1398: Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC): An Aggressive form of Inherited Renal Cancer

Grubb, Robert L.; Franks, Michael; Toro, Jorge R.; Hurley, Kathleen; Choyke, Peter L.; Coleman, Jonathan; Torres‐Cabala, Carlos A.; Merino, María J.; Zbar, Berton; Walther, McCllelan M.; Linehan, W. Marston

doi:10.1016/s0022-5347(18)35532-0

Cited by 1 publication

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“…In this disease, mutation of the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase ( FH ) causes the hyperaccumulation of fumarate, an “oncometabolite” that can directly alter gene‐expression programs . HLRCC tumors are highly invasive and prone to metastasis, and the current standard of care is aggressive surgical resection . In addition to FH ′s driver role in HLRCC, dysregulated levels of fumarate have been implicated in several pathophysiological contexts, including diabetes, non‐hereditary kidney cancer, neuroblastoma, colorectal cancer, and tumors of the adrenal gland .…”

Section: Methodsmentioning

confidence: 99%

“…Second, increased reaction with fumarate might limit the consumption of nitrileimines by abundant water molecules, thereby reducing background fluorescence and increasing sensitivity. Third, the stable nature of tetrazoles could facilitate their delivery to the mitochondria, where FH activity resides and undergoes disruption in HLRCC . This last advantage holds promise both from the perspective of increasing the selectivity of this method, by allowing fumarate to be differentiated from non‐mitochondrial dipolarophiles, as well as for its potential to enable profiling of FH mutational status in living cells.…”

Section: Methodsmentioning

confidence: 99%

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Photoinducible Oncometabolite Detection

et al. 2018

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Dysregulated metabolism can fuel cancer by altering the production of bioenergetic building blocks and directly stimulating oncogenic gene‐expression programs. However, relatively few optical methods for the direct study of metabolites in cells exist. To address this need and facilitate new approaches to cancer treatment and diagnosis, herein we report an optimized chemical approach to detect the oncometabolite fumarate. Our strategy employs diaryl tetrazoles as cell‐permeable photoinducible precursors to nitrileimines. Uncaging these species in cells and cell extracts enables them to undergo 1,3‐dipolar cycloadditions with endogenous dipolarophile metabolites such as fumarate to form pyrazoline cycloadducts that can be readily detected by their intrinsic fluorescence. The ability to photolytically uncage diaryl tetrazoles provides greatly improved sensitivity relative to previous methods, and enables the facile detection of dysregulated fumarate metabolism through biochemical activity assays, intracellular imaging, and flow cytometry. Our studies showcase an intersection of bioorthogonal chemistry and metabolite reactivity that can be applied for biological profiling, imaging, and diagnostics.

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