Mechanisms of Cancer and Treatment-related Symptoms and Toxicities

Taste buds are composed of a heterogeneous collection of taste receptor cells (TRCs) that are continually renewed. Likely because of this regenerative capacity, taste distortion or dysgeusia is a common side effect of many anti-cancer drugs used to treat a host of malignancies. Crucially, patients report loss of taste as an extremely disruptive aspect of cancer treatment, dramatically affecting their quality of life and clinical outcomes. Current interventions for taste loss are minimally effective and consist primarily of dietary modifications and attention to oral hygiene. Here, we submit a revised proposal in response to PA-16-258 Mechanisms of Cancer and Treatment-related Symptoms and Toxicities, with the explicit rationale that understanding how cancer drugs impact taste homeostasis will generate future approaches to ameliorate taste dysfunction for cancer patients. Although a host of cancer drugs cause dysgeusia, we focus on a specific patient population, those suffering from malignant renal cell carcinoma (mRCC), treated with a one or more of 6 specific tyrosine kinase inhibitors (TKIs) used to inhibit receptor tyrosine kinases (RTKs) critical to tumor growth, i.e., VEGFR1-3 and PDGFRb. Importantly, these drugs, sunitinib, pazopanib, axitinib, cabozantinib, lenvatinib, and sorafenib, cause significant and troubling taste distortion for patients. However, how these drugs perturb taste is completely unknown. Intriguingly, interrogating both our own and published RNA sequence data reveals that neither VEGFR1-3 nor PDGFRb are expressed in taste epithelium. However, these TKIs also inhibit numerous other unintended RTKs including PDGFRa, c-Kit and Ret, which are expressed in taste epithelium, whose functions in mRCC are less essential, and whose roles in taste bud homeostasis are little explored. Thus, it is entirely plausible that TKIs used to treat mRCC act on intended VEGFR1-3 and PDGFRb to slow tumor progression, while in taste epithelium unintended RTKs are inhibited causing dysgeusia, thus providing us with a potential future avenue to mitigate taste dysfunction without interfering with cancer therapy. To assess how these targeted TKIs impact taste cell renewal, rather than using time-consuming and expensive mouse models, we propose to use cutting edge lingual organoid technology to rapidly and inexpensively screen for the effect of these drugs on discrete aspects of taste cell renewal. Our explicit hypothesis is that: TKIs used to treat mRCC affect discrete aspects of taste bud cell renewal, and act on RTKs expressed in taste epithelium that are distinct from their anti-tumor targets. This will be tested in 3 aims: Do mRCC TKIs affect activity and/or survival of taste bud progenitor cells (Aim 1); and/or differentiation of all or distinct subsets of TRCs (Aim 2); and which RTKs are inhibited in taste epithelium by TKIs used to treat mRCC patients (Aim 3).

The complaint of fatigue is common among patients receiving radiation therapy (RT) for the treatment of cancer, yet the mechanism of this fatigue is unknown. Many patients report drowsiness with RT, suggesting that sleepiness is contributing to their complaint of fatigue. But drowsiness, like fatigue, is a subjective complaint, which may not correlate with objective measurements of sleepiness and activity. Identifying objectives correlates of fatigue, including sleepiness and reduced activity, will be critical to advancing our understanding of underlying mechanisms. Understanding these mechanisms can lead to new therapies. The studies proposed in this Exploratory/Developmental Research Grant (R21) project will fill a gap in our understanding of the biological mechanisms of fatigue associated with radiation therapy for cancer. The hypothesis motivating this proposal is that sleepiness, reduced activity, and impaired vigilance associated with EGF cytokine elevation contributes to the fatigue experienced by patients receiving radiation therapy for prostate cancer. To test this hypothesis, we plan to measure before, and during RT the following: (1) Levels of the cytokine HB-EGF, (2) activity, (3) subjective sleepiness, (4) objective sleepiness, and (5) fatigue. We will make the same measurements also in a cohort of subjects with prostate cancer who are not treated with RT. All measurements except for objective sleepiness will be repeated at least three months after RT is completed. In each of these five measurements, we hypothesize a change on RT from baseline values. We will test our over-arching hypothesis that the pathway leading to the complaint of fatigue on RT treatment involves an elevation of HB-EGF, reduced activity, and increased sleepiness.