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Inhibition of the kinase activity of leucine-rich repeat kinase 2 (LRRK2) is under investigation as a possible treatment for Parkinson's disease. However, there is no clinical validation as yet, and the safety implications of targeting LRRK2 kinase activity are not well understood. We evaluated the potential safety risks by comparing human and mouse LRRK2 mRNA tissue expression, by analyzing a Lrrk2 knockout mouse model, and by testing selective brain-penetrating LRRK2 kinase inhibitors in multiple species. LRRK2 mRNA tissue expression was comparable between species. Phenotypic analysis of Lrrk2 knockout mice revealed morphologic changes in lungs and kidneys, similar to those reported previously. However, in preclinical toxicity assessments in rodents, no pulmonary or renal changes were induced by two distinct LRRK2 kinase inhibitors. Both of these kinase inhibitors induced abnormal cytoplasmic accumulation of secretory lysosome-related organelles known as lamellar bodies in type II pneumocytes of the lung in nonhuman primates, but no lysosomal abnormality was observed in the kidney. The pulmonary change resembled the phenotype of Lrrk2 knockout mice, suggesting that this was LRRK2-mediated rather than a nonspecific or off-target effect. A biomarker of lysosomal dysregulation, di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP), was also decreased in the urine of Lrrk2 knockout mice and nonhuman primates treated with LRRK2 kinase inhibitors. Our results suggest a role for LRRK2 in regulating lysosome-related lamellar bodies and that pulmonary toxicity may be a critical safety liability for LRRK2 kinase inhibitors in patients.

10037 Background: The optimal treatment and outcome for elderly patients (pts) with localized gastroesophageal (GE) cancer remains unclear as they are underrepresented in clinical trials. We aimed to assess survival in pts ≥75 years according to treatment received. Methods: A retrospective analysis was performed for all pts aged ≥75 years with GE cancer treated in 2012-2014. Frailty was measured using the Charlson comorbidity index (CCI) and ECOG performance status (PS). Overall survival (OS) and disease-free survival (DFS) were assessed via uni- and multivariable Cox proportional hazards regression, adjusting for demographics. Logistic regression analyses were used to examine factors impacting treatment choices. Results: Of 105 pts, median age was 81 years (range: 75-99), primary sites were esophageal (55%, with 43% squamous histology) and gastric (45%). Baseline characteristics included: PS: 0 (31%), 1 (42%), 2 (16%), 3 (10%), 4 (1%); and CCI: 0 (34%), 1 (25%), 2 (19%), ≥3 (22%). Treatment received included radiotherapy alone (RT) (31%); surgery alone (29%); surgery plus adjuvant chemotherapy (chemo) and/or RT (14%); chemoradiation alone (7%) and supportive care (18%). In univariable analyses; age < 85 (p = 0.003), PS < 2 (p = 0.03) and surgery (p < 0.001) were associated with improved OS. Chemo and RT, either alone or in combination, did not significantly improve OS. In multivariable analyses; surgery (HR 0.38, 95% CI 0.21-0.70, p = 0.002) was the only independent predictor for improved OS. Patients with good PS (p = 0.01), gastric disease site (p = 0.01) and adenocarcinoma histology (p = 0.02) were more likely to undergo surgery. Conclusions: At our institution, relatively few pts ≥75 years received multimodality therapy for localized GE cancers. Those pts ≥75 years who underwent surgery had excellent outcomes, but they were well-selected. Comprehensive assessment should be considered for pts ≥75 years with localized GE cancer to ensure optimal treatment selection, particularly given the potential benefit of surgery.

Leucine-rich repeat kinase 2 (LRRK2) has drawn significant interest in the neuroscience research community because it is one of the most compelling targets for a potential disease-modifying Parkinson's disease therapy. Herein, we disclose structurally diverse small molecule inhibitors suitable for assessing the implications of sustained in vivo LRRK2 inhibition. Using previously reported aminopyrazole 2 as a lead molecule, we were able to engineer structural modifications in the solvent-exposed region of the ATP-binding site that significantly improve human hepatocyte stability, rat free brain exposure, and CYP inhibition and induction liabilities. Disciplined application of established optimal CNS design parameters culminated in the rapid identification of GNE-0877 (11) and GNE-9605 (20) as highly potent and selective LRRK2 inhibitors. The demonstrated metabolic stability, brain penetration across multiple species, and selectivity of these inhibitors support their use in preclinical efficacy and safety studies.

