3112 Background: Despite the broad activity of checkpoint inhibitors across tumor types, primary or secondary resistance after initial response represents a major challenge. Tomivosertib (T), a potent and highly selective inhibitor of the immunosuppressive kinases MNK-1 and 2, blocks expression of checkpoint proteins PD-1, PD-L1, and LAG-3 as well as immunosuppressive cytokines IL-6 and IL-8. In preclinical models, T was shown to trigger an anti-tumor immune response and enhance the activity of checkpoint inhibitors in a T-cell dependent manner. In prior clinical studies, T had an acceptable safety profile as a single agent and in combination with anti-PD-L1 agent avelumab. Methods: Patients experiencing insufficient response (progression or stable disease for 12 weeks or more) to any FDA-approved checkpoint inhibitor in any approved indication were eligible. T at 200 mg oral (PO) BID was added to the existing checkpoint inhibitor until disease progression or unacceptable toxicity was noted. Results: 39 pts (23 male, 16 female) were enrolled across seven cancer types. Median age was 68 (range 42-85). Median prior therapies were 2 (range 1-6). The most common cancers were lung (N = 17), urothelial (N = 6), renal (N = 5) and head and neck (N = 5). 36 pts continued on anti PD-1 antibody (Pembrolizumab and Nivolumab, 18 each) and 3 on anti PD-L-1 antibody (Durvalumab 2, Atezolizumab 1) . The most common grade 3/4 treatment related adverse events occurring in more than 1 pt were alanine aminotransferase increase (2), blood creatine phosphokinase increase (2) and maculo-papular rash (2). 7 patients discontinued treatment (18%) due to adverse events attributable to either drug. Three partial responses (PR) per RECIST 1.1 were observed in pts with previous progression on checkpoint inhibitor therapy, one each in NSCLC (1/17), gastric (1/1) and renal cancer (1/5). 7 NSCLC pts (41%) were progression free for ≥ 24 weeks. All NSCLC patients entered the study with progression by RECIST 1.1 on single agent checkpoint inhibitor prior to adding T. Conclusions: The addition of T to existing checkpoint therapy was well tolerated and manifested clinical activity including objective responses in pts with progression on existing checkpoint inhibitor. A Progression Free Survival rate at 24 weeks of 41% was noted in NSCLC patients. Additional studies evaluating the addition of T to checkpoint inhibitor therapy after progression on anti PD-1 or PD-L-1 therapy are planned. Clinical trial information: NCT03616834 .

Highlights d Genome-wide CRISPRi screen reveals more than 600 synthetic lethal partners of eIF4E d Functional interaction between eIF4E and Bcl-xL is important for tumor growth d Mitochondrial dysfunction triggers an eIF4E-dependent adaptive stress response d Interaction between eIF4E and EJC controls the migratory capacity of cancer cells

JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org.The recent groundswell of interest in radical political economy means different things to different people. Taking the development to be a "surge of new ideas 'whose time has come'," Martin Bronfenbrenner attributes the revival of radicalism to a complex of unresolved social problems, such as inequality, pollution, racism and imperialism [2, 747-748]. Taking a very different tack, Paul Sweezy [33] suggests that the clash between conventional economics and its radical, neo-Marxian counterpart might be understood in terms of the pattern of scientific development outlined in Thomas Kuhn's now classic little book, The Structure of Scientific Revolutions [18].1 Kuhn's thesis also provides the background for the high drama at the 1970 meetings of the American Economic Association when John Gurley [15] confronted the assemblage with a ringing denunciation of the alleged weaknesses, blindness, and limitations of conventional economics.2Kuhn's explanation of the process of * For assistance in exploring Kuhn's thesis and its application to radical economics, the author would like to thank the participants in the Notre Dame Seminar in Political Economy; Professor Kenneth Jameson has been especially helpful. The author would also like to thank an anonymous referee for helpful comments on an earlier draft.1 The possibility of applying Kuhn's thesis to economics has occurred to several economists [12, 122ff; 6; 32, 223ff; 4; 3, 209, 224; 9, 47f; 25].2 Refusing to allow the radicals to preempt the use of Kuhn's analysis, Solow [27] in a sharp defense of conventional economics accused the radicals of having "corrupted" Kuhn's notion of a "paradigm" making it a "mere license for loose thinking." Put in Kuhn's terms, the difference between Solow and Gurley is that the first considers society's unresolved problems as "puzzles" to be solved by "articulating" the paradigm of conventional economics, while the latter takes such problems to be "counter-instances" which call for a switch to a new paradigm [18, 79f]. scientific development-by way of paradigm, anomaly, crisis and new paradigm-is very impressive and has aroused considerable interest among philosophers [19]. Used to interpret the "awakening of the sleeping dogs" [2, 747] of radicalism in the late sixties, Kuhn's analysis proves to be very illuminating. It offers a scientific-as opposed to sociological-explanation for the emergence of a radical brand of economics. It suggests that what has propelled radicalism out of the backwaters of heterodoxy into the mainstream of economic speculation is that conventional economics has worked itself into the kind of distinctive situation referred to by Kuhn as a "scientific crisis." 3 Finally, Kuhn's thesis...

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