Publications by authors named "Oliver Jonas"

Article Synopsis
  • This study looked at a new way to place a tiny device in men's tumors to see how they respond to different cancer drugs.
  • They used a special scan to help put the devices in the right spot, just before surgery to remove the tumors.
  • The results showed that the method was safe and let them see how the tumors reacted to the drugs, which might help doctors make better treatment choices in the future.
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Systems that can image in three dimensions at cellular resolution and across different locations within an organism may enable insights into complex biological processes, such as immune responses, for which a single location measurement may be insufficient. In this Letter, we describe an in vivo two-site imaging probe (TIP) that can simultaneously image two anatomic sites with a maximum separation of a few centimeters. The TIP consists of two identical bendable graded index (GRIN) lenses and is demonstrated by a two-photon two-color fluorescence imaging system.

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Background: Percutaneous microwave ablation (pMWA) is a minimally invasive procedure that uses a microwave antenna placed at the tip of a needle to induce lethal tissue heating. It can treat cancer and other diseases with lower morbidity than conventional surgery, but one major limitation is the lack of control over the heating region around the ablation needle. Superparamagnetic iron oxide nanoparticles have the potential to enhance and control pMWA heating due to their ability to absorb microwave energy and their ease of local delivery.

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The lack of reliable predictive biomarkers to guide effective therapy is a major obstacle to the advancement of therapy for high-grade gliomas, particularly glioblastoma (GBM), one of the few cancers whose prognosis has not improved over the past several decades. With this pilot clinical trial (number NCT04135807), we provide first-in-human evidence that drug-releasing intratumoral microdevices (IMDs) can be safely and effectively used to obtain patient-specific, high-throughput molecular and histopathological drug response profiling. These data can complement other strategies to inform the selection of drugs based on their observed antitumor effect in situ.

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Immunotherapies, including anti-PD-1 immune checkpoint blocking (ICB) antibodies, have revolutionized the treatment of many solid malignancies. However, their efficacy in breast cancer has been limited to a subset of patients with triple-negative breast cancer, where ICBs are routinely combined with a range of cytotoxic and targeted agents. Reliable biomarkers predictive of the therapeutic response to ICB in breast cancer are critically missing, though a combination response has been associated with immunogenic cell death (ICD).

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Article Synopsis
  • Tumor-infiltrating immune cells and cancer cells compete for nutrients in the tumor microenvironment, leading to metabolic reprogramming that affects their functions.
  • The study introduced a new method using implantable microdevices to analyze how different metabolites impact the health and endurance of immune versus tumor cells within the native tumor environment.
  • Key findings highlight the importance of metabolites like glutamine and arginine in enhancing immune responses, and suggest that optimizing these metabolic pathways could improve the effectiveness of immunotherapies in cancer treatment.
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Article Synopsis
  • Abiraterone, a treatment for metastatic castrate-resistant prostate cancer (mCRPC), slows disease progression by blocking androgen synthesis and receptor activity, but it also causes mitotic defects that can make cancer cells more sensitive to other treatments.
  • Inhibitors like onvansertib, which target the mitotic regulator polo-like kinase-1 (Plk1), work synergistically with abiraterone to kill a range of cancer cells in an androgen-independent way, leading to increased cancer cell death.
  • Preclinical studies using a mouse model show that the combination of onvansertib and abiraterone significantly enhances tumor growth inhibition compared to either drug used alone, supporting ongoing clinical trials for this
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Graded index (GRIN) lens endoscopy has broadly benefited biomedical microscopic imaging by enabling accessibility to sites not reachable by traditional benchtop microscopes. It is a long-held notion that GRIN lenses can only be used as rigid probes, which may limit their potential for certain applications. Here, we describe bendable and long-range GRIN microimaging probes for a variety of potential micro-endoscopic biomedical applications.

