Chitosan nanoparticle-mediated delivery of miRNA-34a decreases prostate tumor growth in the bone and its expression induces non-canonical autophagy

While several new therapies are FDA-approved for bone-metastatic prostate cancer (PCa), patient survival has only improved marginally. Here, we report that chitosan nanoparticle-mediated delivery of miR-34a, a tumor suppressive microRNA that downregulates multiple gene products involved in PCa progression and metastasis, inhibited prostate tumor growth and preserved bone integrity in a xenograft model representative of established PCa bone metastasis. Expression of miR-34a induced apoptosis in PCa cells, and, in accord with downregulation of targets associated with PCa growth, including MET and Axl and c-Myc, also induced a form of non-canonical autophagy that is independent of Beclin-1, ATG4, ATG5 and ATG7. MiR-34a-induced autophagy is anti-proliferative in prostate cancer cells, as blocking apoptosis still resulted in growth inhibition of tumor cells. Thus, combined effects of autophagy and apoptosis are responsible for miR-34a-mediated prostate tumor growth inhibition, and have translational impact, as this non-canonical form of autophagy is tumor inhibitory. Together, these results provide a new understanding of the biological effects of miR-34a and highlight the clinical potential for miR-34a delivery as a treatment for bone metastatic prostate cancer

Current perspectives on bone metastases in castrate-resistant prostate cancer

Prostate cancer is the most frequent noncutaneous cancer occurring in men. On average, men with localized prostate cancer have a high 10-year survival rate, and many can be cured. However, men with metastatic castrate-resistant prostate cancer have incurable disease with poor survival despite intensive therapy. This unmet need has led to recent advances in therapy aimed at treating bone metastases resulting from prostate cancer. The bone microenvironment lends itself to metastases in castrate-resistant prostate cancer, as a result of complex interactions between the microenvironment and tumor cells. The development of 223radium dichloride (Ra-223) to treat symptomatic bone metastases has improved survival in men with metastatic castrate-resistant prostate cancer. Moreover, Ra-223 may have effects on the tumor microenvironment that enhance its activity. Ra-223 treatment has been shown to prolong survival, and its effects on the immune system are under investigation. Because prostate cancer affects a sizable portion of the adult male population, understanding how it metastasizes to bone is an important step in advancing therapy. Clinical trials that are underway should yield new information on whether Ra-223 synergizes effectively with immunotherapy agents and whether Ra-223 has enhancing effects on the immune system in patients with prostate cancer

Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor–positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor–positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. Significance: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors

Review of social media’s influence on Airbnb accommodation’s booking intention

The impact of social media on the tourism industry has great significance for all stakeholders. The purpose of this paper is to highlight and comprehend how social media’s (Social Networking and Review Sites) influences accommodation’s booking intention, with regards to Airbnb accommodation. To achieve the purpose, the paper focuses on exploring the scope of social media, comprehending the different levels of exposure or usage of social media by different generations, and analyzing the influence of social media in booking Airbnb accommodations. Through these objectives, it intends to emphasize the role of social media in the tourism industry, as well as brings out the benefits for tourists across the globe. This research expresses the factors that are considered to influence Airbnb booking intention through a conceptual framework. In analyzing the scope of choosing Airbnb as a traveler’s accommodation, this study also demonstrates that social media is a useful tool in improving not only the quality of business but also increasing the revenue

Modulation of IGF-1–induced Akt1 and Akt2 phosphorylation in PC-3 cells by dasatinib (DSA) and BMS-754807 (BMS-807).

<p>(A) PC-3 cells were serum starved for 72 hours and then pre-incubated for 2 hours with BMS-754807 at either 2 µM or 5 µM, with dasatinib at 100 nM, or with both agents. After 2 hours, the cells were stimulated with 50 ng/mL recombinant human IGF-1 (rhIGF-1) for 3 minutes. Next, protein was harvested and the (phospho)-proteins IGF-1R, Src, and Akt were determined by western blot (WB). Vinculin was used as the loading control. (B and C) PC-3 cells were stimulated with DSA (100 nM) and BMS-754807 (5 µM) as above, and then the cells were harvested and immunoprecipitated for Akt1 (B) or Akt2 (C), followed by immunoblotting for phospho-Akt. (D) PC-3 cells were treated as in (A), and western blot was run for S6 and phospho-S6.</p

Dasatinib (DSA) and BMS-754807 (BMS-807) decrease intratibial bone destruction and tumor formation and modulate bone turnover markers.

<p>Bone-destructive PC3-MM2 cells were injected intratibially in nude mice. Following treatment with dasatinib, BMS-754807 alone and combined, the mice were euthanized, and x-rays and computed tomographic (CT) scanning of the long bones were done (control, n = 10; dasatinib, n = 9; BMS-754807, n = 9; combination, n = 8). Blood was collected for serum bone turnover markers. (A) The degree of bone destruction was blindly graded in a semiquantitative fashion based on x-rays from all mice. The graph displays the proportion of high-grade lesions (i.e., 2 or 3) in each treatment group. * <i>P</i><0.05 combination vs. dasatinib only. (B) Representative CT scans (top) and x-rays (bottom) from the mice in each group. Arrows and numbers indicate the lesion site and the grade of bone destruction. (C and D) Serum levels of murine alkaline phospatase (C) and N-telopeptide (D) were determined by ELISA. Bars indicates SEM. * <i>P</i><0.05.</p