Biology subjects

Mitchell, J. B.

Publications and source records attributed to Mitchell, J. B..

4 recordsLinked to original sources

bioRxiv2022

Evofosfamide and Gemcitabine Act Synergistically in Pancreatic Cancer Xenografts by Dual Action on Tumor Vasculature and Inhibition of Homologous Recombination DNA Repair

AimsPancreatic ductal adenocarcinomas (PDACs) form hypovascular and hypoxic tumors which are difficult to treat with current chemotherapy regimens. Gemcitabine (GEM) is often used as a first line treatment for PDACs, but has issues with chemoresistance and penetration in the interior of the tumor. Evofosfamide, a hypoxia activated prodrug, has been shown to be effective in combination with GEM, although the mechanism of each drug on the other has not been established. We used two mouse xenografts from two cell lines (MIA Paca-2 and SU 86.86) with different tumor microenvironmental characteristics to probe the action of each drug on the other. ResultsGEM treatment enhanced survival times in mice with SU.86.86 xenografts (HR =0.35, 95% CI=0.13 to 0.90 p=0.03) but had no effect on MIA Paca-2 mice (HR =0.91, 95% CI=0.37 to 2.25, p=0.84). Conversely, evofosfamide had no effect on SU86.86 mice and did not improve survival times to a statistically significant degree (HR=0.57, 95% CI=0.23 to 1.42, p=0.22). In MIA Paca-2 tumors, which were initially poorly perfused, electron paramagnetic resonance (EPR) imaging showed that oxygenation worsened when treated with GEM, providing a direct mechanism for the activation of evofosfamide by GEM and the effectiveness of evofosfamide and GEM combinations. Sublethal amounts of either treatment enhanced the toxicity of other treatment in vitro in Su86.86 but not in MIAPaca-2. Repair of double stranded DNA lesions was enhanced in the combination treatment in Su86.86 but not MIA Paca-2. InnovationsA possible mechanism for the synergy between evofosfamide and GEM has been proposed. ConclusionThe synergy between GEM and evofosfamide appears to stem from the dual action of GEMs effect on tumor vasculature and the GEM inhibition of the homologous recombination DNA repair process. The relative importance of each pathway is dependent on the tumor microenvironment and merits further study.

cancer biology↗

bioRxiv2022

PEGPH20, a PEGylated Human Hyaluronidase, Induces Radiosensitization by Reoxygenation In Pancreatic Cancer Xenografts. A Molecular Imaging Study

PEGylated human hyaluronidase (PEGPH20) enzymatically depletes hyaluronan, an important component of the extracellular matrix, in tumors. The resultant improvement in vascular patency and perfusion has been shown to increase the delivery of therapeutic molecules. We show that PEGPH20 also improves the efficacy of radiation therapy in a human pancreatic adenocarcinoma BxPC3 mouse model overexpressing hyaluronan synthase 3 (BxPC3-HAS3) while exerting little effect on the corresponding wild type tumors. Mice overexpressing HAS3 developed fast growing, radiation resistant tumors that became rapidly more hypoxic as time progressed. Treatment with PEGPH20 increased survival times when used in combination with radiation therapy, significantly more than either radiation therapy or PEGPH20 alone. Radiosensitization in BxPC3-HAS3 tumors was attributed to an increase in local pO2 as studied by by EPR imaging. No effect on survival, radiation treatment, or pO2 was seen in wild type tumors after PEGPH20 treatment. Dynamic contrast enhanced (DCE) MRI and MRI based blood volume imaging showed improved perfusion/permeability and local blood volume, respectively, in BxPC3-HAS3 tumors after PEGPH20 treatment, accounting for the increase in tumor oxygenation. Photoacoustic imaging indicated immediate changes in tumor oxygenation after treatment. Metabolic MRI using hyperpolarized [1-13C] pyruvate suggested a metabolic shift towards decreased glycolytic flux after PEGPH20 treatment. In summary, the results showed that PEGPH20 may be useful for radiosensitization of pancreatic cancer but only in the subset of tumors with substantial hyaluronan accumulation and the response of the treatment may potentially be monitored non-invasive imaging of the hemodynamic and metabolic changes in the tumor microenvironment.

