PET imaging of [52 Mn]Mn-DOTATATE and [52 Mn]Mn-DOTA-JR11.

Manganese-52 is gaining interest as an isotope for PET imaging due to its desirable decay and chemical properties for radiopharmaceutical development. Somatostatin receptor 2 (SSTR2) is significantly overexpressed by neuroendocrine tumors (NETs) and is an important target for nuclear imaging and therapy. As an agonist, [Ga]Ga-DOTATATE has demonstrated significant internalization upon interaction with receptor ligands, whereas [Ga]Ga-DOTA-JR11(as an antagonist) exhibits limited internalization but better pharmacokinetics and increased tumor uptake.

Evaluating the immunologically "cold" tumor microenvironment after treatment with immune checkpoint inhibitors utilizing PET imaging of CD4 + and CD8 + T cells in breast cancer mouse models.

Background: Immune-positron emission tomography (PET) imaging with tracers that target CD8 and granzyme B has shown promise in predicting the therapeutic response following immune checkpoint blockade (ICB) in immunologically "hot" tumors. However, immune dynamics in the low T-cell infiltrating "cold" tumor immune microenvironment during ICB remain poorly understood. This study uses molecular imaging to evaluate changes in CD4 + T cells and CD8 + T cells during ICB in breast cancer models and examines biomarkers of response.

[F]FMISO-PET imaging reveals the role of hypoxia severity in checkpoint blockade response.

Context: Hypoxia within the tumor microenvironment is a critical factor influencing the efficacy of immunotherapy, including immune checkpoint inhibition. Insufficient oxygen supply, characteristic of hypoxia, has been recognized as a central determinant in the progression of various cancers. The reemergence of evofosfamide, a hypoxia-activated prodrug, as a potential treatment strategy has sparked interest in addressing the role of hypoxia in immunotherapy response.

Dual anti-HER2/EGFR inhibition synergistically increases therapeutic effects and alters tumor oxygenation in HNSCC.

Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and hypoxia are associated with radioresistance. The goal of this study is to study the synergy of anti-HER2, trastuzumab, and anti-EGFR, cetuximab, and characterize the tumor microenvironment components that may lead to increased radiation sensitivity with dual anti-HER2/EGFR therapy in head and neck squamous cell carcinoma (HNSCC). Positron emission tomography (PET) imaging ([Zr]-panitumumab and [Zr]-pertuzumab) was used to characterize EGFR and HER2 in HNSCC cell line tumors.

A mouse model of Zhu-Tokita-Takenouchi-Kim syndrome reveals indispensable SON functions in organ development and hematopoiesis.

Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss of function of SON. While patients with ZTTK syndrome live with numerous symptoms, the lack of model organisms hampers our understanding of SON and this complex syndrome.

[Zr]-CD8 ImmunoPET imaging of glioblastoma multiforme response to combination oncolytic viral and checkpoint inhibitor immunotherapy reveals CD8 infiltration differential changes in preclinical models.

Novel immune-activating therapeutics for the treatment of glioblastoma multiforme (GBM) have shown potential for tumor regression and increased survival over standard therapies. However, immunotherapy efficacy remains inconsistent with response assessment being complicated by early treatment-induced apparent radiological tumor progression and slow downstream effects. This inability to determine early immunotherapeutic benefit results in a drastically decreased window for alternative, and potentially more effective, treatment options.

Predicting response to combination evofosfamide and immunotherapy under hypoxic conditions in murine models of colon cancer.

The goal of this study is to develop a mathematical model that captures the interaction between evofosfamide, immunotherapy, and the hypoxic landscape of the tumor in the treatment of tumors. Recently, we showed that evofosfamide, a hypoxia-activated prodrug, can synergistically improve treatment outcomes when combined with immunotherapy, while evofosfamide alone showed no effects in an syngeneic model of colorectal cancer. However, the mechanisms behind the interaction between the tumor microenvironment in the context of oxygenation (hypoxic, normoxic), immunotherapy, and tumor cells are not fully understood.

A mouse model of ZTTK syndrome reveals indispensable SON functions in organ development and hematopoiesis.

Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss-of-function of SON. While ZTTK syndrome patients suffer from numerous symptoms, the lack of model organisms hamper our understanding of both SON and this complex syndrome.

Investigating tumor-host response dynamics in preclinical immunotherapy experiments using a stepwise mathematical modeling strategy.