Although chemotherapeutic advances have recently been heralded in lung adenocarcinomas, such success with small-cell lung cancer (SCLC) has been ominously absent. Indeed, the dismal outlook of this disease is exemplified by the failure of any significant advances in first line therapy since the introduction of the current standard platinum-etoposide doublet over 30 years ago. Moreover, such sluggish progress is compounded by the dearth of FDA-approved agents for patients with relapsed disease. However, over the past decade, novel formulations of drug classes commonly used in SCLC (e.g. topoisomerase inhibitors, anthracyclines, alkylating and platinum agents) are emerging as potential alternatives that could effectively add to the armamentarium of agents currently at our disposal. This review is introduced with an overview on the historical development of chemotherapeutic regimens used in this disease and followed by the recent encouraging advances witnessed in clinical trials with drugs such as amrubicin and belotecan which are forging new horizons for future treatment algorithms.

126 Background: The optimal CRT regimen for neoadjuvant or definitive treatment of locoregional esophageal or gastroesophageal junctional (GEJ) cancer is uncertain. There has been no direct comparison between concurrent Cisplatin/5-FU (CF) as per the CALGB 9781 trial (50.4 Gy) or Carboplatin/Paclitaxel (CP) as per the CROSS trial (41.4 Gy). Methods: A retrospective analysis comparing CF and CP was performed in all patients (pts) with locoregional esophageal or GEJ cancer treated in 2012-2014. Overall survival (OS) and disease-free survival (DFS) were assessed via uni- and multivariable Cox proportional hazards regression, adjusting for age, performance status and Charlson comorbidity index. Pathological complete response (pCR) rates were compared using Fisher’s exact test. Results: 64/86 (74%) pts were male. Median age was 64 years (range: 34-84). Primary sites were esophageal (56%, with 60% squamous histology) and GEJ (44%, with 11% squamous). 22 pts received CRT in 2012 (100% CF), 33 pts in 2013 (58% CF, 42% CP) and 31 pts in 2014 (16% CF, 84% CP). Surgery was undertaken in 19 (41%) CF and 27 (68%) CP pts. Median follow-up was 38 months. We found no significant OS difference between CF and CP overall (HR 0.82, 95% CI: 0.43-1.56, p = 0.55) or in the subgroup having surgery (n = 46; HR 2.01, 95% CI: 0.62-6.55, p = 0.25). However, in the subgroup without surgery (n = 40), CF (n = 27) was superior to CP (n = 13)(HR 0.11, 95% CI: 0.03-0.38, p < 0.001). OS was similar by histology (adenocarcinoma/squamous) in all-comers (p = 0.96), and in CF (p = 0.66) and CP subgroups (p = 0.66). DFS results were similar to OS. There was a non-significant numerical difference in pCR rates between CF (31%) and CP (18%) (p = 0.45). Conclusions: Survival is similar for CF and CP CRT regimens in patients undergoing trimodality therapy. pCR rates were comparable but lower than previously reported. In contrast, in the absence of surgical resection, CP given for CRT results in significantly inferior outcomes. Clinicians may prefer CP for surgical candidates given its toxicity profile. However, when treating with definitive CRT, CF may be preferable to CP as a standard regimen.

21 Background: ACP refers to the process of consideration, documentation and communication of preferences for future care. ACP is crucial for patients (pts) with advanced cancer as it can guide substitute decision makers (SDM) and health care providers (HCP) to align care with preferences, thus improving quality of end-of-life care. Methods: We performed a systematic review of MEDLINE, EMBASE, CINAHL, PsycINFO and Cochrane (Systematic Review and Clinical Trial) databases (1995 to 2015) to identify interventions that facilitate ACP for cancer pts (documentation or discussion of advance directives, SDM or code status). We extracted data on study design, setting, subject numbers, interventions and outcomes. Study quality was assessed using a modified Downs and Black checklist. Results: Of the 64,196 unique citations identified, 10 studies met inclusion criteria for testing interventions using a pre-post or controlled trial design (median sample size 134, range 48-9105). Interventions were categorized based on target audience: health system (n = 4), pts and caregivers (n = 3) or HCP (n = 3). Types of interventions included: introduction of ACP facilitators (n = 4), reminders or prompts (n = 2), and HCP training, videos, website or pt screening (n = 1 each). Heterogeneity in study design, outcome measures and small sample sizes limited study quality and precluded meta-analysis. Prompts such as medical record or email reminders were most consistently associated with improved ACP documentation. System changes incorporating the use of ACP facilitators also improved ACP documentation in 3 out of 4 studies. Interactive HCP training significantly improved confidence to initiate ACP discussions which has been identified as a barrier to timely ACP. Pilot trials showed no significant increase in ACP with educational videos/websites directed at pts. Passive HCP education and one-off reminders were also ineffective. Conclusions: The complexity of ACP is reflected in the multitude of interventions that have been evaluated but none are ready for wide-scale adoption. Further studies of interventions such as prompts and ACP facilitators are needed to inform the best approach to improve ACP uptake in cancer pts.

There is a high demand for potent, selective, and brain-penetrant small molecule inhibitors of leucine-rich repeat kinase 2 (LRRK2) to test whether inhibition of LRRK2 kinase activity is a potentially viable treatment option for Parkinson's disease patients. Herein we disclose the use of property and structure-based drug design for the optimization of highly ligand efficient aminopyrimidine lead compounds. High throughput in vivo rodent cassette pharmacokinetic studies enabled rapid validation of in vitro-in vivo correlations. Guided by this data, optimal design parameters were established. Effective incorporation of these guidelines into our molecular design process resulted in the discovery of small molecule inhibitors such as GNE-7915 (18) and 19, which possess an ideal balance of LRRK2 cellular potency, broad kinase selectivity, metabolic stability, and brain penetration across multiple species. Advancement of GNE-7915 into rodent and higher species toxicity studies enabled risk assessment for early development.

Inhibition of PI3Kδ is considered to be an attractive mechanism for the treatment of inflammatory diseases and leukocyte malignancies. Using a structure-based design approach, we have identified a series of potent and selective benzimidazole-based inhibitors of PI3Kδ. These inhibitors do not occupy the selectivity pocket between Trp760 and Met752 that is induced by other families of PI3Kδ inhibitors. Instead, the selectivity of the compounds for inhibition of PI3Kδ relative to other PI3K isoforms appears to be due primarily to the strong interactions these inhibitors are able to make with Trp760 in the PI3Kδ binding pocket. The pharmacokinetic properties and the ability of compound 5 to inhibit the function of B-cells in vivo are described.

PI3Kδ is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(α, β, δ) and IB (γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3Kδ inhibitors and describe a structural hypothesis for isoform (α, β, γ) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.

Mutations in the genetic sequence of leucine-rich repeat kinase 2 (LRRK2) have been linked to increased LRRK2 activity and risk for the development of Parkinson's disease (PD). Potent and selective small molecules capable of inhibiting the kinase activity of LRRK2 will be important tools for establishing a link between the kinase activity of LRRK2 and PD. In the absence of LRRK2 kinase domain crystal structures, a LRRK2 homology model was developed that provided robust guidance in the hit-to-lead optimization of small molecule LRRK2 inhibitors. Through a combination of molecular modeling, sequence analysis, and matched molecular pair (MMP) activity cliff analysis, a potent and selective lead inhibitor was discovered. The selectivity of this compound could be understood using the LRRK2 homology model, and application of this learning to a series of 2,4-diaminopyrimidine inhibitors in a scaffold hopping exercise led to the identification of highly potent and selective LRRK2 inhibitors that were also brain penetrable.

Optimized conditions allow the reductive cyclization of various aromatic substrates bearing a wide range of functionalities.