cancer biology↗

bioRxiv2020

Reoxygenation after Evofosfamide Treatment in Pancreatic Ductal Adenocarcinoma Xenografts is due to Decreased Oxygen Consumption and not Increased Oxygen Supply

Evofosfamide is designed to release a cytotoxic bromo-isophosphoramide (Br-IPM) moiety in a hypoxic microenvironment. This drug therefore preferentially attacks hypoxic regions in tumors where other standard anti-cancer treatments such as chemotherapy and radiation therapy are often ineffective. Various combination therapies with evofosfamide have been proposed and tested in preclinical and clinical settings. However, the treatment effect of evofosfamide monotherapy on tumor hypoxia has not been fully understood, partly due to the lack of quantitative methods to assess tumor pO2 in vivo. Here, we use quantitative pO2 imaging by EPR to evaluate the change in tumor hypoxia in response to evofosfamide treatment using two pancreatic ductal adenocarcinom a xenograft models; MIA Paca-2 tumors responding to evofosfamide and Su.86.86 tumors which do not respond. EPR imaging showed oxygenation improved globally after evofosfamide treatment in hypoxic MIA Paca-2 tumors, in agreement with the ex vivo results obtained from hypoxia staining by pimonidazole and in apparent contrast to the decrease in Ktrans observed in DCE MRI. This suggests reoxygenation after treatment is due to decreased oxygen demand rather than improved prefusion. Following the change in pO2 after treatment may therefore yield a way of monitoring treatment response. The observation that evofosfamide not only kills the hypoxic region of the tumor but also improves oxygenation in the residual tumor regions provides a rationale for combination therapies using radiation and anti-proliferatives post evofosfamide for improved outcomes.

cancer biology↗

bioRxiv2020

Detecting Early Response to Immune Checkpoint Blockade by Multimodal Molecular Imaging

Immune checkpoint inhibitors have become a standard therapy for several cancers; however, the response is inconsistent and a method for non-invasive assessment has not been established to date. To investigate the capability of multi-modal imaging to evaluate treatment response to immune checkpoint blockade therapy, we employed hyperpolarized 13C MRI on tumor bearing mice using [1-13C] pyruvate and [1,4-13C2] fumarate to detect early changes in tumor glycolysis and necrosis, respectively. Following PD-L1 Ab + CTLA-4 Ab dual immune checkpoint blockade (ICB) therapy, dynamic contrast enhanced (DCE) MRI was used to determine the treatment effect on intratumor perfusion/permeability. Mice bearing MC38 colon adenocarcinoma and B16.F10 melanoma were used as sensitive and less sensitive models, respectively to immune checkpoint dual blockade of PD-L1 and CTLA-4. Glycolytic flux significantly decreased upon treatment in the less ICB sensitive B16.F10 model but remained essentially unchanged in MC38 tumors. Imaging [1,4-13C] fumarate conversion to [1,4-13C] malate showed a significant increase in necrosis in the treatment group for the ICB sensitive MC38 tumor (p = 0.0003), with essentially no change in ICB sensitive B16.F10 tumors. Histological assessment showed increased necrotic tissue with enhanced lymphocyte infiltration in the MC38 treatment group, suggesting immunogenic tumor cell death. Dynamic contrast enhanced MRI showed significantly increased perfusion/permeability of Gd-DTPA in MC38 treated tumor, while a similar trend but statistically non-significant change was observed in B16.F10 treated tumor. These results provide imaging biomarkers to detect early response to cancer immunotherapy, allowing qualitative assessment of tumors treated with immune checkpoint blockade therapy.

cancer biology↗