Amanda A. Hill

Purpose: Facioscapulohumeral muscular dystrophy (FSHD) is a rare, progressive genetic disorder characterized by asymmetric muscle weakness and functional decline. Although it is one of the most common muscular dystrophies, its economic burden in the United States (US) is largely unknown. This study aimed to provide an initial, conservative estimate of annual medical claims costs and identify comorbidities disproportionately affecting individuals with FSHD in the US. Patients and Methods: This retrospective, 1:5 matched case-control study analyzed de-identified claims data from Medicare and commercially insured enrollees from 2018 to 2021. Medical and prescription costs were aggregated and described as means with 95% confidence intervals. T-tests with Bonferroni correction and chi-square tests were used to compare comorbidity prevalence. Results: The study included 383 individuals with FSHD and 1915 matched controls. The mean annual medical claims cost for the FSHD cohort was $19,370 per person with commercial insurance and $11,704 with Medicare, compared with $5250 among controls. Individuals with FSHD also incurred higher prescription claims costs in commercial and Medicare subgroups without comorbidities. The prevalence of cerebrovascular disease (10.18% vs 4.44%) and ear disorders (8.09% vs. 3.39%) was significantly greater in the FSHD cohort (P< 0.05). Conclusion: This exploratory study provides the first US-based description of the direct medical costs of FSHD, demonstrating a substantially higher healthcare burden than that of matched controls. Because the study design likely underestimates costs, the true economic impact may be even greater. These findings establish a critical foundation for future research into the lifetime medical, nonmedical, and caregiver-related costs of FSHD, and highlight the urgent need for effective therapies and supportive care strategies. Plain Language Summary: Facioscapulohumeral muscular dystrophy (FSHD) is a rare muscle disease that causes progressive weakness in the face, shoulders, upper arms, core, and legs. Over time, it can make everyday tasks such as lifting, walking, or speaking more difficult. While FSHD is one of the most common muscular dystrophies, little is known about its financial impact on people living with the condition and the healthcare system in the United States. To better understand this burden, this study evaluated medical insurance claims for individuals with FSHD and compared them with those of individuals without FSHD. We examined costs from both commercial insurance and Medicare between 2018 and 2021. Individuals with FSHD had substantially higher medical costs than those without the condition. Average annual medical claims were $19,370 for those with commercial insurance and $11,704 for those on Medicare, compared with $5250 for matched individuals without FSHD. Individuals with FSHD also had more prescriptions and were more likely to have claims for other health problems, such as stroke-related conditions and ear disorders. These results show that FSHD is associated with a meaningful financial burden on the healthcare system. Because this study was based on claims data and likely underestimates the full cost of care, the real burden may be even higher. Understanding these costs is an important first step toward improving care, planning support services, and encouraging investment in better treatments for people living with FSHD.

Genome-wide CRISPR Nutlin-3 Sensitizing Gene screen data.

GSEA of nutlin-3-treated LPS transcriptome data.

Nutlin-3-treated LPS transcriptome analyses.

Nutlin-3-proteasome inhibitor drug interaction SRB data.

Nutlin-3-carfilzomib-treated LPS transcriptome analyses.

Liposarcoma is the most commonly occurring soft tissue sarcoma and is frequently characterized by amplification of chromosome region 12q13-15 harboring the oncogenes MDM2 and CDK4. This unique genetic profile makes liposarcoma an attractive candidate for targeted therapeutics. While CDK4/6 inhibitors are currently employed for treatment of several cancers, MDM2 inhibitors have yet to attain clinical approval. Here, we report the molecular characterization of the response of liposarcoma to the MDM2 inhibitor nutlin-3. Treatment with nutlin-3 led to upregulation of two nodes of the proteostasis network: the ribosome and the proteasome. CRISPR/Cas9 was used to perform a genome-wide loss of function screen that identified PSMD9, which encodes a proteasome subunit, as a regulator of response to nutlin-3. Accordingly, pharmacological studies with a panel of proteasome inhibitors revealed strong combinatorial induction of apoptosis with nutlin-3. Mechanistic studies identified activation of the ATF4/CHOP stress response axis as a potential node of interaction between nutlin-3 and the proteasome inhibitor carfilzomib. CRISPR/Cas9 gene editing experiments confirmed that ATF4, CHOP, and the BH3-only protein, NOXA, are all required for nutlin-3 and carfilzomib-induced apoptosis. Furthermore, activation of the unfolded protein response using tunicamycin and thapsigargin was sufficient to activate the ATF4/CHOP stress response axis and sensitize to nutlin-3. Finally, cell line and patient-derived xenograft models demonstrated combinatorial effects of treatment with idasanutlin and carfilzomib on liposarcoma growth in vivo. Together, these data indicate that targeting of the proteasome could improve the efficacy of MDM2 inhibitors in liposarcoma.