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Calcium is a critical regulator of neuronal differentiation and neurite outgrowth during development, as well as synaptic plasticity in adulthood. Calcium-and calmodulin-dependent kinase I (CaMKI) can regulate neurite outgrowth; however, the signal transduction cascades that lead to its physiological effects have not yet been elucidated. CaMKI␣ was therefore used as bait in a yeast two-hybrid assay and microtubule affinity regulating kinase 2 (MARK2)/Par-1b was identified as an interacting partner of CaMKI in three independent screens. The interaction between CaMKI and MARK2 was confirmed in vitro and in vivo by coimmunoprecipitation. CaMKI binds MARK2 within its kinase domain, but only if it is activated by calcium and calmodulin. Expression of CaMKI and MARK2 in Neuro-2A (N2a) cells and in primary hippocampal neurons promotes neurite outgrowth, an effect dependent on the catalytic activities of these enzymes. In addition, decreasing MARK2 activity blocks the ability of the calcium ionophore ionomycin to promote neurite outgrowth. Finally, CaMKI phosphorylates MARK2 on novel sites within its kinase domain. Mutation of these phosphorylation sites decreases both MARK2 kinase activity and its ability to promote neurite outgrowth. Interaction of MARK2 with CaMKI results in a novel, calciumdependent pathway that plays an important role in neuronal differentiation.

Purpose Precision oncology develops and implements evidence-based personalized therapies that are based on specific genetic targets within each tumor. However, a major challenge that remains is the provision of a standardized, up-to-date, and evidenced-based precision medicine initiative across a geographic region. Materials and Methods We developed a statewide molecular tumor board that integrates academic and community oncology practices. The Precision Medicine Molecular Tumor Board (PMMTB) has three components: a biweekly Web-based teleconference tumor board meeting provided as a free clinical service, an observational research registry, and a monthly journal club to establish and revise evidence-based guidelines for off-label therapies. The PMMTB allows for flexible and rapid implementation of treatment, uniformity in practice, and the ability to track outcomes. Results We describe the implementation of the PMMTB and its first year of activity. Seventy-seven patient cases were presented, 48 were enrolled in a registry, and 38 had recommendations and clinical follow-up. The 38 subjects had diverse solid tumors (lung, 45%; GI, 21%; breast, 13%; other, 21%). Of these subjects, targeted therapy was recommended for 32 (84%). Clinical trials were identified for 24 subjects (63%), and nontrial targeted medicines for 16 (42%). Nine subjects (28%) received recommended therapy with a response rate of 17% (one of six) and a clinical benefit rate (partial response + stable disease) of 38% (three of eight). Although clinical trials often were identified, patients rarely enrolled. Conclusion The PMMTB provides a model for a regional molecular tumor board with clinical utility. This work highlights the need for outcome registries and improved access to clinical trials to pragmatically implement precision oncology.

2553 Background: Spartalizumab and LAG525 are monoclonal antibodies targeting PD-1 and LAG-3, respectively. Dual blockade of PD-1 and LAG-3 has shown synergistic antitumor activity in preclinical models. Here we describe preliminary efficacy of spartalizumab + LAG525 across seven tumor types. Methods: Phase II, open-label, parallel-cohort study was conducted in pts with solid or hematologic malignances relapsed and/or refractory to standard-of-care therapies. Prior immunotherapy was prohibited. LAG525 (400 mg) and spartalizumab (300 mg) were dosed intravenously every 3 weeks. Primary endpoint was clinical benefit rate at 24 weeks (CBR24), assessed using a Bayesian hierarchical model-based futility analysis. Posterior probability that clinical benefit exceeds historical control (Pr) was estimated to determine futility at interim against prespecified thresholds. Results: As of January 7 2019, 76 pts received spartalizumab + LAG525; 72 pts were eligible for analysis (Table). The Pr cut-off for all arms was > 0.70. Hence, neuroendocrine tumors (NET), small cell lung cancer (SCLC) and diffuse large B-cell lymphoma (DLBCL) cohorts all met the expansion criteria with Pr of 0.971, 0.975 and 0.804 respectively. CBR24 were as follows; NET: 0.86, SCLC: 0.27, DLBCL: 0.43. Prostate, sarcoma and ovarian cohorts did not meet the expansion criterion (Pr > 0.70) but were not declared futile; enrollment was paused pending results of next analysis. Gastroesophageal (GE) cancer cohort was stopped for futility due to Pr (0.071) below the futility threshold. Conclusions: Spartalizumab and LAG525 showed promising activity in NET, SCLC and DLBCL that met expansion criteria. The GE cohort was declared futile. Remaining cohorts are paused pending further analysis. Clinical trial information: NCT03365791. [Table: see text]

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