A Drosophila model for Aromatase Inhibitor-induced Musculoskeletal Pain

Aromatase Inhibitors (AIs) letrozole, anastrozole, and exemestane are used to treat hormone receptor positive breast cancer in post-menopausal women. Despite showing a survival benefit, many patients discontinue treatment because of painful and incapacitating side effects. Most of these patients cannot tolerate any of the three AIs. There is a significant unmet clinical need to reduce AI toxicity to vastly improve patient quality of life and decrease the incidence of patients discontinuing therapy. However, other drugs that block the effects of estrogen (e.g., tamoxifen) do not induce the same muscle and joint pain and up to 40% of patients sometimes tolerate one of the three AIs better than the others. Unfortunately, there is currently no way to identify which patients should avoid a specific AI. Many patients try each of the three in a painful, frustrating, and emotionally draining trial-and-error process. There is a significant clinical need to identify genetic susceptibility to offtarget toxicities of letrozole, anastrozole, and exemestane to match patients with a “best fit” AI from treatment start. This is particularly important in the current clinical landscape when studies are showing significant diseasefree survival benefits of continuing AI therapy for up to 10 years. To address these unmet clinical needs, we developed a Drosophila (fruit fly) model to study Aromatase Inhibitor toxicity. Flies can be easily tested in motor function assays to assess muscular issues such as pain or other impairments. Flies can also be put into a variety of “pain” assays where they are tested for avoidance of noxious stimuli; greater avoidance typically reflects increased pain. Feasibility studies using a wild-type control strains show motor impairment and/or greater noxious temperature avoidance upon AI treatment. Excitingly, 15 divergent wild-type strains tested had different sensitivity AIs as seen with human patients (from no motor impairment to motor impairment in reaction to specific AIs). The rich set of Drosophila assays and tools useful in addressing pain and muscle issues and the growing body of work developing, evaluating, and optimizing therapeutics taken together with our feasibility studies make Drosophila ideally suited to dissect genetic susceptibility to AI side effects that cause patients to discontinue therapy. Our goals are to use unbiased genome-wide screens (Deficiency and Drosophila Genomic Reference Panel screens), systematic candidate screens, and FDA-approved compound screens to identify candidate therapeutics and genetic variants AI toxicity. Identifying genetic predisposition to adverse side effects for each AI will allow clinicians to match patients with a specific AI most likely to be tolerated from the outset, thus eliminating AI switching. We will identify candidate therapeutics as co-therapies to reduce AI side effects and also genetic modifiers that suppress these adverse side effects, thus identifying additional candidate therapeutic targets. This R21 focuses on Drosophila; we have assembled a multi-disciplinary team including breast cancer clinicians and researchers and genomics experts to take our findings into the mammalian models and to validate our candidates in patient datasets in the future.