Publications by authors named "Tara N Fujimoto"

5 Publications

  • Page 1 of 1

A Mail Audit Independent Peer Review System for Dosimetry Verification of a Small Animal Irradiator.

Radiat Res 2020 04 18;193(4):341-350. Epub 2020 Feb 18.

Departments of Radiation Physics.

Dedicated precision orthovoltage small animal irradiators have become widely available in the past decade and are commonly used for radiation biology research. However, there is a lack of dosimetric standardization among these irradiators, which affects the reproducibility of radiation-based animal studies. The purpose of this study was to develop a mail-based, independent peer review system to verify dose delivery among institutions using X-RAD 225Cx irradiators (Precision X-Ray, North Branford, CT). A robust, user-friendly mouse phantom was constructed from high-impact polystyrene and designed with dimensions similar to those of a typical laboratory mouse. The phantom accommodates three thermoluminescent dosimeters (TLDs) to measure dose. The mouse peer review system was commissioned in a small animal irradiator using anterior-posterior and posterior-anterior beams of 225 kVp and then mailed to three institutions to test the feasibility of the audit service. The energy correction factor for TLDs in the mouse phantom was derived to validate the delivered dose using this particular animal irradiation system. This feasibility study indicated that three institutions were able to deliver a radiation dose to the mouse phantom within ±10% of the target dose. The developed mail audit independent peer review system for the verification of mouse dosimetry can be expanded to characterize other commercially available orthovoltage irradiators, thereby enhancing the reproducibility of studies employing these irradiators.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1667/RR15220.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177689PMC
April 2020

Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer.

JCI Insight 2019 07 23;5. Epub 2019 Jul 23.

Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Pancreatic ductal adenocarcinoma (PDAC) requires mitochondrial oxidative phosphorylation (OXPHOS) to fuel its growth, however, broadly inhibiting this pathway might also disrupt essential mitochondrial functions in normal tissues. PDAC cells exhibit abnormally fragmented mitochondria that are essential to its oncogenicity, but it was unclear if this mitochondrial feature was a valid therapeutic target. Here, we present evidence that normalizing the fragmented mitochondria of pancreatic cancer via the process of mitochondrial fusion reduces OXPHOS, which correlates with suppressed tumor growth and improved survival in preclinical models. Mitochondrial fusion was achieved by genetic or pharmacologic inhibition of dynamin related protein-1 (Drp1) or through overexpression of mitofusin-2 (Mfn2). Notably, we found that oral leflunomide, an FDA-approved arthritis drug, promoted a two-fold increase in Mfn2 expression in tumors and was repurposed as a chemotherapeutic agent, improving the median survival of mice with spontaneous tumors by 50% compared to vehicle. We found that the chief tumor suppressive mechanism of mitochondrial fusion was enhanced mitophagy, which proportionally reduced mitochondrial mass and ATP production. These data suggest that mitochondrial fusion is a specific and druggable regulator of pancreatic cancer growth that could be rapidly translated to the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.126915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777817PMC
July 2019

Fasting Reduces Intestinal Radiotoxicity, Enabling Dose-Escalated Radiation Therapy for Pancreatic Cancer.

Int J Radiat Oncol Biol Phys 2019 11 2;105(3):537-547. Epub 2019 Jul 2.

Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Purpose: Chemotherapy combined with radiation therapy is the most commonly used approach for treating locally advanced pancreatic cancer. The use of curative doses of radiation in this disease setting is constrained because of the close proximity of the head of the pancreas to the duodenum. The purpose of this study was to determine whether fasting protects the duodenum from high-dose radiation, thereby enabling dose escalation for efficient killing of pancreatic tumor cells.

Methods And Materials: C57BL/6J mice were either fed or fasted for 24 hours and then exposed to total abdominal radiation at 11.5 Gy. Food intake, body weight, overall health, and survival were monitored. Small intestines were harvested at various time points after radiation, and villi length, crypt depth, and number of crypts per millimeter of intestine were determined. Immunohistochemistry was performed to assess apoptosis and double-strand DNA breaks, and microcolony assays were performed to determine intestinal stem cell regeneration capacity. A syngeneic KPC model of pancreatic cancer was used to determine the effects of fasting on the radiation responses of both pancreatic cancer and host intestinal tissues.

