Redox homeostasis is described as the net physiologic balance between inter-convertible oxidized and reduced equivalents within subcellular compartments that remain in a dynamic equilibrium. This equilibrium is impacted by reactive oxygen species (ROS), which are natural by-products of normal cellular activity. Studies have shown that cancer cells have high ROS levels and altered redox homeostasis due to increased basal metabolic activity, mitochondrial dysfunction, peroxisome activity, as well as the enhanced activity of NADPH oxidase, cyclooxygenases, and lipoxygenases. Glioblastoma (GBM) is the most prevalent primary brain tumor in adults with a median survival of 15 months. GBM is characterized by its extreme resistance to therapeutic interventions as well as an elevated metabolic rate that results in the exacerbated production of ROS. Therefore, many agents with either antioxidant or pro-oxidant mechanisms of action have been rigorously employed in preclinical as well as clinical settings for treating GBM by inducing oxidative stress within the tumor. Among those agents are well-known antioxidant vitamin C and small molecular weight SOD mimic BMX-001, both of which are presently in clinical trials on GBM patients. Despite the wealth of investigations, limited data is available on the response of normal brain vs glioblastoma tissue to these therapeutic interventions. Currently, a sensitive and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was established for the quantification of a panel of oxidative stress biomarkers: glutathione (GSH), cysteine (Cys), glutathione disulfide (GSSG), and cysteine disulfide in human-derived brain tumor and mouse brain samples; this method will be enriched with additional oxidative stress biomarkers homocysteine (Hcy), methionine (Met), and cystathionine (Cyst). Using this enriched method, we propose to evaluate the thiol homeostasis and the redox state of both normal brain and GBM in mice after exposure with redox-active therapeutics. Our results showed that, compared to normal brain (in intact mice), GBM tissue has significantly lower GSH/GSSG and Cys/CySS ratios indicating much higher oxidative stress levels. Contralateral “normal” brain tissue collected from the mice with intracranial GBM were also under significant oxidative stress compared to normal brains collected from the intact mice. Importantly, normal brain tissue in both studies retained the ability to restore redox homeostasis after treatment with a redox-active therapeutic within 24 hours while glioblastoma tissue does not. Ultimately, elucidating the differential redox response of normal vs tumor tissue will allow for the development of more redox-active agents with therapeutic benefit.

Cancers of the reproductive tissues make up a significant portion of the cancer burden and mortality experienced by humans. Humans experience several proximal causative carcinogens that explain a portion of cancer risk, but an evolutionary viewpoint can provide a unique lens into the ultimate causes of reproductive cancer vulnerabilities. A life history framework allows us to make predictions on cancer prevalence based on a species’ tempo of reproduction. Moreover, certain variations in the susceptibility and prevalence of cancer may emerge due to evolutionary trade-offs between reproduction and somatic maintenance. For example, such trade-offs could involve the demand for rapid proliferation of cells in reproductive tissues that arises with reproductive events. In this study, I compiled reproductive cancer prevalence for 158 mammalian species and modeled the predictive power of 13 life history traits on the patterns of cancer prevalence we observed, such as Peto’s Paradox or slow-fast life history strategies. We predicted that fast-life history strategists will exhibit higher neoplasia prevalence risk due to reproductive trade-offs. Furthering this analytical framework can aid in predicting cancer rates and stratifying cancer risk across the tree of life.

Age is the most significant risk factor for cancer development in humans. The somatic mutation theory postulates that the accumulation of genomic mutations over time results in cellular function degradation which plays an important role in understanding aging and cancer development. Specifically, degradation of the mechanisms that underlie somatic maintenance can occur due to decreased immune cell function and genomic responses to DNA damage. Research has shown that this degradation can lead to the accumulation of mutations that can cause cancer in humans. Despite recent advances in our understanding of cancer in non-human species, how this risk factor translates across species is poorly characterized. Here, we analyze a veterinarian cancer dataset of 4,178 animals to investigate if age related cancer prevalence is similar in non-human animals. We intend for this work to be used as a primary step towards understanding the potential overlap and/or uniqueness between human and non-human cancer risk factors. This study can be used to better understand cancer development and how evolutionary processes have shaped somatic maintenance across species.

Glioblastoma (GBM) is the most lethal primary brain tumor in adults with a less than 5% chance of survival beyond 5 years. With few effective therapies beyond the standard of care, there are often treatment resistant recurrences seen in most patients. STAT5 is a protein that has shown to be upregulated in highly invasive and treatment resistant GBM. Elucidating the role of STAT5 in GBM could reveal a node of therapeutic vulnerability in primary and recurrent GBM.