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One of the major shortcomings of nano carriers-assisted cancer therapeutic strategies continues to be the inadequate tumor penetration and retention of systemically administered nanoformulations and its off-target toxicity. Stromal parameters-related heterogeneity in enhanced permeability and retention effect and physicochemical properties of the nanoformulations immensely contributes to their poor tumor extravasation. Herein, a novel tumor targeting strategy, where an intratumorally implanted micromagnet can significantly enhance accumulation of magneto-plasmonic nanoparticles (NPs) at the micromagnet-implanted tumor in bilateral colorectal tumor models while limiting their off-target accumulation, is demonstrated.

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Systematically identifying synergistic combinations of targeted agents and immunotherapies for cancer treatments remains difficult. In this study, we integrated high-throughput and high-content techniques-an implantable microdevice to administer multiple drugs into different sites in tumors at nanodoses and multiplexed imaging of tumor microenvironmental states-to investigate the tumor cell and immunological response signatures to different treatment regimens. Using a mouse model of breast cancer, we identified effective combinations from among numerous agents within days.

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Long-term treatment outcomes for patients with high grade ovarian cancers have not changed despite innovations in therapies. There is no recommended assay for predicting patient response to second-line therapy, thus clinicians must make treatment decisions based on each individual patient. Patient-derived xenograft (PDX) tumors have been shown to predict drug sensitivity in ovarian cancer patients, but the time frame for intraperitoneal (IP) tumor generation, expansion, and drug screening is beyond that for tumor recurrence and platinum resistance to occur, thus results do not have clinical utility.

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A main impediment to effective development of new therapeutics for central nervous system disorders, and for the testing of biological hypotheses in the brain, is the ability to rapidly measure the effect of novel agents and treatment combinations on the pathophysiology of native brain tissue. We have developed a miniaturized implantable microdevice (IMD) platform, optimized for direct stereotactic insertion into the brain, which enables the simultaneous measurement of multiple drug effects on the native brain tissue . The IMD contains individual reservoirs which release microdoses of single agents or combinations into confined regions of the brain, with subsequent spatial analysis of phenotypic, transcriptomic or metabolomic effects.

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Objective: To evaluate the safety and feasibility of implantation and retrieval of a novel implantable microdevice (IMD) in NSCLC patients undergoing operative resection.

Background: Adjuvant therapy has limited impact on postsurgical outcomes in NSCLC due to the inability to predict optimal treatment regimens.

Methods: An IMD measuring 6.

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Advances in the intratumor measurement of drug responses have included a pioneering biomedical microdevice for high throughput drug screening in vivo, which was further advanced by integrating a graded-index lens based two-dimensional fluorescence micro-endoscope to monitor tissue responses in situ across time. While the previous system provided a bulk measurement of both drug delivery and tissue response from a given region of the tumor, it was incapable of visualizing drug distribution and tissue responses in a three-dimensional (3D) way, thus missing the critical relationship between drug concentration and effect. Here we demonstrate a next-generation system that couples multiplexed intratumor drug release with continuous 3D spatial imaging of the tumor microenvironment via the integration of a miniaturized two-photon micro-endoscope.

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Background: Tumor heterogeneity is increasingly being recognized as a major source of variability in the histopathological assessment of drug responses. Quantitative analysis of immunohistochemistry (IHC) and immunofluorescence (IF) images using biomarkers that capture spatialpatterns of distinct tumor biology and drug concentration in tumors is of high interest to the field.

Methods: We have developed an image analysis pipeline to measure drug response using IF and IHC images along spatial gradients of local drug release from a tumor-implantable drug delivery microdevice.

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Implantable drug-delivery microdevices are a key diagnostic and therapeutic tool in medicine with increasing applications. Preparation of such combination drug-delivery devices for human studies requires the development of methods to ensure sterility, safety and integrity on both the device and drug side. Despite growing applications for these technologies, there has been a lack of clear methodology regarding sterilization and preparation to meet strict guidelines set forth by the Food and Drug Administration (FDA).