Results: We demonstrated that a 24-hour fast in mice improved intestinal stem cell regeneration, as revealed by microcolony assay, and improved host survival of lethal doses of total abdominal irradiation compared with fed controls. Fasting also improved survival of mice with orthotopic pancreatic tumors subjected to lethal abdominal radiation compared with controls with free access to food. Furthermore, fasting did not affect tumor cell killing by radiation therapy and enhanced γ-H2AX staining after radiation therapy, suggesting an additional mild radiosensitizing effect.

Conclusions: These results establish proof of concept for fasting as a dose-escalation strategy, enabling ablative radiation in the treatment of unresectable pancreatic cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2019.06.2533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754784PMC
November 2019

Selective EGLN Inhibition Enables Ablative Radiotherapy and Improves Survival in Unresectable Pancreatic Cancer.

Cancer Res 2019 05;79(9):2327-2338

Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

When pancreatic cancer cannot be removed surgically, patients frequently experience morbidity and death from progression of their primary tumor. Radiation therapy (RT) cannot yet substitute for an operation because radiation causes fatal bleeding and ulceration of the nearby stomach and intestines before achieving tumor control. There are no FDA-approved medications that prevent or reduce radiation-induced gastrointestinal injury. Here, we overcome this fundamental problem of anatomy and biology with the use of the oral EGLN inhibitor FG-4592, which selectively protects the intestinal tract from radiation toxicity without protecting tumors. A total of 70 KPC mice with autochthonous pancreatic tumors received oral FG-4592 or vehicle control ± ablative RT to a cumulative 75 Gy administered in 15 daily fractions to a limited tumor field. Although ablative RT reduced complications from local tumor progression, fatal gastrointestinal bleeding was observed in 56% of mice that received high-dose RT with vehicle control. However, radiation-induced bleeding was completely ameliorated in mice that received high-dose RT with FG-4592 (0% bleeding, < 0.0001 compared with vehicle). Furthermore, FG-4592 reduced epithelial apoptosis by half ( = 0.002) and increased intestinal microvessel density by 80% compared with vehicle controls. EGLN inhibition did not stimulate cancer growth, as treatment with FG-4592 alone, or overexpression of HIF2 within KPC tumors independently improved survival. Thus, we provide a proof of concept for the selective protection of the intestinal tract by the EGLN inhibition to enable ablative doses of cytotoxic therapy in unresectable pancreatic cancer by reducing untoward morbidity and death from radiation-induced gastrointestinal bleeding. SIGNIFICANCE: Selective protection of the intestinal tract by EGLN inhibition enables potentially definitive doses of radiation therapy. This might allow radiation to be a surgical surrogate for unresectable pancreatic cancer. http://cancerres.aacrjournals.org/content/canres/79/9/2327/F1.large.jpg.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-18-1785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6666414PMC
May 2019

Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation.

Sci Rep 2019 02 13;9(1):1949. Epub 2019 Feb 13.

Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, United States of America.

Unresectable pancreatic cancer is almost universally lethal because chemotherapy and radiation cannot completely stop the growth of the cancer. The major problem with using radiation to approximate surgery in unresectable disease is that the radiation dose required to ablate pancreatic cancer exceeds the tolerance of the nearby duodenum. WR-2721, also known as amifostine, is a well-known radioprotector, but has significant clinical toxicities when given systemically. WR-2721 is a prodrug and is converted to its active metabolite, WR-1065, by alkaline phosphatases in normal tissues. The small intestine is highly enriched in these activating enzymes, and thus we reasoned that oral administration of WR-2721 just before radiation would result in localized production of the radioprotective WR-1065 in the small intestine, providing protective benefits without the significant systemic side effects. Here, we show that oral WR-2721 is as effective as intraperitoneal WR-2721 in promoting survival of intestinal crypt clonogens after morbid irradiation. Furthermore, oral WR-2721 confers full radioprotection and survival after lethal upper abdominal irradiation of 12.5 Gy × 5 fractions (total of 62.5 Gy, EQD2 = 140.6 Gy). This radioprotection enables ablative radiation therapy in a mouse model of pancreatic cancer and nearly triples the median survival compared to controls. We find that the efficacy of oral WR-2721 stems from its selective accumulation in the intestine, but not in tumors or other normal tissues, as determined by in vivo mass spectrometry analysis. Thus, we demonstrate that oral WR-2721 is a well-tolerated, and quantitatively selective, radioprotector of the intestinal tract that is capable of enabling clinically relevant ablative doses of radiation to the upper abdomen without unacceptable gastrointestinal toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-37147-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374382PMC
February 2019
-->