The development of drugs to treat cancer is hampered by the inefficiency of translating pre-clinical in vitro monoculture and mouse studies into clinical benefit. There is a critical need to improve the accuracy of evaluating pre-clinical drug efficacy through the development of more physiologically relevant models. In this study, a human triculture 3D in vitro tumor microenvironment system (TMES) was engineered to accurately mimic the tumor microenvironment. The TMES recapitulates tumor hemodynamics and biological transport with co-cultured human microvascular endothelial cells, pancreatic ductal adenocarcinoma, and pancreatic stellate cells. We demonstrate that significant tumor cell transcriptomic changes occur in the TMES that correlate with the in vivo xenograft and patient transcriptome. Treatment with therapeutically relevant doses of chemotherapeutics yields responses paralleling the patients' clinical responses. Thus, this model provides a unique platform to rigorously evaluate novel therapies and is amenable to using patient tumor material directly, with applicability for patient avatars.
Background: Acute telestroke consults rely on a rapid, accurate NIH Stroke Scale. An important sign in cortical-based ischemic strokes is a Visual Field Deficit (VFD) contributing up to 3 points on the NIHSS affecting treatment decisions. Remote confrontational VFD testing is challenging and requires a trained assistant. We created a simple, rapid, telecart peripheral device to remotely administer a standardized VF test . The “ V isual fields R apid A ssessment D evice” ( VRAD ) is a wearable eye-glasses device. The device flashes LED lights in the 4 quadrants of each eye via remote control by a teleprovider allowing real-time control and interpretation. Methods: The VRAD Phase I study examined FDA-related human design factors of comfort, speed, and ease of use with direct use of VRAD. The results guided optimization of the prototype in preparation for the Phase II validation clinical trial. Subjects were randomly-selected, consented adult UVA Stroke Unit inpatients, with confirmed ischemic strokes. Following each VF test, blinded teleproviders, the patient ,and the telepresenter (nurse) completed a brief binary response questionnaire with open-ended comments. Biostatistical analysis: N= 20 subjects; 95% confidence interval with precision of +/- 10%. Results: The vast majority of patients, presenters, and providers (95-100%) reported VRAD testing was easy to understand and rapid. Patients: The device was comfortable (90%); 10% felt the stimulus light was too bright and 5% too dim. All identified when the light was on and had enough time to respond. Presenters: All reported rapid testing; 75% felt the device was easy to don on patients. The device was “sturdy and durable” 90%, “easy to use” 75%, “easy to clean” 70%, and “easy to connect” 60%. Providers: Reported the device sufficiently screened standard VFs (90%). All agreed they could remotely administer the test in various settings. Conclusion: The VRAD Phase I trial found the device to be safe, effective, easy to use, and comfortable by patients, providers, and presenters. Based on the results, an upgraded prototype was manufactured for our upcoming Phase II Non-Inferiority Validation Trial (Fall 2021). This data is a proof-of-concept of the value of teleneurology peripheral tools in remote settings.
Prostate cancer remains the most diagnosed cancer among men in the United States behind skin cancer, and advanced prostate cancer is the third leading cause of cancer-related deaths, with a 5-year survival rate of 26%. Radiation is the standard of care for the treatment of prostate cancer at the early and late stages. Checkpoint kinase 2 (CHK2) is a serine/threonine protein kinase whose main function is regulating the DNA damage response (DDR) induced by ionizing radiation. The androgen receptor (AR) is a major driver of prostate cancer, even at the castration-resistant stage of the disease. The development of the second-generation anti-androgen enzalutamide, which is a selective AR antagonist, highlights the enduring importance of the AR. We have previously demonstrated that CHK2 is a critical negative regulator of prostate cancer cell growth, androgen sensitivity, and AR transcriptional activity. We have now uncovered novel molecular interactions between CHK2 and AR that provide mechanistic insight into our observation that CHK2 regulates prostate cancer growth. The AR directly interacts with CHK2, and that interaction increases with radiation. We found that the interaction of CHK2 and AR occurs at sites of DNA damage. The binding of CHK2 with AR can be disrupted with CHK2 kinase inhibitors suggesting that the kinase activity of CHK2 is required. This was verified using kinase-impaired CHK2 variants, including the K373E variant associated with 4.2% of prostate cancer. Furthermore, the radiation-induced increase in CHK2-AR interactions requires AR phosphorylation on both serine 81 and serine 308. Interestingly, CHK2-depletion in LNCaP cells increases ionizing radiation induced AR expression and DNA damage. Together, these data provide the rationale for targeting the CHK2-AR signaling axis to improve the effectiveness of prostate cancer therapies. The combination of CHK2 or CDK1 inhibitors with androgen deprivation therapy (ADT) and radiation shows an additive effect on the repression of tumor cell growth. Nearly every patient with disseminated prostate cancer will relapse following ADT and develop incurable castration-resistant prostate cancer. We have uncovered the molecular details of a signaling axis involving CHK2 and AR that, when perturbed in combination with ADT and/or ionizing radiation, effectively inhibits prostate cancer cell growth. This may enable resensitization of castration-resistant prostate cancer to the currently approved treatment options. Citation Format: Huy Q. Ta, Natalia Dworak, Rosalie Sleppy, Jeffery A. Allende, Daniel Gioeli. Translating the functional interactions of checkpoint kinase 2 and the androgen receptor into more effective therapies for the treatment of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3747.
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