PROAGIO (A Protein Designed to Target Integrin αVβ3)

Large efforts have been made to target integrin αVβ3 of endothelial cells. We have successfully developed a new class of protein (Ref to as ProAgio) by rational protein design using a stable host protein, domain 1 of cell adhesion protein CD2. ProAgio is designed to target integrin αVβ3 at a novel site and induces angiogenic endothelial cell apoptosis by recruiting and activating caspase 8 to the cytoplasmic domain of the targeted integrins. Tests with tumor xenograft models show that ProAgio strongly inhibits tumor growth. Histology analyses indicate that tumor vessels are reduced, while the established vasculatures are not affected. Toxicity analyses demonstrate that ProAgio is not toxic to mouse. Our study develops an effective anti-angiogenesis agent and provides a new platform for development of therapeutics by targeting integrins. We have successfully developed an anti-angiogenesis protein targeting integrin αVβ3 at a novel site by rational protein design. The developed agent is not toxic to non-cancerous blood vessels and other tissue/organs, providing an excellent candidate for future potential clinical development. Our developed protein is one of the very few examples that do not act through targeting VEGF/VEGFR or any other RTK pathways. The βA groove is present in almost all other β integrins. This approach may be applicable to develop agents targeting the similar βA groove of other integrin pairs, which can address wide array of pathological conditions such as AMD, Rheumatoid Arthritis, Osteoporosis etc

HSET Overexpression Fuels Tumor Progression via Centrosome Clustering-Independent Mechanisms in Breast Cancer Patients

Human breast tumors harbor supernumerary centrosomes in almost 80% of tumor cells. Although amplified centrosomes compromise cell viability via multipolar spindles resulting in death-inducing aneuploidy, cancer cells tend to cluster extra centrosomes during mitosis. As a result cancer cells display bipolar spindle phenotypes to maintain a tolerable level of aneuploidy, an edge to their survival. HSET/KifC1, a kinesin-like minus-end directed microtubule motor has recently found fame as a crucial centrosome clustering molecule. Here we show that HSET promotes tumor progression via mechanisms independent of centrosome clustering. We found that HSET is overexpressed in breast carcinomas wherein nuclear HSET accumulation correlated with histological grade and predicted poor progression-free and overall survival. In addition, deregulated HSET protein expression was associated with gene amplification and/or translocation. Our data provide compelling evidence that HSET overexpression is pro-proliferative, promotes clonogenic-survival and enhances cellcycle kinetics through G2 and M-phases. Importantly, HSET co-immunoprecipitates with survivin, and its overexpression protects survivin from proteasome-mediated degradation, resulting in its increased steady-state levels. We provide the first evidence of centrosome clustering-independent activities of HSET that fuel tumor progression and firmly establish that HSET can serve both as a potential prognostic biomarker and as a valuable cancer-selective therapeutic target

Cancer diagnosis and risk of suicide after accounting for prediagnosis psychiatric care: A matched‐cohort study of patients with incident solid‐organ malignancies

BackgroundPrevious studies have demonstrated an association between a diagnosis of cancer and the risk of suicide; however, they failed to account for psychiatric care before a cancer diagnosis, which may confound this relationship. The objective of this study was to assess the effect of a cancer diagnosis on the risk of suicide, accounting for prediagnosis psychiatric care utilization.MethodsAll adult residents of Ontario, Canada who were diagnosed with cancer (1 of prostate, breast, colorectal, melanoma, lung, bladder, endometrial, thyroid, kidney, or oral cancer) between 1997 and 2014 were identified. Noncancer controls were matched 4:1 based on sociodemographics, including a psychiatric utilization gradient (PUG) score (with 0 indicating none; 1, outpatient; 2, emergency department; and 3, hospital admission). A marginal, cause-specific hazard model was used to assess the effect of cancer on the risk of suicidal death.ResultsAmong 676,470 patients with cancer and 2,152,682 matched noncancer controls, there were 8.2 and 11.4 suicides per 1000 person-years of follow-up, respectively. Patients with cancer had an overall higher risk of suicidal death compared with matched patients without cancer (hazard ratio, 1.34; 95% CI, 1.22-1.48). This effect was pronounced in the first 50 months after cancer diagnosis (hazard ratio, 1.60; 95% CI, 1.42-1.81); patients with cancer did not demonstrate an increased risk thereafter. Among individuals with a PUG score 0 or 1, those with cancer were significantly more likely to die of suicide compared with controls. There was no difference in suicide risk between patients with cancer and controls for those who had a PUG score of 2 or 3.ConclusionsA cancer diagnosis is associated with increased risk of death from suicide compared with the general population even after accounting for precancer diagnosis psychiatric care utilization. The specific factors underlying the observed associations remain to be elucidated