Gallium nitrate possesses antineoplastic activity against certain solid tumors and has been demonstrated to be an effective agent in reducing cell proliferation and DNA synthesis in the medulloblastoma Daoy cell line in vitro. In prior studies, gallium inhibited the cellular uptake of 59Fe by brain tumor cells; however, this block in 59Fe uptake was variable and closely paralleled the inhibitory effects of gallium on cell growth. In vivo trials now have been conducted and have yielded some promising results. Nude mice received intradermal injections of medulloblastoma Daoy and then allowed to grow tumors. When the mice had developed at least one tumor between 9 to 10 mm in diameter, a 10-day course of intraperitoneal gallium nitrate injections was initiated. Gallium nitrate treatment reduced overall tumor growth rate and reduced actual tumor size. Nephrotoxicity was severe, but may be preventable by continuous gallium infusion and use of diuretics and hyperhydration.

We review some reactions devised in our laboratory for the rapid assembly of pyridines and pyridones. Applications of the new methods in the total synthesis of lavendamycin, pyridoacridine and phenanthroizidine alkaloids (pyridine chemistry), and of camptothecin, nothapodytine B and streptonigrone (pyridone-forming reactions) are described.

A total synthesis of streptonigrone, 1, is described, which incorporates a one-step synthesis of substituted pyridones devised in our laboratory. Other aspects of the synthesis that differentiate the present approach from previous ones are the use of a Conrad-Limpach reaction, rather than the customary Friedlander methodology, to assemble the quinoline segment of 1, and the implementation of an anionic sequence for the functionalization of a key pyridone intermediate.

Paralleling the diversity of genetic and protein activities, pathologic human tissues also exhibit diverse radiographic features. Here we show that dynamic imaging traits in non-invasive computed tomography (CT) systematically correlate with the global gene expression programs of primary human liver cancer. Combinations of twenty-eight imaging traits can reconstruct 78% of the global gene expression profiles, revealing cell proliferation, liver synthetic function, and patient prognosis. Thus, genomic activity of human liver cancers can be decoded by noninvasive imaging, thereby enabling noninvasive, serial and frequent molecular profiling for personalized medicine.

Objectives: To compare the dose intensity and toxicity profiles for patients undergoing chemotherapy at the Townsville Cancer Centre (TCC), a tertiary cancer centre in northern Queensland, with those for patients treated in Mount Isa, supervised by the same medical oncologists via teleoncology. Design: A quasi-experimental design comparing two patient groups. Setting: TCC and Mount Isa Hospital, which both operate under the auspices of the Townsville Teleoncology Network (TTN). Participants: Eligible patients who received chemotherapy at TCC or Mt Isa Hospital between 1 May 2007 and 30 April 2012. Intervention: Teleoncology model for managing cancer patients in rural towns. Main outcome measures: Dose intensity (doses, number of cycles and lines of treatment) and toxicity rates (rate of serious side effects, hospital admissions and mortality). Results: Over 5 years, 89 patients received a total of 626 cycles of various chemotherapy regimens in Mount Isa. During the same period, 117 patients who received a total of 799 cycles of chemotherapy at TCC were eligible for inclusion in the comparison group. There were no significant differences between the Mount Isa and TCC patients in most demographic characteristics, mean numbers of treatment cycles, dose intensities, proportions of side effects, and hospital admissions. There were no toxicity-related deaths in either group. Conclusion: It appears safe to administer chemotherapy in rural towns under the supervision of medical oncologists from larger centres via teleoncology, provided that rural health care resources and governance arrangements are adequate.

Synthetic hydroxydienone precursors to spiroleucettadine and to an isomer thereof resist cyclization to the orthoamide-type functionality present in the proposed structure of the natural product.

We review some reactions devised in our laboratory for the rapid assembly of pyridines and pyridones. Applications of the new methods in the total synthesis of lavendamycin, pyridoacridine and phenanthroizidine alkaloids (pyridine chemistry), and of camptothecin, nothapodytine B and streptonigrone (pyridone-forming reactions) are described.