SUMMARY The LKB1 (also called STK11) tumor suppressor is mutationally inactivated in ~20% of non-small cell lung cancers (NSCLC). LKB1 is the major upstream kinase activating the energy-sensing kinase AMPK, making LKB1-deficient cells unable to appropriately sense metabolic stress. We tested the therapeutic potential of metabolic drugs in NSCLC and identified phenformin, a mitochondrial inhibitor and analog of the diabetes therapeutic metformin, as selectively inducing apoptosis in LKB1-deficient NSCLC cells. Therapeutic trials in Kras-dependent mouse models of NSCLC revealed that tumors with Kras and Lkb1 mutations, but not those with Kras and p53 mutations showed selective response to phenformin as a single agent, resulting in prolonged survival. This study suggests phenformin as a cancer metabolism-based therapeutic to selectively target LKB1-deficient tumors.

In retrospective studies, 68 Ga-PSMA-11 positron emission tomographic (PET) imaging improves detection of biochemically recurrent prostate cancer compared with conventional imaging. OBJECTIVE To assess 68 Ga-PSMA-11 PET accuracy in a prospective multicenter trial.

SUMMARY Background A 57 years old male had been diagnosed with grade III/IV glioblastoma multiforme. The patient had then enrolled in an adoptive cellular immunotherapy trial. The trial involved infusion of ex vivo expanded autologous cytolytic CD8+ T cells (CTLs), genetically engineered to express the interleukin-13 zetakine gene (therapeutic gene, encoding a receptor protein that targets the T cells to the tumor cells), and the Herpes Simplex virus 1 thymidine kinase (HSV1-tk) suicide gene/positron emission tomography (PET) imaging reporter gene. Investigations Whole-body and brain PET scan with 9-[4-[18F]Fluoro-3-(hydroxymethyl)butyl]guanine ([18F]FHBG) to detect HSV1-tk expressing CTLs, and safety monitoring following injection of [18F]FHBG. Diagnosis Magnetic resonance imaging detection of grade III/IV glioblastoma multiforme plus recurrence of two tumors after resection of the initial tumor. Management Surgical resection of original glioblastoma tumor, enrollment in CTL therapy trial, re-resection of glioma recurrence, infusion of approximately 1 X 109 CTL into the site of tumor re-resection, and [18F]FHBG PET scan to detect infused CTLs.

A B S T R A C T PurposeEvaluation of treatment effects in malignant brain tumors is challenging because of the lack of reliable response predictors of tumor response. This study examines the predictive value of positron emission tomography (PET) using [18 F] fluorothymidine (FLT), an imaging biomarker of cell proliferation, in patients with recurrent malignant gliomas treated with bevacizumab in combination with irinotecan. Patients and MethodsPatients with recurrent malignant gliomas treated with biweekly cycles of bevacizumab and irinotecan were prospectively studied with FLT-PET at baseline, after 1 to 2 weeks, and after 6 weeks from start of treatment. A more than 25% reduction in tumor FLT uptake as measured by standardized uptake value was defined as a metabolic response. FLT responses were compared with response as shown by magnetic resonance imaging (MRI) and patient survival. ResultsTwenty-one patients were included, and 19 were assessable for metabolic response evaluation with FLT-PET. There were nine responders (47%) and 10 nonresponders (53%). Metabolic responders survived three times as long as nonresponders (10.8 v 3.4 months; P ϭ .003), and tended to have a prolonged progression-free survival (P ϭ .061). Both early and later FLT-PET responses were more significant predictors of overall survival (1 to 2 weeks, P ϭ .006; 6 weeks, P ϭ .002), compared with the MRI responses (P ϭ .060 for both 6-week and best responses). ConclusionFLT-PET as an imaging biomarker seems to be predictive of overall survival in bevacizumab and irinotecan treatment of recurrent gliomas. Whether FLT-PET performed as early as 1 to 2 week after starting treatment is as predictive as the study indicates at 6 weeks warrants further investigation.

No abstract

Aging does not alter significantly dipyridamole-induced hyperemic flows; although coronary vascular resistance after dipyridamole was somewhat increased in older subjects. The gradual decline of the myocardial blood flow reserve correlates with an age-related increase of baseline myocardial work and blood flow. These findings suggest that the reduced flow reserve with age is primarily due to increased cardiac work and blood flow at rest rather than to an abnormal vasodilator capacity.

High-grade gliomas are aggressive cancers that often become rapidly fatal. Immunotherapy using CD8+ cytotoxic T lymphocytes (CTLs), engineered to express both herpes simplex virus type-1 thymidine kinase (HSV1-TK) and interleukin (IL)-13 zetakine chimeric antigen receptor (CAR), is a treatment strategy with considerable potential. To optimize this and related immunotherapies, it may be helpful to monitor CTL viability and trafficking to glioma cells. We show that noninvasive positron emission tomography (PET) imaging with 9-[4-[18F]fluoro-3-(hydroxymethyl)butyl]guanine ([18F]FHBG) can track HSV1-tk reporter gene expression present in CAR-engineered CTLs. [18F]FHBG imaging was safe and enabled the longitudinal imaging of T cells stably transfected with a PET reporter gene in patients. Further optimization of this imaging approach for monitoring in vivo cell trafficking should greatly benefit various cell-based therapies for cancer.

The EGFR/PI3K/Akt/mTOR signaling pathway is activated in many cancers including glioblastoma, yet mTOR inhibitors have largely failed to show efficacy in the clinic. Rapamycin promotes feedback activation of Akt in some patients, potentially underlying clinical resistance and raising the need for alternative approaches to block mTOR signaling. AMPK is a metabolic checkpoint that integrates growth factor signaling with cellular metabolism, in part by negatively regulating mTOR. We used pharmacological and genetic approaches to determine whether AMPK activation could block glioblastoma growth and cellular metabolism, and we examined the contribution of EGFR signaling in determining response in vitro and in vivo. The AMPK-agonist AICAR, and activated AMPK adenovirus, inhibited mTOR signaling and blocked the growth of glioblastoma cells expressing the activated EGFR mutant, EGFRvIII. Across a spectrum of EGFR-activated cancer cell lines, AICAR was more effective than rapamycin at blocking tumor cell proliferation, despite less efficient inhibition of mTORC1 signaling. Unexpectedly, addition of the metabolic products of cholesterol and fatty acid synthesis rescued the growth inhibitory effect of AICAR, whereas inhibition of these lipogenic enzymes mimicked AMPK activation, thus demonstrating that AMPK blocked tumor cell proliferation primarily through inhibition of cholesterol and fatty acid synthesis. Most importantly, AICAR treatment in mice significantly inhibited the growth and glycolysis (as measured by 18 fluoro-2-deoxyglucose microPET) of glioblastoma xenografts engineered to express EGFRvIII, but not their parental counterparts. These results suggest a mechanism by which AICAR inhibits the proliferation of EGFRvIII expressing glioblastomas and point toward a potential therapeutic strategy for targeting EGFR-activated cancers.