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Objective: The purpose of this article is to report the translational process of an implantable microdevice platform with an emphasis on the technical and engineering adaptations for patient use, regulatory advances, and successful integration into clinical workflow.

Methods: We developed design adaptations for implantation and retrieval, established ongoing monitoring and testing, and facilitated regulatory advances that enabled the administration and examination of a large set of cancer therapies simultaneously in individual patients.

Results: Six applications for oncology studies have successfully proceeded to patient trials, with future applications in progress.

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We analytically investigate the feasibility of long graded-index (GRIN)-lens-based microendoscopes through wavefront shaping. Following the very well-defined ray trajectories in a GRIN lens, mode-dependent phase delay is first determined. Then, the phase compensation needed for obtaining diffraction limited resolution is derived.

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Percutaneously implanted miniaturized devices such as fiducial markers, miniaturized sensors, and drug delivery devices have an important and expanding role in diagnosing and treating a variety of diseases. However, there is a need to develop and evaluate anchoring methods to ensure that these microdevices remain secure without dislodgement, as even minimal migration within tissues could result in loss of microdevice functionality or clinical complications. Here we describe two anchoring methods made from biocompatible materials: (1) a self-expanding nitinol mesh anchor and (2) self-expanding hydrogel particles contained within pliable netting.

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By observing the activity of anti-cancer agents directly in tumors, there is potential to greatly expand our understanding of drug response and develop more personalized cancer treatments. Implantable microdevices (IMD) have been recently developed to deliver microdoses of chemotherapeutic agents locally into confined regions of live tumors; the tissue can be subsequently removed and analyzed to evaluate drug response. This method has the potential to rapidly screen multiple drugs, but requires surgical tissue removal and only evaluates drug response at a single timepoint when the tissue is excised.

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REV1/POLζ-dependent mutagenic translesion synthesis (TLS) promotes cell survival after DNA damage but is responsible for most of the resulting mutations. A novel inhibitor of this pathway, JH-RE-06, promotes cisplatin efficacy in cancer cells and mouse xenograft models, but the mechanism underlying this combinatorial effect is not known. We report that, unexpectedly, in two different mouse xenograft models and four human and mouse cell lines we examined in vitro cisplatin/JH-RE-06 treatment does not increase apoptosis.

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Purpose: Recently developed implantable microdevices can perform multi-drug response assessment of cancer drugs in-vivo, with potential to develop highly optimized personalized cancer treatment strategies. However, minimally invasive/interventional image-guided methods of in-vivo microdevice implantation, securement, and retrieval are needed for broad clinical translation. Here we demonstrate proof-of-concept of an interventional microdevice implantation and retrieval method for personalized drug response assessment, using ex-vivo phantom, ex-vivo tissue, and in-vivo murine models.

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There is an unmet need for new antimitotic drug combinations that target cancer-specific vulnerabilities. Based on our finding of elevated biomolecule oxidation in mitotically arrested cancer cells, we combined Plk1 inhibitors with TH588, an MTH1 inhibitor that prevents detoxification of oxidized nucleotide triphosphates. This combination showed robust synergistic killing of cancer, but not normal, cells that, surprisingly, was MTH1-independent.

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We hypothesized that candidate dependencies for which there are small molecules that are either approved or in advanced development for a nononcology indication may represent potential therapeutic targets. To test this hypothesis, we performed genome-scale loss-of-function screens in hundreds of cancer cell lines. We found that knockout of , which encodes prolyl hydroxylase domain-containing protein 2 (PHD2), reduced the proliferation of a subset of clear cell ovarian cancer cell lines .

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We describe a label-free approach based on Raman spectroscopy, to study drug-induced apoptosis in vivo. Spectral-shifts at wavenumbers associated with DNA, proteins, lipids, and collagen have been identified on breast and melanoma tumor tissues. These findings may enable a new analytical method for rapid readout of drug-therapy with miniaturized probes.

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