Biology subjects

Blocker, S. J.

Publications and source records attributed to Blocker, S. J..

3 recordsLinked to original sources

bioRxiv2021

Cytostatic hypothermia and its impact on glioblastoma and survival

Novel therapeutic approaches are needed for patients with glioblastoma (GBM) who otherwise have limited options. Here we studied and deployed non-freezing cytostatic hypothermia to stunt GBM growth. This contrasts with ablative, cryogenic hypothermia: a double-edged sword against tumors infiltrating otherwise healthy tissue. We investigated three grades of hypothermia in vitro and identified a cytostatic window of 20-25{degrees}C. For some glioma lines, 18 h/d of cytostatic hypothermia was sufficient to halt division in vitro. Cytostatic hypothermia induced cell cycle arrest, reduced metabolite production and consumption, and reduced inflammatory cytokine synthesis. Next, we fabricated an experimental device to test local cytostatic hypothermia in vivo in two rodent models of GBM: utilizing the rat F98 and the human U-87 MG lines. Hypothermia more than doubled the median survival of F98 bearing rats from 3.9 weeks to 9.7 weeks and two rats survived through 12 weeks. All U-87 MG bearing rats that successfully received cytostatic hypothermia survived their study period. Thus, this approach lengthened survival without chemical interventions. Unlike targeted therapeutics that are successful in preclinical models but fail in clinical trials, cytostatic hypothermia affects multiple cellular processes simultaneously. This, alongside reduced cellular division, suggests that opportunities for tumor evolution are reduced and the likelihood of translation to larger species may be more likely. In addition, based on our work, designs, and the literature, engineering a patient-centric device is tangible. Taken together, cytostatic hypothermia could be a novel approach to cancer therapy and eventually serve a valuable role to patients with GBM. One Sentence SummaryHypothermia influences multiple cellular pathways, can be a safe and effective approach to halt glioblastoma growth, and holds translational promise.

bioengineering↗

bioRxiv2019

The impact of respiratory gating on improving volume measurement of murine lung tumors in micro-CT imaging

Small animal imaging has become essential in evaluating new cancer therapies as they are translated from the preclinical to clinical domain. However, preclinical imaging faces unique challenges that emphasize the gap between mouse and man. One example is the difference in breathing patterns and breath-holding ability, which can dramatically affect tumor burden assessment in lung tissue. As part of a co-clinical trial studying immunotherapy and radiotherapy in sarcomas, we are using micro-CT of the lungs to detect and measure metastases as a metric of disease progression. To effectively utilize metastatic disease detection as a metric of progression, we have addressed the impact of respiratory gating during micro-CT acquisition on improving lung tumor detection and volume quantitation. Accuracy and precision of lung tumor measurements with and without respiratory gating were studied by performing experiments with in vivo images, simulations, and a pocket phantom. When performing test-retest studies in vivo, the variance in volume calculations was 5.9% in gated images and 15.8% in non-gated images, compared to 2.9% in post-mortem images. Sensitivity of detection was examined in images with simulated tumors, demonstrating that reliable sensitivity (true positive rate (TPR) [≥] 90%) was achievable down to 1.0 mm3 lesions with respiratory gating, but was limited to [≥] 8.0 mm3 in non-gated images. Finally, a clinically-inspired \"pocket phantom\" was used during in vivo mouse scanning to aid in refining and assessing the gating protocols. Application of respiratory gating techniques reduced variance of repeated volume measurements and significantly improved the accuracy of tumor volume quantitation in vivo.

cancer biology↗

bioRxiv2018

Bridging the translational gap: Implementation of multimodal small animal imaging strategies for tumor burden assessment in a co-clinical trial

In designing co-clinical cancer studies, preclinical imaging brings unique challenges that emphasize the gap between man and mouse. Our group is developing quantitative imaging methods for the preclinical arm of a co-clinical trial studying immunotherapy and radiotherapy in a soft tissue sarcoma model. In line with treatment for patients enrolled in the clinical trial SU2C-SARC032, primary mouse sarcomas are imaged with multi-contrast micro-MRI (T1 weighted, T2 weighted, and T1 with contrast) before and after immune checkpoint inhibition and pre-operative radiation therapy. Similar to the patients, after surgery the mice will be screened for lung metastases with micro-CT using respiratory gating. A systems evaluation was undertaken to establish a quantitative baseline for both the MR and micro-CT systems against which others systems might be compared. We have constructed imaging protocols which provide clinically-relevant resolution and contrast in a genetically engineered mouse model of sarcoma. We have employed tools in 3D Slicer for semi-automated segmentation of both MR and micro-CT images to measure tumor volumes efficiently and reliably in a large number of animals. Assessment of tumor burden in the resulting images was precise, repeatable, and reproducible. Furthermore, we have implemented a publicly accessible platform for sharing imaging data collected during the study, as well as protocols, supporting information, and data analyses. In doing so, we aim to improve the clinical relevance of small animal imaging and begin establishing standards for preclinical imaging of tumors from the perspective of a co-clinical trial.

bioengineering↗