No abstract

Clear cell renal cell carcinoma (ccRCC) is considered an immunotherapy-responsive disease; however, the reasons for this remain unclear. Studies have variably implicated PBRM1 mutations as a predictive biomarker of immune checkpoint blockade (ICB) response, and separate studies demonstrate that expression of human endogenous retroviruses (hERVs) might be an important class of tumor-associated antigens. We sought to understand if specific mutations were associated with hERV expression. Two large, annotated genomic datasets, TCGA KIRC and IMmotion150, were used to correlate mutations and hERV expression. PBRM1 mutations were consistently associated with increased hERV expression in primary tumors. In vitro silencing of PBRM1, HIF1A and HIF2A followed by RNA-seq was performed in UMRC2 cells, confirming that PBRM1 regulates hERVs in a HIF1− and HIF2− dependent manner and that hERVs of the HERVERI superfamily are enriched in PBRM1-regulated hERVs.Our results uncover a role of PBRM1 in the negative regulation of hERVs in ccRCC.Moreover, the HIF-dependent nature of hERV expression explains the previously reported ccRCC-specific clinical associations of PBRM1 mutant ccRCC with both a good prognosis as well as improved clinical outcomes to ICB. SynopsisOur results uncover a novel role of PBRM1 in the negative regulation of hERVs in ccRCC. Dependence on HIF expression may explain ccRCC-specific clinical associations of PBRM1-mutant ccRCC with both positive prognosis and improved clinical response to ICB.

Upregulation of the PI3K pathway has been implicated in the initiation and progression of several types of cancer, including renal cell carcinoma (RCC). Although several targeted therapies have been developed for RCC, durable and complete responses are exceptional. Thus, advanced RCC remains a lethal disease, underscoring the need of robust biomarker-based strategies to treat RCC. We report a synthetic lethal interaction between inhibition of phosphatidylinositol 3-kinase beta (PI3Kβ) and loss of SETD2 methyltransferase. Clear cell RCC (ccRCC)-derived SETD2 knockout 786-0 and SETD2 mutant A498 cells treated with TGX221 (PI3Kβ-specific) and AZD8186 (PI3Kβ- and δ-specific) inhibitors displayed decreased cell viability, cell growth, and migration compared to SETD2 proficient 786-0 cells. Inhibition of the p110 δ and α isoforms alone had modest (δ) and no (α) effect on ccRCC cell viability, growth, and migration. In vivo, treatment of SETD2 mutant A498 cells, but not SETD2 proficient 786-0 cells, with AZD8186 significantly decreased tumor growth. Interestingly, inhibition of the downstream effector AKT (MK2206) recapitulated the effects observed in AZD8186-treated SETD2 deficient cells. Our data show that specific inhibition of PI3Kβ causes synthetic lethality with SETD2 loss and suggest targeting of the AKT downstream effector pathway offers a rationale for further translational and clinical investigation of PI3Kβ-specific inhibitors in ccRCC.

No abstract

456 Background: Bladder cancer patients’ care is often managed by caregivers, yet caregiving can create a physiologic and emotional burden that compromises the caregivers’ own quality of life (QOL). Our objective was to determine the impact of disease stage on caregiver QOL among a large national cohort of bladder cancer patients. Methods: We performed a cross-sectional survey of bladder cancer caregivers using the Bladder Cancer Advocacy Network Patient Survey Network and Inspire platforms to determine caregiver QOL using the CareGiver QOL questionnaire (CarGOQoL). Caregivers were also queried regarding demographic, socioeconomic and clinical characteristics of their loved one. We present descriptive statistics and a multiple linear regression model to identify factors independently associated with QOL domain score. Results: 132 respondents self-identified as caregivers of patients with bladder cancer. Among respondents, 85% were a spouse, 86% were female, and 97% were white. The mean age was 63 years (range 34 to 72 years) and 73% of respondents completed college. The highest cancer stage for patients was non-invasive in 42%, muscle-invasive in 33%, and metastatic in 24%. On bivariable analysis, stage was associated with leisure and social support but was not associated with global QOL, psychologic or physical well-being, burden, relationship with healthcare, administration and finances, coping, self-esteem or private life. However, on multivariable analysis controlling for age, race, years since diagnosis, and comorbidity, stage was significantly associated with Caregiver QOL (p=0.04). Conclusions: Disease stage significantly impacts QOL among bladder cancer caregivers. As the caregiver is increasingly considered as a stakeholder in survivorship efforts, future interventions should consider targeting social support among caregivers of patients with advanced bladder cancer.