FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy.

Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance

Process-Oriented Evaluation of Climate and Weather Forecasting Models

Realistic climate and weather prediction models are necessary to produce confidence in projections of future climate over many decades and predictions for days to seasons. These models must be physically justified and validated for multiple weather and climate processes. A key opportunity to accelerate model improvement is greater incorporation of process-oriented diagnostics (PODs) into standard packages that can be applied during the model development process, allowing the application of diagnostics to be repeatable across multiple model versions and used as a benchmark for model improvement. A POD characterizes a specific physical process or emergent behavior that is related to the ability to simulate an observed phenomenon. This paper describes the outcomes of activities by the Model Diagnostics Task Force (MDTF) under the NOAA Climate Program Office (CPO) Modeling, Analysis, Predictions and Projections (MAPP) program to promote development of PODs and their application to climate and weather prediction models. MDTF and modeling center perspectives on the need for expanded process-oriented diagnosis of models are presented. Multiple PODs developed by the MDTF are summarized, and an open-source software framework developed by the MDTF to aid application of PODs to centers’ model development is presented in the context of other relevant community activities. The paper closes by discussing paths forward for the MDTF effort and for community process-oriented diagnosis

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Maitake Mushroom Extract in Myelodysplastic Syndrome (MDS): A Phase II Study

Abstract Abstract 5043 Background: MDS is a heterogeneous group of hematologic diseases characterized by ineffective erythropoiesis and an increased risk of AML. MDS-related deaths are commonly due to infection resulting from impaired immunity, including quantitative and functional neutrophil defects. Maitake extract is from the fruit body of Grifola frondosa mushroom and is widely used in Asia as an adjunctive treatment for malignant diseases. This hot water extract is composed of a central beta 1,6-glucan core surrounded by beta 1,3-branches. Maitake extract enhances hematopoiesis by increasing G-CSF production with subsequent stem cell proliferation and differentiation of granulocyte-monocyte colony forming cells. Maitake also activates macrophages through Dectin-1 receptor binding, increases the weight and number of nucleated cells in the spleen and improves innate immune response in animal and human models. Activated macrophages may reduce iron stores. Compared to G-CSF, maitake may have fewer side-effects, is less costly, and may produce a comparable improvement in granulocyte function. Materials and Methods: MDS patients with IPSS Low and Int-1 risk disease and ANC>500, plts >20K were enrolled. Following double baseline measurements, patients received the maitake extract at 3mg/kg PO BID for 12 weeks. Primary endpoints include change in neutrophil counts and alterations in granulocyte function as measured by the respiratory burst test. The respiratory burst test is a highly sensitive and quantitative flow cytometric assay of granulocyte and monocyte function to assess the production of spontaneous reactive oxygen species (ROS) and stimulated response to 3 activators: opsonized E. coli, phorbol ester and the chemotactic peptide N-formylmethiolyl-leucyl-phenylalanine (fMLP). Results were compared to age-matched normal healthy volunteers. Responses were assessed using the modified International Working Group (IWG) MDS response criteria. Secondary endpoints include serial assessment of hemoglobin and platelet levels, reticulocyte count, monocyte function, and GM-CSF and G-CSF levels. Iron studies were assessed throughout treatment to determine whether the maitake indirectly alters iron stores potentially decreasing iron overload. Results: 14 eligible patients (pts) (8M, 6F; median age 69, range 52–83 yrs) received the maitake extract. IPSS risk categories included: Low-risk, n=7; Int-1, n=7. WHO Stage: RA=2; RARS=1; RCMD=6; RCMD-RS=1; RCUD=1; MDS-U=1; CMML-1=2. Two pts received prior 5-azacytidine therapy. Mean fMLP-stimulated granulocyte function in pts at baseline was lower than control values. Monocyte baseline response to E. coli was significantly reduced (p<0.01); ROS production to phorbol ester was also lower than in controls. No patients met criteria for response using the modified IWG response criteria. Preliminary analyses showed that ROS responses to E. coli stimulation increased by weeks 7–9 in pts who were deficient at baseline. Monocyte ROS production increased in 2 pts by 2–6 fold at week 7. There was a 2–15 fold increase in the neutrophil response to fMLP by week 7 and a 2–35 fold increase in monocyte response to fMLP at week 9. Monocyte response to E. coli increased between 3–10 fold in 2 pts with peak values during weeks 7–9. The two pts with the most pronounced response by fMLP and ROS production also had eosinophilia, which resolved following study participation. The most common toxicities were diarrhea (grade 1) in 6 pts, eosinophilia (2–2.8 × normal) in 3 pts, increases in AST (grade 1) and ALT (grade 1) in 4 pts and nausea (grade 1) in 1 patient. Two pts were removed from the study, one for diarrhea possibly related to study medication and one for disease progression. Conclusion: Maitake mushroom extract is well tolerated without evidence of clinically significant adverse hepatic, renal or metabolic abnormalities. No clinical responses were seen. Based on our preliminary data, the maitake extract appears to enhance ROS in both unstimulated and stimulated cells, confirming preclinical data. The improvement in granulocyte and monocyte function in our in vitro studies suggests that maitake may enhance immune responses in MDS pts. Eosinophilia was noted but the significance remains uncertain at this time. The study is ongoing. Updated results will be presented. Disclosures: No relevant conflicts of interest to declare

Tumor FAK orchestrates immunosuppression in ovarian cancer via the CD155/TIGIT axis

High-grade serous ovarian cancer (HGSOC) is a lethal malignancy characterized by an immunosuppressive tumor microenvironment containing few tumor infiltrating lymphocytes (TILs) and an insensitivity to checkpoint inhibitor immunotherapies. Gains in the PTK2 gene encoding focal adhesion kinase (FAK) at Chr8 q24.3 occur in ∼70% of HGSOC tumors, and elevated FAK messenger RNA (mRNA) levels are associated with poor patient survival. Herein, we show that active FAK, phosphorylated at tyrosine-576 within catalytic domain, is significantly increased in late-stage HGSOC tumors. Active FAK costained with CD155, a checkpoint receptor ligand for TIGIT (T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains), in HGSOC tumors and a selective association between FAK and TIGIT checkpoint ligands were supported by patient transcriptomic database analysis. HGSOC tumors with high FAK expression were associated with low CD3 mRNA levels. Accordingly, late-stage tumors showed elevated active FAK staining and significantly lower levels of CD3+ TILs. Using the KMF (Kras, Myc, FAK) syngeneic ovarian tumor model containing spontaneous PTK2 (FAK) gene gains, the effects of tumor intrinsic genetic or oral small molecule FAK inhibitior (FAKi; VS-4718) were evaluated in vivo. Blocking FAK activity decreased tumor burden, suppressed ascites KMF-associated CD155 levels, and increased peritoneal TILs. The combination of FAKi with blocking TIGIT antibody (1B4) maintained elevated TIL levels and reduced TIGIT+ T regulatory cell levels, prolonged host survival, increased CXCL13 levels, and led to the formation of omental tertiary lymphoid structures. Collectively, our studies support FAK and TIGIT targeting as a rationale immunotherapy combination for HGSOC

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy.

Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance