Avik Som

Binocular Goggle Augmented Imaging and Navigation System provides real-time fluorescence image guidance for tumor resection and sentinel lymph node mapping

The inability to identify microscopic tumors and assess surgical margins in real-time during oncologic surgery leads to incomplete tumor removal, increases the chances of tumor recurrence, and necessitates costly repeat surgery. To overcome these challenges, we have developed a wearable goggle augmented imaging and navigation system (GAINS) that can provide accurate intraoperative visualization of tumors and sentinel lymph nodes in real-time without disrupting normal surgical workflow. GAINS projects both near-infrared fluorescence from tumors and the natural color images of tissue onto a head-mounted display without latency. Aided by tumor-targeted contrast agents, the system detected tumors in subcutaneous and metastatic mouse models with high accuracy (sensitivity = 100%, specificity = 98% ± 5% standard deviation). Human pilot studies in breast cancer and melanoma patients using a near-infrared dye show that the GAINS detected sentinel lymph nodes with 100% sensitivity. Clinical use of the GAINS to guide tumor resection and sentinel lymph node mapping promises to improve surgical outcomes, reduce rates of repeat surgery, and improve the accuracy of cancer staging.

Protonation and Trapping of a Small pH-Sensitive Near-Infrared Fluorescent Molecule in the Acidic Tumor Environment Delineate Diverse Tumors In Vivo

Enhanced glycolysis and poor perfusion in most solid malignant tumors create an acidic extracellular environment, which enhances tumor growth, invasion, and metastasis. Complex molecular systems have been explored for imaging and treating these tumors. Here, we report the development of a small molecule, LS662, that emits near-infrared (NIR) fluorescence upon protonation by the extracellular acidic pH environment of diverse solid tumors. Protonation of LS662 induces selective internalization into tumor cells and retention in the tumor microenvironment. Noninvasive NIR imaging demonstrates selective retention of the pH sensor in diverse tumors, and two-photon microscopy of ex vivo tumors reveals significant retention of LS662 in tumor cells and the acid tumor microenvironment. Passive and active internalization processes combine to enhance NIR fluorescence in tumors over time. The low background fluorescence allows tumors to be detected with high sensitivity, as well as dead or dying cells to be delineated from healthy cells. In addition to demonstrating the feasibility of using small molecule pH sensors to image multiple aggressive solid tumor types via a protonation-induced internalization and retention pathway, the study reveals the potential of using LS662 to monitor treatment response and tumor-targeted drug delivery.

Acidic extracellular pH of tumors induces octamer-binding transcription factor 4 expression in murine fibroblasts in vitro and in vivo.

Octamer-binding transcription factor 4 (OCT-4) is an important marker of cellular de-differentiation that can be induced by environmental stressors, such as acidity. Here we demonstrate that chronic acidic stress in solid tumors induced OCT-4 expression in fibroblasts and other stromal cells in four tumor models. The results have implications for how tumors utilize pH modulation to recruit associated stromal cells, induce partial reprogramming of tumor-associated stromal cells, and respond to therapy.

Extracellular pH Modulates Neuroendocrine Prostate Cancer Cell Metabolism and Susceptibility to the Mitochondrial Inhibitor Niclosamide

Neuroendocrine prostate cancer is a lethal variant of prostate cancer that is associated with castrate-resistant growth, metastasis, and mortality. The tumor environment of neuroendocrine prostate cancer is heterogeneous and characterized by hypoxia, necrosis, and numerous mitoses. Although acidic extracellular pH has been implicated in aggressive cancer features including metastasis and therapeutic resistance, its role in neuroendocrine prostate cancer physiology and metabolism has not yet been explored. We used the well-characterized PNEC cell line as a model to establish the effects of extracellular pH (pH 6.5, 7.4, and 8.5) on neuroendocrine prostate cancer cell metabolism. We discovered that alkalinization of extracellular pH converted cellular metabolism to a nutrient consumption-dependent state that was susceptible to glucose deprivation, glutamine deprivation, and 2-deoxyglucose (2-DG) mediated inhibition of glycolysis. Conversely, acidic pH shifted cellular metabolism toward an oxidative phosphorylation (OXPHOS)-dependent state that was susceptible to OXPHOS inhibition. Based upon this mechanistic knowledge of pH-dependent metabolism, we identified that the FDA-approved anti-helminthic niclosamide depolarized mitochondrial potential and depleted ATP levels in PNEC cells whose effects were enhanced in acidic pH. To further establish relevance of these findings, we tested the effects of extracellular pH on susceptibility to nutrient deprivation and OXPHOS inhibition in a cohort of castrate-resistant prostate cancer cell lines C4-2B, PC-3, and PC-3M. We discovered similar pH-dependent toxicity profiles among all cell lines with these treatments. These findings underscore a potential importance to acidic extracellular pH in the modulation of cell metabolism in tumors and development of an emerging paradigm that exploits the synergy of environment and therapeutic efficacy in cancer.

