Task Determining Gender Differences in the Incidence of Lung Adenocarcinoma After Space Radiation Exposure
Last Published:  07/30/21 01:05:34 PM (Central)
Short Title: Gender Differences in Radiation-induced Lung Adenocarcinoma
Responsible HRP Element: Space Radiation
Collaborating Org(s):
Funding Status: Active - Currently funded and in progress
Procurement Mechanism(s):
Specific Aim 1: Determine whether there are sex differences in the incidence and
aggressiveness of lung adenocarcinomas after charged particle irradiation.

Aim 1A: Determine the incidence of lung cancer resulting from low LET radiation exposures
(137Cs [?-ray, 0.02 keV/?m]and proton exposures mimicking the 1972 Solar particle event [30-
180 MeV/n, 1.2-0.2 keV/μM]), and high LET exposures (28Si [600 MeV/n, 50.4 keV/μm] and 40Ca
[533 MeV/n, 107.7 keV/μm]) in male vs female BALB/c mice.

Aim 1B: Determine if there is a sex difference in the incidence of lung tumor aggressiveness
(invasion/metastasis) in the same irradiated cohorts in Aim 1a by pathologic interrogation.
Specific Aim 2: Characterize the lung tumors generated either spontaneously or by radiation
exposure at both the tissue and molecular level.

Specific Aim 2: Characterize the lung tumors generated either spontaneously or by radiation
exposure at both the tissue and molecular level.

Aim 2A: Determine if there are sex differences in the characterization of such tumors that may
point to underlying mechanisms for risk for carcinogenesis or aggressiveness of tumors via
transcriptomics and miRNA expression analysis of tumors. Confirm where possible the
molecular markers identified at the tissue level by histology and/or immune histochemistry.

Aim 2B: Determine if biomarker(s) based upon the appearance of circulating miRNA in plasma
or whether there are DNA copy number changes contained within circulating fragmented DNA
(cfDNA) that occur over time post-irradiation that are indicative of lung cancer risk from either
low vs. high LET radiation exposure.

Aim 2C: Determine if the appearance and extent of phosphotidyl serine on the exosomes found
in the blood of irradiated animals are a marker for lung cancer risk when examined over time

Specific Aim 3: Determine whether the FDA investigational new drug GC4419 can mitigate
spontaneous and radiation-induced lung cancer incidence in animals when exposed to
simulated GCR and SPE’s.

Aim 3A: Determine the incidence of lung cancer in mice when GC4419 is provided ad libitum
just before and for 20 weeks post-irradiation.

Aim 3B: Determine whether there are molecular changes (transcriptomics and miRNA
expression) in the lung tissues of irradiated animals without tumors as a function of time when
exposed to GC4419 or not vs unirradiated controls.

Aim 3C: Using the molecular signatures established in Aim 2, determine if GC4419 alters such
signatures that were indicative of either high vs. low LET radiation or tumor aggressiveness and
whether there is a correlation between GC4419 exposure, lung cancer incidence, and the
appearance of circulating, exosomal phosphotidyl serine.
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