A unique model for SDH-deficient GIST: an endocrine-related cancer

Abstract

We describe a unique patient-derived xenograft (PDX) and cell culture model of succinate dehydrogenase-deficient gastrointestinal stromal tumor (SDH-deficient GIST), a rare mesenchymal tumor that can occur in association with paragangliomas in hereditary and non-hereditary syndromes. This model is potentially important for what it might reveal specifically pertinent to this rare tumor type and, more broadly, to other types of SDH-deficient tumors. The primary tumor and xenografts show a very high proliferative fraction, and distinctive morphology characterized by tiny cells with marked autophagic activity. It is likely that these characteristics resulted from the combination of the germline mutation and a somatic G12D mutation. The most broadly relevant findings to date concern oxygen and oxidative stress. In paragangliomas harboring x mutations, both hypoxic signaling and oxidative stress are putative drivers of tumor growth. However, there are no models for SDH-deficient paragangliomas. This related model is the first from a-mutated human tumor that can be experimentally manipulated to study mechanisms of oxygen effects and novel treatment strategies. Our data suggest that tumor growth and survival require a balance between protective effects of hypoxic signaling vs deleterious effects of oxidative stress. While reduced oxygen concentration promotes tumor cell survival, a further survival benefit is achieved with antioxidants. This suggests potential use of drugs that increase oxidative stress as novel therapies. In addition, autophagy, which has not been reported as a major finding in any type of SDH-deficient tumor, is a potential target of agents that might trigger autophagic cell death.

An enolase inhibitor for the targeted treatment of ENO1-deleted cancers

“…PK experiments indicate that drug exposures required for efficacy against ENO1 -heterozygous deleted cancer cells can be sustained in NHP even though not in mice ( Figure 7a ). Our data also show selective sensitivity in mitochondrial oxidative phosphorylation deficient cancers driven by TCA cycle loss-of-function mutations as well as those “addicted” to glycolysis due to mutations in VHL 11 , 12 , 59 ( Extended Data Figure 7 ). Beyond these defined genomic populations with Enolase deficiencies, unique sensitivity to Enolase inhibition has also been documented in other genetic settings 60 , 61 testifying to greater utility of POMHEX and HEX.…”

Kinetic modeling of H2O2 dynamics in the mitochondria of HeLa cells

“…a quantity is often measured experimentally by Western blotting, and at baseline can characterize the variability between different cell types [10,69]. PLOS COMPUTATIONAL BIOLOGY fractional oxidation in Table 4 represents the dimer fraction for the Prxs and the fraction of Gpxox + GpxSSG for the Gpxs.…”

“…We next investigated the effect of the total available pool of Prx3 on the dimer fraction of Prx3, calculated as a quantity is often measured experimentally by Western blotting, and at baseline can characterize the variability between different cell types [ 10 , 69 ]. Fig 2C plots this quantity as well as the fractional oxidation of other peroxidases found within the mitochondria.…”

Establishment of Patient-Derived Succinate Dehydrogenase–Deficient Gastrointestinal Stromal Tumor Models for Predicting Therapeutic Response

“…These models have accelerated our understanding of major pathways being affected; however, they often do not recapitulate the complete panel of patient-specific mutations and epigenetic alterations, pathway interactions and gene expression profiles. Patientderived xenografts (PDX) have been utilized for SDH-deficient GISTs, but the length of time required for establishing this model limits its use for preclinical and high-throughput drug testing (19,20). Attempts to generate long-term cultures from these PDXs have had limited success (19), underscoring the requirement of better patient-derived models for functional and mechanistic studies.…”