Stereotactic body radiotherapy for the treatment of oligometastatic renal cell carcinoma.

Objectives: Renal cell carcinoma (RCC) is considered radioresistant, but stereotactic radiosurgery can control intracranial metastases. Advances in radiotherapy, such as stereotactic body radiotherapy (SBRT), allow high-dose radiation delivery to extracranial sites. Herein, we report our experience treating oligometastatic RCC with SBRT.

Cooperative interaction between the MUC1-C oncoprotein and the Rab31 GTPase in estrogen receptor-positive breast cancer cells.

Rab31 is a member of the Ras superfamily of small GTPases that has been linked to poor outcomes in patients with breast cancer. The MUC1-C oncoprotein is aberrantly overexpressed in most human breast cancers and also confers a poor prognosis. The present results demonstrate that MUC1-C induces Rab31 expression in estrogen receptor positive (ER+) breast cancer cells.

Molecular pathways: interferon/stat1 pathway: role in the tumor resistance to genotoxic stress and aggressive growth.

STAT1 is activated by IFNs and other cell signals. Following activation, STAT1 is translocated to the nuclei and activates transcription of IFN-stimulated genes. Although the activation of STAT1 by IFNs is classically associated with antiviral defense and tumor-suppressive functions, emerging data indicate that expression of the STAT1 pathway confers cellular resistance to DNA-damaging agents and mediates aggressive tumor growth.

Inhibition of serine palmitoyltransferase delays the onset of radiation-induced pulmonary fibrosis through the negative regulation of sphingosine kinase-1 expression.

The enforcement of sphingosine-1-phosphate (S1P) signaling network protects from radiation-induced pneumonitis. We now demonstrate that, in contrast to early postirradiation period, late postirradiation sphingosine kinase-1 (SphK1) and sphingoid base-1-phosphates are associated with radiation-induced pulmonary fibrosis (RIF). Using the mouse model, we demonstrate that RIF is characterized by a marked upregulation of S1P and dihydrosphingosine-1-phosphate (DHS1P) levels in the lung tissue and in circulation accompanied by increased lung SphK1 expression and activity.

Spleen cells from young but not old immunized mice eradicate large established cancers.

Purpose: Solid tumors that have grown two weeks or longer in mice and have diameters larger than 1 cm are histologically indistinguishable from autochthonous human cancers. When experimental tumors reach this clinically relevant size, they are usually refractory to most immunotherapies but may be destroyed by adoptive T-cell transfer. However, TCR-transgenic T cells and/or tumor cells overexpressing antigens are frequently used in these experiments.

Radiation-inducible immunotherapy for cancer: senescent tumor cells as a cancer vaccine.

Radiotherapy offers an effective treatment for advanced cancer but local and distant failures remain a significant challenge. Here, we treated melanoma and pancreatic carcinoma in syngeneic mice with ionizing radiation (IR) combined with the poly(ADP-ribose) polymerase inhibitor (PARPi) veliparib to inhibit DNA repair and promote accelerated senescence. Based on prior work implicating cytotoxic T lymphocytes (CTLs) as key mediators of radiation effects, we discovered that senescent tumor cells induced by radiation and veliparib express immunostimulatory cytokines to activate CTLs that mediate an effective antitumor response.

Everolimus exhibits efficacy as a radiosensitizer in a model of non-small cell lung cancer.

Signaling pathways that activate mTOR (mammalian target of rapamycin) are altered in many human cancers and these alterations are associated with prognosis and treatment response. mTOR inhibition can restore sensitivity to DNA damaging agents such as cisplatin. The rapamycin derivative everolimus exhibits antitumor activity and is approved for patients with renal cell cancer.

Expression signature of IFN/STAT1 signaling genes predicts poor survival outcome in glioblastoma multiforme in a subtype-specific manner.