Improving Dialysis Adherence for High Risk Patients Using Automated Messaging: Proof of Concept

Comorbidities and socioeconomic barriers often limit patient adherence and self-management with hemodialysis. Missed sessions, often associated with communication barriers, can result in emergency dialysis and avoidable hospitalizations. This proof of concept study explored using a novel digital-messaging platform, EpxDialysis, to improve patient-to-dialysis center communication via widely available text messaging and telephone technology. A randomized controlled trial was conducted through Washington University-affiliated hemodialysis centers involving ESRD patients with poor attendance, defined as missing 2–6 sessions over the preceding 12 weeks. A cross-over study design evaluated appointment adherence between intervention and control groups. Comparing nonadherence rates eight weeks prior to enrollment, median appointment adherence after using the system increased by 75%, and median number of unintended hospitalization days fell by 31%. A conservative cost-benefit analysis of EpxDialysis demonstrates a 1:36 savings ratio from appointment adherence. EpxDialysis is a low-risk, cost-effective, intervention for increasing hemodialysis adherence in high-risk patients, especially at centers caring for vulnerable and low-income patients.

Abstract LB-232: Nano-CaCO3 as a novel pH-sensitive nanoparticle platform for cancer therapy

Introduction: The acidic extracellular environment of tumors potentiates their aggressiveness and metastasis, but few methods exist to selectively modulate the extracellular pH (pHe) environment of tumors. Transient flushing of biological systems with alkaline fluids or proton pump inhibitors is impractical and nonselective. Here we report a nanoparticles-based strategy to intentionally modulate the pHe in tumors and restricts it growth. Methods: We developed two independent facile methods to synthesize monodisperse non-doped vaterite nano-CaCO3 with distinct size range between 20 and 300 nm. Biochemical simulations were used to simulate pH changes in vivo using the particle. In vitro and in vivo assays were used to determine pH changes. IV injections of the nanoparticles were implemented in a xenograft model of fibrosarcoma to determine growth changes. Results: Biochemical simulations indicate that the dissolution of calcium carbonate nanoparticles (nano-CaCO3) dissolution in vivo increases pH asymptotically to 7.4. Using murine models of cancer, we demonstrate that the selective accumulation of nano-CaCO3 in tumors increases tumor pHe over time. The persistent neutralization of tumor pHe from nano-CaCO3 induces tumor growth stasis. Conclusions: We have been able to create a novel nanoparticle based on widely existing in vivo components (Calcium and CO3) that safely equilibrates acidic pH of tumors up to normal physiological pH. As expected, this modulation restricts growth of implanted tumors in vivo. Future studies will study the effect of these particles on metastasis, and synergy with other therapeutic modalities. Citation Format: Avik Som, Ramesh Raliya, Walter Akers, Joseph Ippolito, Srikanth Singamaneni, Pratim Biswas, Samuel Achilefu. Nano-CaCO3 as a novel pH-sensitive nanoparticle platform for cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-232.

Nano-CaCO3 as a novel pH sensitive theranostic platform for solid tumors

Theranostic platforms allow the capability of both diagnostic level imaging and therapy for diseases such as cancer. The decreased pH found in the extracellular environment in cancer is an ideal target for cancer theranostics, because it is both a unique and universal hallmark that distinguishes tumor regions from normal tissue, but also that the decreased pH has been linked to tumor growth and metastasis. We describe herein the development of nano-CaCO3, a novel nanoparticle that can both increase pH in vivo resulting in therapeutic benefit, but also dissolves only at pHs less than 7.4 in vivo, creating a pH sensitivity to the nanoparticle that can be used to detect the more acidic pH ranges in vivo. As a result, nano-CaCO3 is pH sensitive theranostic platform for cancer detection and treatment in vivo.