Immunotherapies such as checkpoint blockade to PD1 and CTLA4 can have varied effects on individual tumors. To quantify the successes and failures of these therapeutics, we developed a stepwise mathematical modeling strategy and applied it to mouse models of colorectal and breast cancer that displayed a range of therapeutic responses. Using longitudinal tumor volume data, an exponential growth model was utilized to designate response groups for each tumor type.

Optimizing combination therapy in a murine model of HER2+ breast cancer.

Human epidermal growth factor receptor 2 positive (HER2+) breast cancer is frequently treated with drugs that target the HER2 receptor, such as trastuzumab, in combination with chemotherapy, such as doxorubicin. However, an open problem in treatment design is to determine the therapeutic regimen that optimally combines these two treatments to yield optimal tumor control. Working with data quantifying temporal changes in tumor volume due to different trastuzumab and doxorubicin treatment protocols in a murine model of human HER2+ breast cancer, we propose a complete framework for model development, calibration, selection, and treatment optimization to find the optimal treatment protocol.

Combination Therapy with Trastuzumab and Niraparib: Quantifying Early Proliferative Alterations in HER2+ Breast Cancer Models.

HER2-targeted treatments have improved survival rates in HER2+ breast cancer patients, yet poor responsiveness remains a major clinical obstacle. Recently, HER2+ breast cancer cells, both resistant and responsive to HER2-targeted therapies, have demonstrated sensitivity to poly-(ADP-ribose) polymerase (PARP) inhibition, independent of DNA repair deficiencies. This study seeks to describe biological factors that precede cell viability changes in response to the combination of trastuzumab and PARP inhibition.

Utility of Targeted Positron Emission Tomography Imaging to Predict Schwannoma Growth in a Murine Tumor Model.

Objective: To identify if targeted positron emission tomography (PET) imaging with radiolabeled antibodies can predict tumor growth rate and ultimate tumor size in a murine flank schwannoma model.

Study Design: Animal research study.

Methods: Rat schwannoma cells were cultured and implanted into 40 athymic nude mice.

Voltage-Gated Sodium Channel Na1.7 Inhibitors with Potent Anticancer Activities in Medullary Thyroid Cancer Cells.

Our results from quantitative RT-PCR, Western blotting, immunohistochemistry, and the tissue microarray of medullary thyroid cancer (MTC) cell lines and patient specimens confirm that VGSC subtype Na1.7 is uniquely expressed in aggressive MTC and not expressed in normal thyroid cells and tissues. We establish the druggability of Na1.

[Zr]-Atezolizumab-PET Imaging Reveals Longitudinal Alterations in PDL1 during Therapy in TNBC Preclinical Models.

Triple-negative breast cancers (TNBCs) currently have limited treatment options; however, PD-L1 is an indicator of susceptibility to immunotherapy. Currently, assessment of PD-L1 is limited to biopsy samples. These limitations may be overcome with molecular imaging.

Human Epidermal Growth Factor Receptor 2/Human Epidermal Growth Factor Receptor 3 PET Imaging: Challenges and Opportunities.

Human epidermal growth factor receptor 2 (HER2) and HER3 provide actionable targets for both therapy and imaging in breast cancer. Further, clinical trials have shown the prognostic impact of receptor status discordance in breast cancer. Intra- and intertumoral heterogeneity of both HER and hormone receptor expression contributes to inherent errors in tissue sampling, and single biopsies are incapable of identifying discordance in biomarker expression.

Evaluation of a CD206-Targeted Peptide for PET Imaging of Macrophages in Syngeneic Mouse Models of Cancer.

Tumor-associated macrophages (TAMs) are large phagocytic cells that play numerous roles in cancer biology and are an important component of the relationship between immune system response and tumor progression. The peptide, RP832c, targets the Mannose Receptor (CD206) expressed on M2-like macrophages and is cross-reactive to both human and murine CD206. Additionally, it exhibits therapeutic properties through its ability to shift the population of TAMs from an M2-like (protumor) toward an M1-like phenotype (antitumor) and has demonstrated promise in inhibiting tumor resistance in PD-L1 unresponsive melanoma murine models.

Cdk5 mediates rotational force-induced brain injury.

Millions of traumatic brain injuries (TBIs) occur annually. TBIs commonly result from falls, traffic accidents, and sports-related injuries, all of which involve rotational acceleration/deceleration of the brain. During these injuries, the brain endures a multitude of primary insults including compression of brain tissue, damaged vasculature, and diffuse axonal injury.

