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Glioblastoma (GBM) is the most common type of primary brain tumor in adults, with a 5-year overall survival of only 7%. Oncolytic viruses are a promising and active area of research in GBM with the recent approval of an oncolytic HSV-1 vector, teserpaturev (Delytact, also known as G47Δ, Daiichi Sankyo) for recurrent GBM based on an overall survival of 92% at 1 year. G207, an HSV-1 vector more attenuated than teserpaturev, recently reported acceptable tolerability with evidence of responses in children with recurrent or progressive high-grade glioma. These vectors are not expressing any cDNA transgene that may enhance and prolong antitumor activity. We report here the development of ONCR-GBM, an oncolytic HSV-1 vector specifically engineered for safety using a microRNA attenuation strategy to limit viral replication in healthy cell type of the CNS. ONCR-GBM has been developed from a novel potently oncolytic strain of HSV-1 and optimized for infection of GBM tumor cells. Antitumor efficacy has been further enhanced through the expression of multiple payloads designed to modify the immunosuppressive tumor microenvironment of GBM. We previously reported that a vector expressing IL-12 and a PD-1 antagonist nanobody achieved > 90% survival after a single injection in the GL261-Nectin1 orthotopic model. This vector promoted immune cell recruitment and activation in tumors and protected surviving animals from a subsequent tumor rechallenge. Additional payloads selected for interfering with the immune suppressive stroma in GBM have been evaluated for potentiating the response of IL-12 and anti PD-1 expressing HSV-1. We will present the outcome of the in vivo screen, and the selection of the optimal combination of payloads featured in ONCR-GBM clinical candidate.

Both previous and additional genetic knockdown studies reported herein implicate G protein-coupled receptor kinase 6 (GRK6) as a critical kinase required for the survival of multiple myeloma (MM) cells. Therefore, we sought to develop a small molecule GRK6 inhibitor as an MM therapeutic. From a focused library of known kinase inhibitors, we identified two hits with moderate biochemical potencies against GRK6. From these hits, we developed potent (IC50 < 10 nM) analogues with selectivity against off-target kinases. Further optimization led to the discovery of an analogue (18) with an IC50 value of 6 nM against GRK6 and selectivity against a panel of 85 kinases. Compound 18 has potent cellular target engagement and antiproliferative activity against MM cells and is synergistic with bortezomib. In summary, we demonstrate that targeting GRK6 with small molecule inhibitors represents a promising approach for MM and identify 18 as a novel, potent, and selective GRK6 inhibitor.

The transcription factor B cell lymphoma 6 (BCL6) is required for the generation of an effective humoral immune response through the development and maintenance of germinal centers (GCs). The inhibition of the protein−protein interaction between BCL6 and its corepressors has been implicated as a therapeutic target for diffuse large B-cell lymphoma (DLBCL), a type of non-Hodgkin’s lymphoma (NHL). Using structure-based drug design, we initiated a program to identify novel BCL6 inhibitors. We identified a high micromolar virtual screening hit which was then optimized for potent biophysical binding and anti-proliferative cellular activity resulting in the identification of OICR-10268, a potent and selective Bcl6 inhibitor. Citation Format: Iain D. Watson, Methvin Isaac, Brian Wilson, Anh Chau, Justin Morin, Pandiaraju Subramanian, Ahmed Mamai, Babu Joseph, Michael Prakesch, David Uehling, Ayome Abibi, Richard Marcellus, Craig Strathdee, Ratheesh Subramaniam, Brigitte Theriault, Jeffrey Winston, Manuel Chan, Carly Griffin, Herman Cheung, Taira Kiyota, Elijus Undzys, Ahmed Aman, Gennady Poda, Doug Kuntz, Neil C. Pomroy, Gil G. Privé, Rima Al-awar. Discovery of OICR-10268: A potent and selective BCL6 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 7.

