Identifying new targeted therapies that kill tumor cells while sparing normal tissue is a major challenge of cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to identify compounds that exploit the loss of the von Hippel–Lindau (VHL) tumor suppressor gene, which occurs in about 80% of renal cell carcinomas (RCCs). RCCs, like many other cancers, are dependent on aerobic glycolysis for ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding glucose uptake in vivo without toxicity to normal tissue. Activity of STF-31 in these experimental renal tumors can be monitored by [18F]fluorodeoxyglucose uptake by micro–positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human tumors. Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy.

Purpose To determine whether HPV DNA can be detected in the plasma of patients with HPV(+) oropharyngeal carcinoma (OP) and to monitor its temporal change during radiotherapy (RT). Methods and Materials We used PCR to detect HPV DNA in the culture media of HPV(+) SCC90, VU147T and the plasma of SCC90 and HeLa tumor bearing mice, non-tumor controls and those bearing HPV(-) tumors. We used real time quantitative PCR (qPCR) to quantify plasma HPV DNA in 40 HPV(+) OP, 24 HPV(-) head and neck cancer (HNC) patients and 10 non-cancer volunteers. Tumor HPV status was confirmed by p16INK4a staining and HPV16/18 PCR or HPV ISH. 14 patients had serial plasma samples for HPV DNA quantification during RT. Results HPV DNA was detectable in the plasma samples of SCC90- and HeLa-bearing mice but not in controls. It was detected in 65% of pretreatment plasma samples from HPV(+) OP patients using E6/7 qPCR. None of the HPV(-) HNC or non-cancer controls had detectable HPV DNA. Pretreatment plasma HPV DNA copy number correlated significantly with nodal metabolic tumor volume (assessed on FDG-PET). Serial measurements in 14 patients showed rapid decline in HPV DNA that became undetectable at RT completion. In 3 patients, HPV DNA rose to discernable level at the time of metastasis. Conclusions Xenograft studies indicated that plasma HPV DNA is released from HPV(+) tumors. Circulating HPV DNA is detectable in most HPV(+) OP patients. Plasma HPV DNA may be a valuable tool for identifying relapse.

Galectin-1 (Gal-1), a carbohydrate-binding protein whose secretion is enhanced by hypoxia, promotes tumor aggressiveness by promoting angiogenesis and T cell apoptosis. However, the importance of tumor versus host Gal-1 in tumor progression is undefined. Here we offer evidence that implicates tumor Gal-1 and its modulation of T cell immunity in progression. Comparing Gal-1 deficient mice as hosts for Lewis lung carcinoma cells where Gal-1 levels were preserved or knocked down, we found that tumor Gal-1 was more critical than host Gal-1 in promoting tumor growth and spontaneous metastasis. Enhanced growth and metastasis associated with Gal-1 related to its immunomodulatory function, insofar as the benefits of Gal-1 expression to Lewis lung carcinoma growth were abolished in immune-deficient mice. In contrast, angiogenesis, as assessed by microvessel density count, was similar between tumors with divergent Gal-1 levels when examined at a comparable size. Our findings establish that tumor rather than host Gal-1 is responsible for mediating tumor progression through intratumoral immune modulation, with broad implications in developing novel targeting strategies for Gal-1 in cancer.

Cancer cells exist in harsh microenvironments that are governed by various factors, including hypoxia and nutrient deprivation. These microenvironmental stressors activate signaling pathways that affect cancer cell survival. While others have previously measured microenvironmental stressors in tumors, it remains difficult to detect the real-time activation of these downstream signaling pathways in primary tumors. In this study, we developed transgenic mice expressing an X-box binding protein 1 (XBP1)-luciferase construct that served as a reporter for endoplasmic reticulum (ER) stress and as a downstream response for the tumor microenvironment. Primary mammary tumors arising in these mice exhibited luciferase activity in vivo. Multiple tumors arising in the same mouse had distinct XBP1-luciferase signatures, reflecting either higher or lower levels of ER stress. Furthermore, variations in ER stress reflected metabolic and hypoxic differences between tumors. Finally, XBP1-luciferase activity correlated with tumor growth rates. Visualizing distinct signaling pathways in primary tumors reveals unique tumor microenvironments with distinct metabolic signatures that can predict for tumor growth. Cancer Res; 70(1); 78-88.

Lens-specific expression of TGF-beta1 induced ASC formation in the absence of the Smad3 signaling mediator, suggests that alternative TGF-beta-signaling pathways participate in this ocular fibrotic model.