covered by an internal and external skin varying from very thick and dense to very thin and porous. Some of the differences in membrane structure were qualitatively explained on the basis of a model developed by Reuvers [52] for the formation of flat-sheet membranes by immersion precipitation. Release experiments were carried out using PLLA hollow fibres filled with a 25 wt.% dispersion of micronized 3H-levonorgestrel in castor oil, and a receiving fluid consisting of 40 wt.% aqueous ethanol. The hollow fibre levonorgestrel release rates were found to be dependent on the membrane structure of the hollow fibre wall. For the different hollow fibre samples, zero-order levonorgestrel release rates were found, in the range of 0.1–10 μg/cm/day. Possible release mechanisms are discussed. Preliminary in vivo (rabbit) release experiments showed that constant levonorgestrel blood plasma levels could be obtained for a period up to 210 days. It is concluded that the new biodegradable hollow fibre reservoir device shows very promising properties for possible application as a long-acting contraceptive delivery system