Cross-talk among oncogenic signaling and metabolic pathways may create
opportunities for novel therapeutic strategies in cancer. Here we show that
acute inhibition of EGFR-driven glucose metabolism induces minimal cell death,
yet lowers the apoptotic threshold in a subset of patient-derived glioblastoma
(GBM) cells. Mechanistic studies revealed that, following attenuated glucose
consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis.
Consequently, pharmacological stabilization of p53 with the brain-penetrant
small molecule, Idasanutlin, in combination with targeting EGFR-driven glucose
metabolism promoted synthetic lethality in orthotopic xenograft models. Notably,
neither inhibition of EGFR signaling, nor genetic analysis of
EGFR, was sufficient to predict sensitivity to this new
therapeutic combination. Conversely, rapid changes in
18F-fluorodeoxyglucose (18F-FDG) uptake using non-invasive
positron emission tomography was an effective predictive biomarker of response
in vivo. Together, these studies identify a critical link between oncogene
signaling, glucose metabolism, and cytoplasmic p53, which could be exploited for
combination therapy in GBM and potentially, other malignancies.
Lu-PSMA for mCRPC, the median OS was 14 mo. Despite the heterogeneous study population and the premature study termination, the efficacy profile of 177 Lu-PSMA appeared to be favorable and comparable with both activity regimens (6.0 vs. 7.4 GBq). Results justify confirmation with real-world data matched-pair analysis and further clinical trials to refine and optimize the 177 Lu-PSMA therapy administration scheme to improve tumor radiation dose delivery and efficacy.
Comprehensive molecular analysis of individual tumors provides great potential for personalized cancer therapy. However, the presence of a particular genetic alteration is often insufficient to predict therapeutic efficacy. Drugs with distinct mechanisms of action can affect the biology of tumors in specific and unique ways. Therefore, assays that can measure drug-induced perturbations of defined functional tumor properties can be highly complementary to genomic analysis. PET provides the capacity to noninvasively measure the dynamics of various tumor biologic processes in vivo. Here, we review the underlying biochemical and biologic basis for a variety of PET tracers and how they may be used to better optimize cancer therapy.
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