Multiple myeloma (MM) is one of the most common hematological malignancies, but current therapy options are limited to high-dose chemotherapy or high-risk stem-cell transplantation. In a recent kinome-wide RNAi study by Tiedemann and colleagues (2010), the G-protein coupled receptor kinase 6 (GRK6) was identified as a critical kinase required for survival of MM cells. This study also suggests that MM cells, but not other cell types, are dependent on GRK6; and that gene silencing by shRNA or siRNA of GRK6, but not other GRKs, results in decreased survival. At present, the G protein-coupled receptor (GPCR) signaling mediated by GRK6 in MM cells is not well understood. Through gene silencing techniques and expression of either the wild-type or kinase-dead form of GRK6 protein, we determined that a functional GRK6 kinase domain is required for survival of MM cells. These findings helped validate that the GRK6 kinase domain is a potential target for MM, and have spurred the investigation of small molecule kinase inhibitors of GRK6. By screening a cassette of compounds that are known as kinase inhibitors, compounds with moderate potency in preliminary biochemical assays were identified and further evaluated. As part of this effort we identified CX-4945, which is a known potent and selective ATP-competitive small molecule protein kinase CK2 inhibitor (IC₅₀ of 1 nM for recombinant human CK2α) as a moderately potent inhibitor of GRK6 (IC₅₀ on GRK6 = 300-500 nM). Herein we describe the design and synthesis of novel analogs of CX-4945 and key structure activity relationships (SAR) of this chemical series against GRK6 that serve as a platform for further optimization.

As noted in Chapter 1 of this book, one weakness in current research into the impact of tertiary education is that it tends to assume that similar rules of advancement operate throughout the labor market. Although research demonstrates a relationship between educational qualifications and employment outcomes, such research does not sufficiently acknowledge that the value of qualifications differs in different fields. For example, although educational qualifications are a prerequisite to advance in some areas of the labor market, they are not as commonly required in others, such as sales and other service sector occupations. Policy makers in New Zealand and the United Kingdom also tend to assume that similar rules of advancement operate in all areas of the labor market. For this reason, they have devoted considerable energy to encouraging all people to engage in education and to achieve educational qualifications, irrespective of the rules of advancement in operation in the fields where graduates hope to work. The introduction of national qualifications frameworks in New Zealand, England, Scotland, and Wales, for instance, was partially predicated on a desire to create systems of qualifications that would drive up innovation by motivating all to succeed in education and training and to demonstrate this by gaining qualifications. Nevertheless, as shown in previous chapters, in some fields, the qualifications gained by individuals have struggled to attract much interest from employers. This suggests that labor market relationships are facilitated in these fields in other ways.

This chapter further explores the theoretical terrain on which this book is based. It begins by providing a very general description of contemporary debates concerning processes of social class reproduction ongoing in the labor market, some of which are mediated by the tertiary education system. The complex nature of the interaction that exists between individual-level variables, such as socioeconomic status and gender, and institutional variables, such as the programs on offer, as well as ongoing social and economic change, mean it is difficult, if not impossible, to provide a precise assessment of the relationships among labor markets, social class, and tertiary education. Despite our lack of understanding and the necessarily general nature of the discussion offered in this chapter, it is argued that a better knowledge of the role played by providers of tertiary education in constructing and using networks can improve our understanding of social class reproduction processes. Networks of various kinds work in diverse ways to structure and regulate social relationships, such as those based on social class (Lin 2001). An increased knowledge of such processes will enable us to understand better how providers of tertiary education are responding to the new policy environment.

The previous chapter argued that exploring processes of social reproduction within fields would improve our understanding of the role tertiary education has in helping to structure competition for advancement. This chapter builds on this argument by exploring the influence of social networks in the allocation of employment and in promoting innovation. This discussion provides a basis to explore knowledge creation and knowledge transfer and the processes of social reproduction that result from this. Granovetter (1995) helped dispel the myth that gaining employment is an open process. The professional, technical, managerial workers he studied relied primarily on their set of personal contacts to find information about employment opportunities, rather than more formal or impersonal routes. He also argued that not everyone pursued jobs via personal contacts. A critical point was that his subjects’ social networks structured the possibilities open to them.