Proteins leave the endoplasmic reticulum (ER) for the plasma membrane via the classical secretory pathway, but routes bypassing the Golgi apparatus have also been observed. Apical and basolateral protein secretion in epithelial Madin-Darby canine kidney (MDCK) cells display differential sensitivity to Brefeldin A (BFA), where low concentrations retard apical transport, while basolateral transport still proceeds through intact Golgi cisternae. We now describe that BFA-mediated retardation of glycoprotein and proteoglycan transport through the Golgi apparatus induces surface transport of molecules lacking Golgi modifications, possessing those acquired in the ER. Low concentrations of BFA induces apical Golgi bypass, while higher concentrations were required to induce basolateral Golgi bypass. Addition of the KDEL ER-retrieval sequence to model protein cores allowed observation of apical Golgi bypass in untreated MDCK cells. Basolateral Golgi bypass was only observed after the addition of BFA or upon cholesterol depletion. Thus, in MDCK cells, an apical Golgi bypass route can transport cargo from pre-Golgi organelles in untreated cells, while the basolateral bypass route is inducible.

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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e13634 Background: Norway, a country with a publicly funded health care system, was in 2018-19 lagging behind with respect to implementation of precision cancer medicine (PCM). Methods: Our approach mid-2019 was very simple and set out three aims: i) To establish access to advanced molecular diagnostics to allow identification and stratification of cancer patients into clinical trials; ii) To increase the volume of clinical trials with a PCM approach to gain experience and build competence; and iii) In parallel work for implementation of PCM into standard of care. Results: In a trans-disciplinary project we worked along four lines: i) Gathered support to have oncologists, hematologists, pathologists and cancer researchers join a nation-wide, bottom-up initiative with a few common priorities; ii) Liaised with executives and regulators in regional health care systems, The Ministry of Health and other public stakeholders and charities to have the top-down approaches meet the bottom-up initiative; iii) Aligned with industry to explore the possibility of a public-private partnership and iv) Coordinated with other PCM initiatives internationally. Over the past two years we have thus built and raised funding for: a) The InPreD-Norway national infrastructure delivering precision cancer diagnostics for patient identification and stratification into clinical trials (publicly reimbursed) and operating the national molecular tumor board; b) the IMPRESS-Norway national researcher-initiated PCM intervention trial (https://impressnorway.com), which opened for inclusion Q2 2021 and runs at all hospitals that treat cancer patients (18 hospitals). The trial is modelled on and coordinated with the Dutch DRUP trial and aligned with similar trials in the Nordic countries; c) the INSIGHT/INCLUDE projects for research on control cohorts, use of real world evidence (RWE), health economics and reimbursement models, and ethics, legal aspects and governance; and d) the CONNECT public-private partnership (https://www.connectnorway.org) for PCM implementation with 29 partners (14 pharma & biotech companies, 9 public partners and 4 NGOs) for interaction with InPreD and IMPRESS initiatives and providing a forum that includes regulators and payors for policy discussions of reimbursement models and regulatory framework. Conclusions: Our experience could serve as a model for building a functioning ecosystem for implementation of PCM. Unique aspects include the nation-wide initiative, the population effect of the diagnostics to be offered and the integration of a public-private partnership.

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