Previous reports have implicated an induction of genes in IFN/STAT1 (Interferon/STAT1) signaling in radiation resistant and prosurvival tumor phenotypes in a number of cancer cell lines, and we have hypothesized that upregulation of these genes may be predictive of poor survival outcome and/or treatment response in Glioblastoma Multiforme (GBM) patients. We have developed a list of 8 genes related to IFN/STAT1 that we hypothesize to be predictive of poor survival in GBM patients. Our working hypothesis that over-expression of this gene signature predicts poor survival outcome in GBM patients was confirmed, and in addition, it was demonstrated that the survival model was highly subtype-dependent, with strong dependence in the Proneural subtype and no detected dependence in the Classical and Mesenchymal subtypes.

Hypofractionated image-guided radiation therapy for patients with limited volume metastatic non-small cell lung cancer.

Introduction: Outcomes data treating patients with oligometastatic (≤ 5 metastases) non-small cell lung carcinoma (NSCLC) with hypofractionated image-guided radiotherapy (HIGRT) are limited.

Methods: Consecutive oligometastatic NSCLC patients were reviewed from a prospective database. Patients were included if all active diseases were treated with HIGRT.

MicroRNA expression characterizes oligometastasis(es).

Background: Cancer staging and treatment presumes a division into localized or metastatic disease. We proposed an intermediate state defined by ≤ 5 cumulative metastasis(es), termed oligometastases. In contrast to widespread polymetastases, oligometastatic patients may benefit from metastasis-directed local treatments.

p50 (NF-κB1) is an effector protein in the cytotoxic response to DNA methylation damage.

The functional significance of the signaling pathway induced by O(6)-methylguanine (O(6)-MeG) lesions is poorly understood. Here, we identify the p50 subunit of NF-κB as a central target in the response to O(6)-MeG and demonstrate that p50 is required for S(N)1-methylator-induced cytotoxicity. In response to S(N)1-methylation, p50 facilitates the inhibition of NF-κB-regulated antiapoptotic gene expression.

Mg ATP and antioxidants augment the radioprotective effect of surfactant copolymers.

Mediated by reactive oxygen species, the damaging effects of high-intensity ionizing irradiation on tissues are dose, frequency, oxygen concentration, and tissue property dependent. Intense ionizing irradiation exposure may cause rapid cellular necrosis by peroxidation of membrane lipids leading to membrane disruption. This leads to a loss of the transmembrane ionic gradients and a subsequent depletion of the cellular ATP store, followed by cellular generation of reactive oxygen species.

Stereotactic body radiotherapy for multisite extracranial oligometastases: final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease.

Background: A subset of patients with metastatic cancer in limited organs may benefit from metastasis-directed therapy. The authors investigated whether patients with limited metastases could be safely treated with metastasis-directed radiotherapy.

Methods: Patients with 1 to 5 metastatic cancer sites with a life expectancy of >3 months received escalating stereotactic body radiotherapy (SBRT) doses to all known cancer sites.

Improved survival time trends for glioblastoma using the SEER 17 population-based registries.

The EORTC/NCIC 22981/26981 study demonstrated an improvement in median overall survival (OS) from 12.1 to 14.6 months in patients with glioblastoma (GBM) who received temozolomide with post-operative radiotherapy (RT).

Progression of cancer from indolent to aggressive despite antigen retention and increased expression of interferon-gamma inducible genes.

Many cancers escape host immunity without losing tumor-specific rejection antigens or MHC class I expression. This study tracks the evolution of one such cancer that developed in a mouse following exposure to ultraviolet light. The primary autochthonous tumor was not highly malignant and was rejected when transplanted into naïve immunocompetent mice.

Role of sphingolipids in murine radiation-induced lung injury: protection by sphingosine 1-phosphate analogs.

Clinically significant radiation-induced lung injury (RILI) is a common toxicity in patients administered thoracic radiotherapy. Although the molecular etiology is poorly understood, we previously characterized a murine model of RILI in which alterations in lung barrier integrity surfaced as a potentially important pathobiological event and genome-wide lung gene mRNA levels identified dysregulation of sphingolipid metabolic pathway genes. We hypothesized that sphingolipid signaling components serve as modulators and novel therapeutic targets of RILI.