Molecular Imaging of Oxygenation Changes during Immunotherapy in Combination with Paclitaxel in Triple Negative Breast Cancer.

Hypoxia is a common feature of the tumor microenvironment, including that of triple-negative breast cancer (TNBC), an aggressive breast cancer subtype with a high five-year mortality rate. Using [F]-fluoromisonidazole (FMISO) positron emission tomography (PET) imaging, we aimed to monitor changes in response to immunotherapy (IMT) with chemotherapy in TNBC. TNBC-tumor-bearing mice received paclitaxel (PTX) ± immune checkpoint inhibitors anti-programmed death 1 and anti-cytotoxic T-lymphocyte 4.

Mathematical Model of Triple-Negative Breast Cancer in Response to Combination Chemotherapies.

Triple-negative breast cancer (TNBC) is a heterogenous disease that is defined by its lack of targetable receptors, thus limiting treatment options and resulting in higher rates of metastasis and recurrence. Combination chemotherapy treatments, which inhibit tumor cell proliferation and regeneration, are a major component of standard-of-care treatment of TNBC. In this manuscript, we build a coupled ordinary differential equation model of TNBC with compartments that represent tumor proliferation, necrosis, apoptosis, and immune response to computationally describe the biological tumor affect to a combination of chemotherapies, doxorubicin (DRB) and paclitaxel (PTX).

Analysis of simplicial complexes to determine when to sample for quantitative DCE MRI of the breast.

Purpose: A method is presented to select the optimal time points at which to measure DCE-MRI signal intensities, leaving time in the MR exam for high-spatial resolution image acquisition.

Theory: Simplicial complexes are generated from the Kety-Tofts model pharmacokinetic parameters K and v . A geometric search selects optimal time points for accurate estimation of perfusion parameters.

Quantifying the Effects of Combination Trastuzumab and Radiation Therapy in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

Background: Trastuzumab induces cell cycle arrest in HER2-overexpressing cells and demonstrates potential in radiosensitizing cancer cells. The purpose of this study is to quantify combination trastuzumab and radiotherapy to determine their synergy. Methods: In vitro, HER2+ cancer cells were treated with trastuzumab, radiation, or their combination, and imaged to evaluate treatment kinetics.

Systemic Checkpoint Blockade by PD-L1 Single-Chain Antibody Confers Potent Antitumor Immunity and Long-term Survival.

Immune checkpoint inhibitors (ICI) are promising in adjuvant settings for solid tumors and hematologic malignancies. They are currently used in the treatment as mAbs in high concentrations, raising concerns of toxicity and adverse side effects. Among various checkpoint molecules, targeting the programmed cell death protein-1 (PD-1)-programmed death-ligand 1 (PD-L1) axis has garnered more clinical utility than others have.

Evaluating the Accuracy of FUCCI Cell Cycle In Vivo Fluorescent Imaging to Assess Tumor Proliferation in Preclinical Oncology Models.

Purpose: The primary goal of this study is to evaluate the accuracy of the fluorescence ubiquitination cell cycle indicator (FUCCI) system with fluorescence in vivo imaging compared to 3'-deoxy-3'-[F]fluorothymidine ([F]-FLT) positron emission tomography (PET)/computed tomography (CT) and biological validation through histology. Imaging with [F]-FLT PET/CT can be used to noninvasively assess cancer cell proliferation and has been utilized in both preclinical and clinical studies. However, a cost-effective and straightforward method for in vivo, cell cycle targeted cancer drug screening is needed prior to moving towards translational imaging methods such as PET/CT.

Quantifying Tumor Heterogeneity via MRI Habitats to Characterize Microenvironmental Alterations in HER2+ Breast Cancer.

This study identifies physiological habitats using quantitative magnetic resonance imaging (MRI) to elucidate intertumoral differences and characterize microenvironmental response to targeted and cytotoxic therapy. BT-474 human epidermal growth factor receptor 2 (HER2+) breast tumors were imaged before and during treatment (trastuzumab, paclitaxel) with diffusion-weighted MRI and dynamic contrast-enhanced MRI to measure tumor cellularity and vascularity, respectively. Tumors were stained for anti-CD31, anti-ɑSMA, anti-CD45, anti-F4/80, anti-pimonidazole, and H&E.