Response of human prostate cancer cells and tumors to combining PARP inhibition with ionizing radiation.

Radiation therapy remains a promising modality for curative treatment of localized prostate cancer, but dose-limiting toxicities significantly limit its effectiveness. Agents that enhance efficacy at lower radiation doses might have considerable value in increasing tumor control without compromising organ function. Here, we tested the hypothesis that the PARP inhibitor ABT-888 (veliparib) can enhance the response of prostate cancer cells and tumors to ionizing radiation (IR).

Oligometastases revisited.

We previously proposed a clinical state of metastasis termed 'oligometastases' that refers to restricted tumor metastatic capacity. The implication of this concept is that local cancer treatments are curative in a proportion of patients with metastases. Here we review clinical and laboratory data that support the hypothesis that oligometastasis is a distinct clinical entity.

Ionizing radiation-induced foci persistence screen to discover enhancers of accelerated senescence.

Much like replicative senescence, the irreversible cell-cycle arrest induced by eroded telomeres, accelerated senescence occurs when replicative cells suffer irreparable DNA double-strand breaks (DSBs). Along with apoptosis and necrosis, senescence is a desirable outcome in cancer treatment with ionizing radiation (IR) or chemotherapy. In both normal and cancer cells, DSBs promote the assembly of IR-induced foci (IRIF), domains of modified chromatin that serve a key role in DNA damage signaling.

The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity.

The most widely held explanation for the efficacy of local radiotherapy (RT) is based on direct cytotoxicity to cancer cells through the induction of lethal DNA damage. Recent studies have shown that local ablative radiation of established tumors can lead to increased T-cell priming and T-cell-dependent tumor regression, but the underlying mechanism remains unclear. Here, we describe an essential role for type I IFN in local RT-mediated tumor control.

Where it's at really matters: in situ in vivo vascular endothelial growth factor spatially correlates with electron paramagnetic resonance pO2 images in tumors of living mice.

Purpose: Tumor microenvironments show remarkable tumor pO(2) heterogeneity, as seen in prior EPR pO(2) images (EPROI). pO(2) correlation with hypoxia response proteins is frustrated by large rapid pO(2) changes with position.

Procedures: To overcome this limitation, biopsies stereotactically located in the EPROI were used to explore the relationship between vascular endothelial growth factor A (VEGF) concentrations in living mouse tumors and the local EPROI pO(2).

Efficacy of the multi-kinase inhibitor enzastaurin is dependent on cellular signaling context.

The number of targeted small molecules being developed in oncology is increasing rapidly. Many of these are designed to inhibit multiple kinases, and thus the mechanisms of responsiveness and predictive biomarkers can be difficult to discern. In fact, with few exceptions, multi-kinase inhibitors are developed with limited mechanism-based patient selection.

MUC1-C Oncoprotein Interacts Directly with ATM and Promotes the DNA Damage Response to Ionizing Radiation.

The ataxia-telangiectasia mutated (ATM) kinase is activated in the cellular response to ionizing radiation (IR) and is of importance to the repair of DNA double strand breaks (DSBs). The MUC1 oncoprotein is aberrantly overexpressed in human breast carcinomas. The present work demonstrates that the MUC1 C-terminal subunit (MUC1-C) constitutively interacts with ATM in human breast cancer cells.

Predictors of competing mortality in early breast cancer.

Background: Death in the absence of disease recurrence (competing mortality) is an important determinant of disease-free survival (DFS) in early breast cancer. The authors sought to identify predictors of this event using competing risks modeling.

Methods: A cohort study was made of 1231 consecutive women with stage I to II invasive breast cancer diagnosed between 1986 and 2004, treated with breast conservation therapy.